Diagnostic principles.5th edition(2021) برای بزرگنمایی عکسها کلیک را روی ان نگه دارید..... ■■■Cervical&Vaginal【1】 • Fig. 1.1 Liquid-Based Slide Preparation Methods. (A) ThinPrep method. 1. The sample vial sits on a stage, and a hollow plastic cylinder with a 20 mm diameter polycarbonate filter bonded to its lower surface is inserted into the vial. A rotor spins the cylinder for a few seconds, dispersing the cells. 2. A vacuum is applied to the cylinder, trapping cells on the filter. The instrument monitors cell density on the filter. 3. With continued application of vacuum, the cylinder (with cells attached to the filter) is inverted 180 degrees, and the filter is pressed against a glass slide. The slide is immediately dropped into an alcohol bath. (B) SurePath method. 1. The sample is vortexed. 2. Cell clusters are disaggregated by syringing the sample through a small orifice. 3. The sample is poured into a centrifuge tube filled with a density gradient reagent. 4. Sedimentation is performed in a centrifuge. A pellet is obtained, resuspended, and the sedimentation is repeated. 5. The tubes are transferred to the PrepStain instrument, where a robotic arm transfers the fluid into a cylinder. Cells settle by gravity onto a cationic polyelectrolyte-coated slide. The same robotic arm also dispenses sequential stains to individual cylinders Fig. 1.2 Automated Pap Screening Devices. (A) ThinPrep Imaging System: the Imager. The Imager con- sists of (left to right): the Imaging Station, an Image Processor and Server, and a user interface consisting of a monitor, keyboard, and mouse. (B) Thin Prep Imaging System-the Review Scope. Imaging data are electronically linked to a customized microscope called the Review Scope. After the ThinPrep slides have been imaged on the Imager, they are brought to the microscope for location-guided review. In addition to a microscope, there is a console (with display and keypad) and a navigator pod. (C) BD FocalPoint System. (D) BD FocalPoint Guided Screening Review Scope. Imaging data are electronically linked to a custom- ized microscope (the Review Scope). After the SurePath slides have been imaged, they are brought to the microscope for location-guided review Fig. 1.3 Method for Estimating the Adequacy of the Squamous Component of Liquid-Based Preparations. (A) At magnification x40, 10 fields are counted starting at the edge (horizontal or vertical) and including the center of the preparation. (B) An attempt is made to include "holes" in proportion to their size, making sure that the fields counted cover both cellular and sparsely cellular areas in proportion to their size • Fig. 1.4 Superficial and Intermediate Squamous Cells. The mature squamous epithelium of the ectocervix in women of reproductive age is composed throughout most of Its thickness by superficial (arrowhead) and intermediate (arrow) cells • Fig. 1.5 Parabasal and Basal Cells (postpartum smear). Parabasal cells (large arrow) are oval and typically have dense cytoplasm. Basal cells (small arrow) are similar but have less cytoplasm. Many cells have abundant pale-yellow staining glycogen, a characteristic but non- specific feature of squamous cells of pregnancy and the postpartum period Fig. 1.6 Parabasal Cells (postmenopausal smear). (A) Atrophic epithelium is composed almost exclu- sively of parabasal cells, often arranged in broad, flowing sheets. (B) Transitional cell metaplasia. In this uncommon condition, the atrophic epithelium resembles transitional cell epithelium by virtue of its longi- tudinal nuclear grooves. Nuclear membrane irregularities raise the possibility of a high-grade squamous intraepithelial lesion, but the chromatin is pale and finely textured Fig. 1.7 Parabasal Cells (postmenopausal smear). (A) Degenerated parabasal cells in atrophic Pap test results have hypereosinophilic cytoplasm and a pyknotic nucleus. Note the granular background, which is commonly seen. (B) Dark blue blobs are seen in some atrophic smears. These featureless structures should not be interpreted as a significant abnormality Fig. 1.8 Squamous Metaplasia. Interlocking parabasal-type cells, as seen here, represent squamous metaplasia Fig. 1.9 Keratosis. (A) Hyperkeratosis. Anucleate squames are a protective response of the squamous epithelium. (B) Parakeratosis. Parakeratosis appears as plaques, as seen here, or isolated cells Fig. 1.10 Endocervical Cells. (A) Normal endocervical cells are often arranged in cohesive sheets. Note the even spacing of the nuclei, their pale, finely granular chromatin, and the honeycomb appearance imparted by the sharp cell membranes. (B) Sometimes they appear as strips or isolated cells. Abundant intracytoplasmic mucin results in a cup-shaped nucleus Fig. 1.11 Tubal Metaplasia. Ciliated endocervical cells are occasionally seen Fig. 1.12 Endometrial Cells. (A) Spontaneously exfoliated endometrial cells, as in menses, are small cells arranged in balls. Cytoplasm is scant. Nuclei around the perimeter appear to be wrapping around adjacent cells (arrow), a characteristic but nonspecific feature. (B) Some exfoliated endometrial cells have a double- contoured appearance and resemble a sombrero. The inner, dense core consists of endometrial stromal cells and the outer rim of endometrial glandular cells Fig. 1.13 Mimics of Exfoliated Endometrial Cells. (A) High-grade squamous intraepithelial lesion (HSIL). The cells of some HSILS are small, but still larger than endometrial cells and usually arranged in flatter aggregates rather than spheres. (B) Squamous cell carcinoma (SQC). Some poorly differentiated SQCS are indistinguishable from endometrial cells. The granular debris ("tumor diathesis") is more prominent than in most normal menstrual Pap test results. (C) Adenocarcinoma in situ (AIS). Some cases of AIS have an endometrioid appearance, but mitoses (arrows) are distinctly uncommon in exfoliated endometrial cells. (D) Small cell carcinoma. The cells resemble endometrial cells but are even darker. There is nuclear smear- ing, which is not characteristic of benign endometrial cells Fig. 1.14 Endometrial Cells, Directly Sampled. (A) An intact endometrial tubule is surrounded by well- preserved endometrial stromal cells. (B) Benign stromal cells are elongated and mitotically active (arrow) and might suggest a high-grade squamous intraepithelial lesion or malignancy. The pale, finely granular chromatin and the association with intact endometrial glands are clues to a benign interpretation. (C) The glandular cells are crowded and mitotically active (arrow), but evenly spaced Fig. 1.15 Syncytiotrophoblast. The nuclei of these multinucleated cells are dark and coarsely granular, unlike those of histiocytes Fig. 1.16 Follicular Cervicitis. (A) This smear from a 61-year-old woman contains numerous lympho- cytes in various stages of maturation, including an occasional plasma cell (arrow). Most normal lympho- cytes have a round nuclear contour, unlike the cells of a high-grade squamous intraepithelial lesion, to which they bear a superficial resemblance. (B) Lymphocytes are also a mimic of exfoliated endometrial cells. They are roughly the same size or a bit smaller, more heterogeneous in size, and less tightly clustered than most endometrial cells Fig. 1.17 Histiocytes. Histiocytes have abundant multivacuolated cytoplasm and an oval, occasionally folded nucleus Fig. 1.18 Lactobacilli. These bacteria are part of the normal flora of the vagina. Note the bare nuclei of the intermediate cells, which are subject to cytolysis by these organisms Fig. 1.19 Artifacts and Contaminants. (A) "Cornflaking." This refractile brown artifact results from bub- bles of air trapped on superficial squamous cells, resulting in obscuring of the nuclei. It can be reversed by returning the slide through xylene and alcohol to water, then restaining and recoverslipping. (B) Lubricant artifact. In this example, the lubricant is purple and has a granular, thread-like appearance. Depending on the formulation, it may be purple or red, and sometimes it has a denser, sheet-like appearance. (C) "String of pearls." (D) "Cockleburs." This is the name given to radiating arrays of club-shaped orange bodies composed of lipid, glycoprotein, and calcium, surrounded by histiocytes. They are most commonly asso- ciated with, but not limited to, pregnant patients. They have no clinical significance. (E) Trichome. These large star-shaped structures are derived from plants. They stain a pale yellow and have from three to eight legs. Trichomes are produced by many different plants and vary in color, size, and shape. (F) Carpet beetle parts. These arrow-shaped structures are contaminants from sources such as gauze pads and tampons Fig. 1.20 Shift in Flora Suggestive of Bacterial Vaginosis. Numerous small bacteria cover large portions of the slide. In some but not all cases, these bacteria adhere to squamous cells ("clue cells"), giving them the appearance of a shag rug, as seen here. Lactobacilli are absent Fig. 1.21 Trichomonas Vaginalis. (A) This organism is pear-shaped, with a pale oval nucleus and red cyto- plasmic granules, often inconspicuous. The flagellum, barely seen here, is usually inapparent (SurePath preparation, image courtesy Keith V. Nance, MD, UNC Rex Healthcare, Raleigh, NC). (B) "Trich picnic." Numerous faintly visible organisms are aggregated, in this example on a platform of squamous cells Fig. 1.22 Candida. Pseudohyphae and yeast forms, some of them budding from pseudohyphae, are seen. Note the skewered squa- mous cells Fig. 1.23 Actinomyces Spp. These bacterial colonies resemble dark cotton balls. The organisms are filamentous, shown here protruding from the mass of bacteria Fig. 1.24 Viral Cytopathic Changes. (A) Herpes simplex. The nuclei of infected cells are filled with viral particles, which impart a pale, homogeneous appearance. Nuclear chromatin is visible only at the periph- ery of some nuclei. Some have a well-defined eosinophilic intranuclear inclusion. (B) Cytomegalovirus. Each cell has a large basophilic intranuclear inclusion that is surrounded by a halo; the cytoplasm contains multiple small basophilic inclusions as well. This patient was immunocompetent and symptom free, and the inclusions were identified in only a few cells Fig. 1.25 Benign Squamous Cell Changes. (A) "PM cells." Nuclear enlargement, with little in the way of nuclear membrane irregularity or hyperchromasia, is a common finding in intermediate squamous cells from perimenopausal women. Such bland nuclear enlargement should not be mistaken for a significant atypia. (B) A similar bland nuclear enlargement can occur in squamous metaplastic cells Fig. 1.26 Nonspecific Halos. (A) Small halos around the nuclei of squamous cells are nonspecific and do not represent human papillomavirus-related changes. (B) Some normal squamous cells have abundant glycogen that mimics koilocytosis. Note the normal nucleus Fig. 1.27 Reactive Endocervical Cells. (A) A common finding, reactive endocervical cells are enlarged and have a prominent nucleolus. (B) Isolated cells can be as big as mature squamous cells and mimic a low-grade squamous intraepithelial lesion (LSIL), but a prominent nucleolus is uncharacteristic of an LSIL Fig. 1.28 Reactive Endocervical Cells (microglandular hyperpla- sia). These cells are enlarged and have a prominent large cytoplasmic vacuole Fig. 1.29 Typical Repair. Reparative epithelium is cohesive and arranged in a monolayered, streaming sheet Fig. 1.30 Treatment Effect. (A) Radiation effect. Radiation looks like a wild reparative reaction, with very large cells, multinucleation, cytoplasmic vacuolization, and a curious "two-tone" (pink and blue) cytoplas- mic staining pattern. (B) Chemotherapy effect. Similar changes are seen with some cytotoxic drugs. This patient received busulfan after a stem cell transplant for leukemia Fig. 1.31 Intrauterine Device (IUD) Effect. The two types of cells are seen here: a vacuolated cell and a small dark cell with scant cytoplasm. This combination is characteristic of IUD effect Fig. 1.32 Glandular Cells Status Post Hysterectomy. The squamous mucosa of the vagina has undergone focal mucinous metaplasia Fig. 1.33 Endometriosis of the Cervix. (A) The dark and pseudostratified nuclei of endometrial-type epi- thelium mimic endocervical neoplasia. (B) A cervical biopsy reveals the tell-tale mix of benign endometrial glands and stroma Fig. 1.34 Human Papillomavirus (HPV) Detection By in Situ Hybridization. The dark brown signal is centered around the nuclei of infected cells. (Courtesy Miu-Fun Chau, Dakocytomation, Carpinteria, CA.) Fig. 1.35 Low-Grade Squamous Intraepithelial Lesions (LSIL). (A) LSIL. Classic koilocytes, as seen here, have a large cytoplasmic cavity with a sharply defined inner edge and are frequently binucleated. Nuclear enlargement may not be as marked as in the nonkoilocytic LSILS. (B) Nonkoilocytic LSIL. Nuclei are significantly enlarged and show hyperchromasia and nuclear contour irregularity. No definite koilocytes are seen. This pattern was once called mild dysplasia or CIN1 Fig. 1.36 Low-Grade Squamous Intraepithelial Lesion, Keratinizing Type. A squamous pearl is being formed Fig. 1.37 High-Grade Squamous Intraepithelial Lesion (HSIL). (A) These cells have scant cytoplasm and a markedly hyperchromatic nucleus with highly irregular nuclear contours. (B) Cells with a moderate amount of cytoplasm, formerly called moderate dysplasia or CIN 2, are included in the HSIL category Fig. 1.38 High-Grade Squamous Intraepithelial Lesion (HSIL). The cells of an HSIL are often arranged in dark, three-dimensional groups in which individual cell borders are indistinct (syncytium-like) Fig. 1.39 High-Grade Squamous Intraepithelial Lesion (HSIL). Some HSILS are comprised of very small, dispersed, highly atypical cells. The nucleus of these small cells is not much larger than that of normal inter- mediate cells. They are nevertheless identified as abnormal because of their hyperchromasia, markedly irregular nuclear outline, or both. Some HSIL cells have cytoplasmic vacuoles. These do not indicate a glandular lesion • Fig. 1.40 High-Grade Squamous Intraepithelial Lesion (HSIL). The cells of some HSILS have an elongated configuration that makes them look columnar. In the absence of strips, rosettes, or feathering, this should not be taken for evidence of glandular differentiation (i.e., an adenocarcinoma in situ) Fig. 1.41 High-Grade Squamous Intraepithelial Lesion (HSIL), Keratinizing Type. Although the cells show differentiation by keratin- izing, they are classified as HSIL if the nuclei are sufficiently abnormal Fig. 1.42 Endocervical Polyp Atypia Mimicking HSIL. (A) The slide contains scattered isolated cells with dark nuclei. (B) The surface of the endocervical polyp reveals a single layer of reactive endocervical cells Fig. 1.43 Utility of Cell Blocks in Evaluating Hyperchromatic Cell Clusters. (A) The distinction between a squamous and glandular lesion can be problematic, especially when individual cells in dark cell clusters are poorly visualized. (B) A cell block prepared from the residual liquid-based sample in this case clarified the findings as HSIL Fig. 1.44 Squamous Intraepithelial Lesion, Cannot Determine Grade. When a lesion is extensively keratinized and there is no definite high-grade squamous intraepithelial lesion, it is difficult to grade. Colposcopically directed biopsies showed (A) CIN1 and (B) CIN2,3, • Fig. 1.45 Squamous Cell Carcinoma. Slides from deeply invasive tumors show abundant tumor dia- thesis, a granular precipitate of lysed blood and cell fragments. In some cases, the malignant cells can be hard to identify Fig. 1.46 Squamous Cell Carcinoma (SQC), Non-Keratinizing. The malignant cells have irregularly distributed chromatin and a prominent nucleolus, characteristic features of invasive SQCS Fig. 1.47 Squamous Cell Carcinoma (SQC), Nonkeratinizing. The sheet-like arrangement of poorly differentiated squamous carcinoma cells with nucleoli and mitoses mimics the appearance of reparative epithelium, but the crowding and haphazard arrangement of the cells are not typical of repair Fig. 1.48 Squamous Cell Carcinoma, Keratinizing. (A) In keratinizing carcinomas, the cells have mark- edly aberrant shapes, as seen here. "Fiber cells" are numerous. (B) Tumor diathesis and a tadpole cell are seen in this tumor Fig. 1.49 Atypical Squamous Cells of Undetermined Significance (ASC-US). (A) The nucleus of this mature squamous cell is significantly enlarged and there is moderate hyperchromasia. Cells like this, par- ticularly if few in number, are suggestive but not diagnostic of a squamous intraepithelial lesion. (B) Some cells have large cytoplasmic cavities but minimal nuclear atypia. It is preferable to diagnose such cases as ASC-US when abnormal cells are few and the changes minimal Fig. 1.50 Atypical Squamous Cells of Undetermined Significance, Associated with Atrophy. (A) Histologic section of benign atrophy-associated atypia. (B) A cytologic smear shows occasional markedly enlarged, hyperchromatic nuclei Fig. 1.51 Atypical Squamous Cells of Undetermined Significance, with Features of Atypical Parakeratosis. Small, keratinized squa- mous cells with mild variation in nuclear size and contour may repre- sent either a reactive process or a significant squamous lesion Fig. 1.52 Atypical Squamous Cells of Undetermined Significance, Atypical Repair Reaction. In some cases of repair there is such strik- ing nuclear atypia that an invasive cancer cannot be excluded. The flat, sheet-like arrangement with nuclear separation, the finely textured chromatin, and the prominent streaming appearance are more typical of benign repair rather than cancer. (Contrast with Fig. 1.47.) Fig. 1.53 Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion (HSIL). These metaplastic-like cells show significant nuclear membrane irregularity. There is no hyperchro- masia or nuclear size variation, however, which makes the diagnosis of HSIL uncertain Fig. 1.54 Atypical Squamous Cells, Cannot Exclude High-Grade Squamous Intraepithelial Lesion (HSIL). (A) Immature squamous metaplastic cells sometimes show some nuclear atypia, which raises the possibility of HSIL, but the degree of nuclear enlargement, hyperchromasia, and membrane irregularity is insufficient for a definite diagnosis. (B) Subsequent colposcopy revealed benign immature squamous metaplasia, and a human papillomavirus (HPV) test was negative for high-risk HPV Fig. 1.55 Adenocarcinoma in Situ (AIS). (A) At first glance, some groups of neoplastic cells resemble the hyperchromatic crowded groups of a high-grade squamous intraepithelial lesion. Only slight feathering is seen (arrows). (B) The columnar features are subtle with liquid-based preparations. (C) A picket-fence arrangement is indicative of glandular differentiation Fig. 1.56 Adenocarcinoma in Situ (AIS). (A) Rosettes are highly characteristic of AIS and virtually never seen with high-grade squamous intraepithelial lesion, benign endocervical cells, or lower uterine segment (LUS) or endometrial epithelium. (B) The endocervical glandular nature of these neoplastic cells is betrayed by "feathering." Fig. 1.57 Adenocarcinoma in Situ (AIS) Compared to Tubal Metaplasia. (A) Endocervical AIS. Cells are columnar in shape, dark, crowded, and arranged in a curved strip. (B) A cone biopsy revealed AIS. (C) Tubal metaplasia. Atypical glandular cells bear a resemblance to those in (A), except that cilia are identified. (D) Subsequent biopsy specimens showed tubal metaplasia of surface endocervical epithelium Fig. 1.58 Endocervical Adenocarcinoma. (A) The cells are round rather than elongated as in adenocar- cinoma in situ. They are crowded and hyperchromatic, and a tumor diathesis is present. Tumor diathesis on liquid-based preparations appears as clumps and as a granular ring around groups of malignant cells ("clinging diathesis"). (B) High magnification reveals nuclear crowding and very large nucleoli Fig. 1.59 Endocervical Adenocarcinoma Compared to Reactive Endocervical Cells. (A) Endocervical adenocarcinoma, well-differentiated. The cells are enlarged and crowded, but the features are not conclu- sive for malignancy (note the absence of tumor diathesis). A diagnosis of atypical glandular cells was made. (B) Histologic sections showed adenocarcinoma. (C) Reactive endocervical cells. These cells appear simi- lar to those in (A). (D) Biopsy specimens in this patient confirmed reactive changes due to inflammation Fig. 1.60 Endocervical Adenocarcinoma. These malignant cells show variation in nuclear size, with very prominent nucleoli and coarsely granular chromatin Fig. 1.61 Minimal Deviation Adenocarcinoma. (A) The cells are sometimes impossible to distinguish from normal endocervical cells, as in this case. (B) A cone biopsy revealed deeply invasive, misshapen neoplastic glands Fig. 1.62 Endometrial Adenocarcinoma Compared to Intrauterine Device (IUD) Effect. (A) Endometrial adenocarcinoma, endometrioid type. These malignant cells are large, vacuolated, and associated with neutrophils. (B) IUD effect. Benign cells in women with an IUD are indistinguishable morphologically from those of endometrial adenocarcinomas Fig. 1.63 "Bag of Polys" Cells: Differential Diagnosis. (A and B): Endometrial adenocarcinoma. (A) "Bag of polys'' cells have a large cytoplasmic vacuole filled with neutrophils, often obscuring the nuclear detail of the neoplastic cell. (B) The histologic correlate is seen in the surface of the endometrial adenocarcinoma. (C and D): Inflamed endocervical polyp. (C) The large vacuolated cells are associated with neutrophils, just like the cells of endometrial adenocarcinoma. (D) Histologic sections reveal an acutely inflamed polyp lined by reactive endocervical cells infiltrated by polys Fig. 1.64 Atypical Glandular Cells. (A) Atypical endocervical cells. These cells are columnar and clearly of endocervical origin but crowded and hyperchromatic. Although mitoses were not seen, the case was reported as "atypical endocervical cells, favor neoplastic." (B) Atypical endometrial cells. These cells have enlarged nuclei with slightly irregular contours and some infiltration by neutrophils Fig. 1.65 Small Cell Neuroendocrine Carcinoma of the Cervix. The malignant cells have dark nuclei and scant cytoplasm Fig. 1.66 Malignant Melanoma of the Vagina. The malignant spin- dled and epithelioid cells are noncohesive. There is focal finely granular melanin pigment (arrow) Fig. 1.67 Psammoma Bodies. These calcific spheres are dark blue or purple and have concentric laminations. They are often fractured, as seen here. These psammoma bodies originated from a borderline serous tumor of the ovary. When cells from ovarian or tubal neoplasms travel through the endometrial cavity, they can be seen on cervical or vaginal Pap samples Fig. 1.68 Endometrial Cells in a Woman Older Than 45 Years of Age. These cells are indistinguishable from menstrual endometrial cells (see Fig. 1.12A) Fig. 1.69 Bare Squamous Cell Nuclei. They are about the size of endometrial cells and sometimes aggregate. Cells that lack cytoplasm should not be interpreted as endometrial cells ■■■【2】Respiratory&Mediastinum Fig.2.1 Normal Ciliated Bronchial Cells (Bronchial Brushing). These columnar cells have oval nuclei and finely stippled chromatin. Numerous cilia project from the apical surface (Papanicolaou stain) Fig. 2.2 Anthracotic Pigment and a Mimic (Black Particles). (A) Pulmonary macrophages have abundant foamy cytoplasm that often contains black carbon particles (anthracotic pigment), as seen here (Papanicolaou stain). (B) Abundant extracellular black metallic particles from an endobronchial ultrasound- guided procedure should not be construed as anthracotic pigment (hematoxylin and eosin stain) Fig. 2.3 Mesothelial Cells (Fine-Needle Aspiration). Benign mesothelial cells are occasionally seen in percutaneous fine-needle aspirates. They are arranged in flat, cohesive sheets. The cells have a round or oval nucleus, a small nucleolus, and a moderate amount of cytoplasm. A slit-like space between the cells ("windows") can be appreciated (Papanicolaou stain) Fig. 2.4 Reactive Bronchial Cells. (A) Reactive bronchial cells can show marked nuclear size variation. Note that cilia-evidence of their benign nature-are retained (bronchial brushing, Papanicolaou stain). (B) In chronic lung diseases, as in this case of a patient with asthma, clusters of reactive bronchial cells can assume a spherical shape ("Creola body") and resemble the cells of an adenocarcinoma. Normal nuclear features and cilia indicate their benign nature (bronchial washing, Papanicolaou stain) Fig. 2.5 Benign Treatment Effect (Bronchoalveolar Lavage). Bronchial cells exposed to cytotoxic che- motherapy or radiation undergo marked cellular changes that mimic adenocarcinoma and/or squamous cell carcinoma. Nucleomegaly, smudgy hyperchromasia, vacuolization (cytoplasmic and nuclear), and a low nuclear-to-cytoplasmic ratio are characteristic (hematoxylin and eosin stain) Fig. 2.6 Reserve Cell Hyperplasia (Bronchial Brushing). These small cells have dark nuclei and show nuclear molding. They are distinguished from small cell carcinoma by their extremely small size and the lack of necrosis. Compare these cells with the adjacent bronchial columnar cells (Papanicolaou stain) Fig. 2.7 Type II Pneumocyte Hyperplasia (Bronchoalveolar Lavage). In patients with lung injury, type II pneumocytes are markedly enlarged and mimic adenocarcinoma, as seen here. (A hemosiderin-laden macro- phage is also present.) This patient had diffuse infiltrates and marked respiratory distress due to diffuse alveo- lar damage. In such clinical settings, an unequivocal diagnosis of malignancy should be avoided, inasmuch as most patients with lung cancer are not usually seriously III at presentation (Papanicolaou stain) Fig. 2.8 Curschmann's Spiral (Sputum). These coils of inspissated mucus are commonly seen in respiratory specimens and are a nonspe- cific finding (Papanicolaou stain) Fig 2.9 Ferruginous Bodies (Bronchoalveolar Lavage). Patients with asbestos exposure and a high burden of asbestos fibers in lung tissue demonstrate ferruginous bodies in bronchoalveolar lavage fluid: golden-brown, beaded, rod-like structures with bulbous ends. Inflammatory cells such as macrophages may be associated with ferruginous bodies (Papanicolaou stain) Fig. 2.10 Charcot-Leyden Crystals (Bronchial Washing). These needle-shaped crystals from a patient with asthma are a byproduct of eosinophil degranulation (Papanicolaou stain) Fig. 2.11 Corpora Amylacea (Bronchoalveolar Lavage). These large acellular bodies are somewhat variable in appearance. They may be spherical, as seen here, or angulated. They have fine radial striations and may have concentric laminations. Occasionally, there may be a central pigmented core. They are produced in the lung and other organs and have no known significance. Pulmonary corpora amyla- cea are not calcific, which distinguishes them from psammoma bod- ies and the laminated spheres of pulmonary alveolar microlithiasis (Papanicolaou stain) Fig. 2.12 Vegetable Cells (Sputum). Some vegetable cells have elongated shapes and large nuclei, resembling the cells of keratinized squamous cell carcinoma. Their rectangular shape, uniform size, and refractile cellulose wall, however, help identify them as vegetable cells (Papanicolaou stain) Fig. 2.13 Alternaria (Bronchoalveolar Lavage). This pigmented fungus is rarely pathogenic. It can con- taminate virtually any cytologic specimen, including cervicovaginal smears, cerebrospinal fluids, and urines. (A) The slender septate stalks (conidiophores) are occasionally branched (not shown). (B) The conidia are snowshoe shaped and have both transverse and longitudinal septations (Papanicolaou stain) Fig. 2.14 Nocardia (Bronchoalveolar Lavage). (A) The filamentous, beaded bacterial forms are visual- ized with Gram stains. (B) They are positive with modified acid-fast stains Fig. 2.15 Granulomas (Fine-Needle Aspiration). (A) Granulomas are tight aggregates of epithelioid histio- cytes. They have a syncytial appearance because individual cell borders are indistinct (Papanicolaou stain). (B) Note the curved, elongated, boomerang-like shapes of some of the nuclei (Romanowsky stain) Fig. 2.16 Coccidioides Immitis. (A) A fractured spherule releases endospores, resulting in the appear- ance of a broken ping-pong ball (Papanicolaou stain). (B) A similar fractured spherule is seen in sections from the cell block (hematoxylin and eosin stain) Fig. 2.17 Paracoccidioidomycosis. A silver stain highlights the ship's- wheel appearance of yeast forms budding off from the central parent yeast. The broad-based budding resembles that of Blastomyces spe- cies; hence, its alternative term, South American blastomycosis Fig. 2.18 Aspergillus Niger Fruiting Body. This sample was obtained by fine-needle aspiration of a lung mass (cell block, periodic acid-Schiff stain) Fig. 2.19 Mucor Spp. (Fine-Needle Aspiration). Broad, ribbon-like, aseptate hyphae with right-angle branching are characteristic of this fungus (Papanicolaou stain) Fig. 2.20 Pneumocystis Jirovecii (Bronchoalveolar Lavage). (A) With the Papanicolaou stain, the pneu- mocystis organisms are not seen, but foamy proteinaceous spheres characteristic of this infection are identified. (B) The cysts, which have a cup-shaped configuration and a central dark zone, are seen with the methenamine silver stain. (C) The Giemsa stain outlines the cysts as negative images and stains the intracystic bodies or trophozoites. Each cyst, as seen here, contains eight intracystic bodies. (D) The direct immunofluorescence test is highly sensitive, revealing green fluorescent-stained organisms and their extracellular products Fig. 2.21 Strongyloides (Sputum). These large roundworms are distinguished by their short buccal cavi- ties (arrow) (Papanicolaou stain) Fig. 2.22 Granulomatosis with Polyangiitis (Fine-Needle Aspiration). A granular background consisting of necrotic collagen without acute inflammation is characteristic (Papanicolaou stain) Fig. 2.23 Nodular Pulmonary Amyloid (Fine-Needle Aspiration). (A) Amyloid has a glassy, amorphous appearance with embedded stromal cells. (B) The cell block shows dense, eosinophilic, paucicellular amy- loid. (Inset) A Congo red stain examined with polarized light demonstrates green birefringence Fig. 2.24 Pulmonary Alveolar Proteinosis (Bronchoalveolar Lavage). (A) Hematoxylin and eosin (H&E)- stained cell block sections show numerous acellular eosinophilic aggregates. (B) Globule, tear drop, and carrot-shaped aggregates are pathognomonic of pulmonary alveolar proteinosis (H&E stain) Fig. 2.25 Organizing Pneumonia (Fine-Needle Aspiration). (A) Large, crushed tissue fragments com- prised of fibroblasts and collagen are characteristic (Romanowsky stain). (B) Fibroblasts and collagen fill alveolar spaces, resulting in nodular masses (Masson bodies) (Romanowsky stain). (C) High magnification reveals a mix of fibroblasts, pneumocytes, macrophages, and collagen (Papanicolaou stain). (D) Cell block preparations show fragments of collagenous tissue with loosely arranged fibroblasts admixed with chronic inflammatory cells (hematoxylin and eosin stain) Fig. 2.26 Pulmonary Hamartoma (Fine-Needle Aspiration). (A) Loose myxoid material is often present (smear, Romanowsky stain). (B) The transition between fibromyxoid material and cartilage is seen. Benign epithelial cells are also present (cell block, hematoxylin and eosin [H&E) stain). (C) Mature cartilage may be a prominent component (cell block, H&E stain). (D) The epithelial component can be monomorphic and cuboidal, as seen here, resembling benign mesothelial cells (smear, Romanowsky stain) Fig. 2.27 Sclerosing Pneumocytoma (Fine-Needle Aspiration). (A) Papillary formations have a lining of pneumocyte-like cells around a cellular core of round stromal cells (Papanicolaou stain). (B) The stromal cells are monomorphic, with a round nucleus and one or more small nucleoli (Papanicolaou stain). (Figures courtesy Dr. Natasha Rekhtman, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.) Fig. 2.28 Receptor Tyrosine Kinase Signaling in Cancer. This sim- plified diagram illustrates the pathways by which receptor tyrosine kinases (RTKs) stimulate growth, invasion, and angiogenesis (see text for details). BRAF, v-raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; EML4-ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; ERK, extracellular-signal-regulated kinase; HER2, protein kinase erbb- 2; IGF-1R, insulin-like growth factor 1 receptor; PI3K, phosphatidylino- sitol 3-kinase; RAS, Rat sarcoma viral oncogene homolog; VEGFR, vascular endothelial growth factor receptor Fig. 2.29 Immunohistochemical and Cytogenetic Testing of Lung Malignancies. (A) Immunoreactivity for ALK (as seen here) is sensitive and specific for translocations involving the ALK gene. (B) EML4-ALK intrachromosomal translocation is recognized by dual color split-apart fluorescence in situ hybridization. The arrows (left portion of diagram) point to the breakpoints within chromosome 2 that result in the intrachromosomal translocation. On the right, red and green probes flanking the ALK locus on chromosome 2p23.2 reveal red-green doublets at the wild type ALK loci (arrowhead) but are split apart when ALK is rearranged and fused to EML4 on the same chromosome at 2p21 (arrow). The rearranged probes appear far apart because the chromatin of interphase nuclei is dispersed relative to that of chromosomal DNA (Figure courtesy Dr. Lucian Chirieac, Department of Pathology, Brigham and Women's Hospital, Boston, Mass.). C, ROS1 immunohistochemistry is recommended as a screening test for tumors with ROS1 trans- locations, but positive immunoreactivity (as seen here) should be confirmed by molecular or cytogenetic methods. D, In specimens containing at least 100 tumor cells, partial Fig.2.30 Well-Differentiated Squamous Cell Carcinoma (Fine-Needle Aspiration). (A) Well-differentiated squamous cell carcinomas are composed of cells with dense, orangeophilic cytoplasm and hyperchro- matic, often pyknotic nuclei, some with angular contours (Papanicolaou stain). (B) Bizarre, elongated, spindle-shaped cells are common. Often there is abundant granular debris, seen here, and inflammation (Papanicolaou stain) Fig. 2.31 Poorly Differentiated Squamous Cell Carcinoma (Fine- Needle Aspiration). Poorly differentiated squamous carcinoma cells are often arranged in thick groups of pulled out, spindle-shaped cells, rather than as isolated cells. The nuclei are enlarged, and chromatin is coarsely granular, in contrast to the dense, frequently pyknotic nuclei of well-differentiated (keratinizing) squamous cell carcinomas Fig. 2.32 Atypical Squamous Metaplasia (Fine-Needle Aspiration). Cavitary fungal infections, like this one by an Aspergillus species (inset), are among the causes of reactive squamous atypia, a mimic of squa- mous cell carcinoma (hematoxylin and eosin stain) Fig. 2.33 NUT Carcinoma of the Mediastinum (Fine-Needle Aspiration). (A) Tumor cells have a dis- persed pattern on smears, with uniform, rounded nuclei, distinct nucleoli, and minimal cytoplasm (Papanicolaou stain). (B) NUT carcinoma mimics other tumors, including small cell carcinoma, lymphoma, and germ cell tumors due to its dyscohesive nature and scant cytoplasm. (C) Hematoxylin and eosin stains may show pale or clear cytoplasm. (D) Diffuse nuclear NUT protein expression is diagnostic and correlates with NUT gene rearrangement and mis-expression. Here the characteristic "speckled" pattern is seen Fig. 2.34 Adenocarcinoma (Acinar Predominant). The cells of this tumor are relatively uniform in size and shape, with small or medium-sized nucleoli. The finely textured chromatin is characteristic of adeno- carcinomas as compared with squamous cancers. There are two prominent acinar spaces. Note the indistinct cell borders, imparting a syncytial-like appearance to this sheet of malignant cells. Contrast with the mesothelial cells in Fig. 2.3, where slit-like spaces separate adjacent cells (smear, Papanicolaou stain) Fig. 2.35 Adenocarcinoma (Lepidic Predominant). (A) Nonmucinous. These cells are hyperchromatic and have a high nuclear-to-cytoplasmic ratio, with scant microvacuolated cytoplasm. There are no clues to suggest a lepidic predominant pattern (bronchoalveolar lavage, Papanicolaou stain). (B) Mucinous. The flat honeycomb-like sheet of these uniform tumor cells is characteristic, as are the intranuclear pseudoin- clusions (arrows). Nuclear grooves are better seen with the Papanicolaou stain (not shown). Overall, the nuclear changes are reminiscent of papillary carcinoma of the thyroid (smear, Romanowsky stain) Fig. 2.36 Adenocarcinoma (Solid Predominant). (A) These malignant cells are arranged in large, densely packed, solid clusters (Romanowsky stain). (B) High magnification of this tumor reveals marked nuclear enlargement, with irregular nuclear contours and prominent nucleoli. Note the microvacuolated cytoplasm, a characteristic feature of adenocarcinomas as compared with squamous cancers (Romanowsky stain) Fig. 2.37 Adenocarcinoma (Papillary Predominant). These crowded malignant cells line a fibrovascular stalk (cell block, hematoxylin and eosin stain) Fig. 2.38 Adenocarcinoma (Micropapillary Predominant). (A) The cells are arranged in very tight balls without a fibrovascular core (smear, Romanowsky stain). (B) The nuclear features, including the prominent nucleoli, are better seen with alcohol-fixed preparations. This pattern can be mimicked by other adeno- carcinomas, especially when samples are processed using liquid-based methods (see Fig. 2.35A) (smear, Papanicolaou stain) Fig. 2.39 Giant Cell Carcinoma (Fine-Needle Aspiration). The huge multinucleated cells with striking nuclear atypia of this tumor are obvi- ously malignant (Papanicolaou stain) Fig. 2.40 Typical Carcinoid Tumor (Fine-Needle Aspiration). The tumor cells have a moderate amount of coarsely granular cytoplasm and a "salt-and-pepper" chromatin pattern. Rosettes are seen in some carcinoid tumors (Papanicolaou stain) Fig. 2.41 Atypical Carcinoid Tumor (Fine-Needle Aspiration). (A) These tumors resemble typical car- cinoid tumors, forming loose clusters of cells with ovoid nuclei and a salt-and-pepper chromatin pat- tern (Papanicolaou stain). (B) Atypical carcinoids have more pleomorphism and nuclear enlargement, an increased number of mitoses (arrow), and focal necrosis, important distinguishing features (Papanicolaou stain) Fig. 2.42 Small Cell Carcinoma (Bronchial Brushing). (A) The cells are fragile, and many appear as bare nuclei. Where intact, the cytoplasm is scant. Some nuclei are stretched (carrot-shaped), and there is extensive necrosis manifested by granular debris and extensive apoptosis. Better-preserved cells have finely textured chromatin (Papanicolaou stain). (B) Nuclear molding is prominent. The small, so-called para- nuclear blue body in the center of the field, is a characteristic of small cell carcinomas (Romanowsky stain) Fig. 2.43 Pulmonary Lymphoepithelioma-Like Carcinoma (Fine-Needle Aspiration). (A) This tumor yields geographic fragments of uniformly atypical cells (Papanicolaou stain). (B) Hematoxylin and eosin-stained cell block preparation demonstrates large atypical cells surrounded and infiltrated by small lymphocytes Fig.2.44 Epithelioid Angiosarcoma of the Lung. (A) The large polygonal tumor cells demonstrate marked nuclear atypia, prominent nucleoli, and may resemble poorly differentiated carcinoma (Papanicolaou stain). (B) Cell block sections show sheet-like growth (hematoxylin and eosin stain) Fig. 2.45 Ewing Sarcoma of Lung (Fine-Needle Aspiration). (A) Smears shows loosely cohesive, vas- cular fragments (Romanowsky stain) (B) Individual cells are uniform, with a round nucleus, a fine chromatin pattern, and a small nucleolus (Romanowsky stain) Fig. 2.46 Metastatic Ductal Carcinoma of the Breast. This patient had a history of invasive ductal carcinoma of the breast. (A) Fine-needle aspiration of the lung. The smear shows clusters of tumor cells with prominent nucleoli and mucin-filled intracellular lumens (Papanicolaou stain). (B) Breast lumpectomy. Comparison with the previously resected tumor shows close similarity, supporting the diagnosis of metas- tasis to the lung from the breast primary (hematoxylin and eosin stain) Fig.2.47 Thymoma (Fine-Needle Aspiration). (A) Smears reveal clusters of epithelioid cells (Romanowsky stain). (B) Cell block sections show lymphocytes admixed with neoplastic thymocytes. A resection revealed mixed B2 and B3 type thymoma (hematoxylin and eosin stain) Fig. 2.48 Seminoma of the Mediastinum. Fragile large neoplastic cells and numerous small lymphocytes are surrounded by a "tigroid" background caused by spilled cytoplasmic glycogen (Romanowsky stain) ■■■Urine&Bladder【3】 Fig. 3.1 Normal Voided Urine. Most benign voided urine samples show a mixture of urothelial cells and squamous cells. In voided urine, most of the urothelial cells are of "intermediate" type, with an oval or pyramidal shape; they resemble the parabasal cells of the cervix Fig. 3.2 Cytoplasmic Inclusions (Melamed-Wolinska Bodies). Degenerating urothelial cells frequently have round, red (or sometimes green) cytoplasmic inclusions of varying sizes. A normal columnar- shaped urothelial cell is also present Fig. 3.3 Umbrella Cells (Ureteral Washing). These are the largest urothelial cells. They cover the surface of the urothelium and are often binucleated or multinucleated. Normal columnar urothelial cells are also present Fig. 3.4 Benign Urothelial Cells Can Have a Folded and Flattened Nucleus (Catheterized Specimen). The nucleus of benign urothelial cells is not always perfectly round. Some indentation and deformation, including straight edges that give the cells a flat geometric contour, are common. They are recognized as benign because of their normal nuclear-to-cytoplasmic ratio and normochromasia Fig. 3.5 Basal Urothelial Cells (Catheterized Specimen). Basal uro- thelial cells are rare in voided urine but common in catheterized speci- mens and usually tightly clustered Fig. 3.6 Seminal Vesicle or Prostatic Epithelial Cells (Voided Urine). These cells are recognized because of their golden-brown pig- ment. Sometimes they are less well preserved than seen here Fig. 3.7 Ileal Loop Specimen. (A) Most of the cells in an ileal loop specimen are degenerated intestinal cells and look very much like macrophages. (B) Degenerated intestinal cells can have Melamed-Wolinska bodies (arrows) just like urothelial cells. Lubricant is present (arrowheads) Fig. 3.8 Polyomavirus Infection. (A) In some cases, the nucleus is filled with and expanded by a glassy basophilic inclusion. Nuclear chromatin is pushed to the nuclear membrane, giving it a thickened and beaded appearance. (B) Some of the affected cells have a characteristic tear-drop or comet shape. (C) The inclusions do not always completely fill the nucleus, leaving clumps and threads of visible chromatin. Note the marked nuclear enlargement by comparison with the nuclei of normal squamous cells. (D) Some chromatin texture is visible. Note how round the nucleus is Fig. 3.9 Condyloma Acuminatum of Bladder (Catheterized Urine). (A) The sample contains koilocytes.(B) A bladder biopsy confirmed the diagnosis (hematoxylin and eosin stain) Fig. 3.10 Chemotherapy Effect (Catheterized Urine). This enor- mous multinucleated cell has a normal nuclear-to-cytoplasmic ratio. Note that, where the nuclei are not overlapped, one can tell that the chromatin is finely textured. Coarse vacuolization is typical of benign reactive changes, including chemotherapy and radiation effect Fig. 3.11 Benign Stone Atypia (Voided Urine). In some patients with stones, urothelial cells are markedly abnormal, with hyperchromatic and angulated nuclei. A distinction from urothelial carcinoma in such cases is impossible. The patient's age (27 years old) was the only clue that these cells might not be malignant. A subsequent computed tomogra- phy scan demonstrated bilateral renal stones. The exceptional atypia of these cells prompted a suspicious interpretation. Cystoscopic evalua- tion of the bladder, kidneys, and ureters was normal Fig. 3.12 Nephrogenic Adenoma (Catheterized Urine). (A) The cells are smaller than intermediate uro- thelial cells, with granular cytoplasm and a round nucleus. (B) A bladder biopsy demonstrates the resem- blance to renal tubular epithelium (hematoxylin and eosin stain). The cells are positive for PAX8 (Inset) Fig. 3.13 High-Grade Urothelial Carcinoma (Catheterized Urine). Numerous isolated malignant cells have an enlarged nucleus, coarsely textured chromatin, and a markedly increased nuclear-to- cytoplasmic ratio. An occasional cell has a mucin vacuole, which is not uncommon Fig. 3.14 High-Grade Urothelial Carcinoma With Jet-Black Chromatin (Ileal Loop Specimen). The cells have markedly irregular nuclear outlines, including nuclear points, but in many places the chro- matin is smooth and black rather than coarsely granular Fig. 3.15 High-Grade Urothelial Carcinoma With Straight and Curved Nuclei (Voided Urine). The nuclei are elongate and dark, with either a straight or curved edge that imparts a sickle or crescent-moon shape Fig. 3.16 High-Grade Urothelial Carcinoma With Umbrella-Cell Features (Catheterized Urines). (A) This malignant cell is large, with a markedly enlarged nucleus and prominent nucleoli. In most examples, like this one, the nuclear-to-cytoplasmic ratio is elevated, and there are usually far too many such cells for them to be normal umbrella cells, yet the nuclear membrane is smooth and regular, and the chromatin is finely textured. (B) Some of these "umbrella-cell" variants have obviously malignant nuclei, even though the nuclear-to-cytoplasmic ratio is only mildly increased Fig. 3.17 High-Grade Urothelial Carcinoma With Pale Chromatin (Catheterized Urine). (A) The malig- nant cells have markedly enlarged nuclei but relatively pale chromatin, and there is a mitosis (arrow). (B) The marked nuclear enlargement can be appreciated by comparing to adjacent normal urothelial cells on the right Fig. 3.18 High-Grade Urothelial Carcinoma With Smooth Round Nuclei and Granular Chromatin. The nuclear-to-cytoplasmic ratio is very high, and chromatin is coarse and clumpy Fig. 3.19 High-Grade Urothelial Carcinoma With Smooth Round Nuclei and Prominent Nucleoli. The nuclear-to-cytoplasmic ratio is increased, and nucleoli are prominent Fig. 3.20 High-Grade Urothelial Carcinoma With Small Nuclei (Ileal Loop). The nuclear-to-cytoplasmic ratio is very high, the nuclear out- line is irregular, and the cells may have one or more nucleoli, but the chromatin is not coarse and clumpy. These cells are smaller than reac- tive urothelial cells Fig. 3.21 High-Grade Urothelial Carcinoma With Extensive Degeneration (Voided Urine). The sharp angularity ("points") of degenerated cells helps to identify them as malignant Fig. 3.22 Urothelial Carcinoma Variants. (A) Some of the malignant cells show squamous differentiation, manifested by cytoplasmic orangeophilia. (B) Some urothelial carcinomas have foci of adenocarcinoma Fig. 3.23 Suspicious for Urothelial Carcinoma. The suspicious cells are few in number and poorly preserved. The irregularity of the nuclear membrane is more typical of malignancy than polyomavirus effect Fig. 3.24 Clear Cell Adenocarcinoma. The cells are large, with abundant clear cytoplasm, large nuclei, and large nucleoli Fig. 3.25 Prostatic Carcinoma (Voided Urine). Many prostate can- cers are impossible to distinguish from urothelial carcinoma. Inset, Immunohistochemistry for prostatic markers can be helpful (cell block, prostate specific antigen) Fig. 3.26 Metastatic Colon Cancer to the Bladder Neck (Voided Urine). (A) The majority of the malig- nant cells are round, with dark, angulated nuclei. Distinction from urothelial carcinoma is not possible by cytomorphology. (B) A cell block preparation contains occasional degenerated malignant cells. (Inset) the malignant cells show nuclear reactivity for CDX-2, commonly seen in colon cancers and usually absent in urothelial cancers. The malignant cells were also positive for cytokeratin 20 and negative for cytokeratin 7, the typical keratin profile of colon cancer Fig. 3.27 The Urovysion Test for Bladder Cancer. (A) Benign urothelial cell nuclei show two signals with fluorescent centromeric probes for chromosomes 3 (red), 7 (green), and 17 (aqua), as well as two intact segments of 9p21 with a fluorescent locus-specific probe (yellow). (B) Malignant urothelial cells show increased copy number for chromosomes 3 (red), 7 (green), and 17 (aqua), and some nuclei show loss of 9p21 (yellow) ■■■Pleural&Percardial【4】 Fig. 4.1 Mesothelial Cells. (A) Many characteristic features of meso- thelial cells are seen here: the peripheral lucent zone or "lacy skirt" (arrow); the dense perinuclear zone; the occasional binucleation; and the slit-like separation ("window") between adjacent cells. A few histio- cytes (arrowheads) with folded nuclei and vacuolated cytoplasm are also present (Papanicolaou stain). (B) Peripheral halos are well seen in this cell block section. Note also the large multinucleated mesothelial cell, a nonspecific finding (hematoxylin and eosin stain) Fig. 4.2 Reactive Mesothelial Changes (Peritoneal Fluid, Cirrho- sis). Some benign fluids contain a population of moderately enlarged mesothelial cells with large, hyperchromatic, irregular nuclei (Papani- colaou stain) Fig. 4.3 Histiocytes (Pleural Fluid, Congestive Heart Failure). (A) Like mesothelial cells, histiocytes are usually isolated cells, but centrifugation for cell block sections compresses them into large groups. Compare the histiocytes, which have an oval or folded nucleus, to the mesothelial cell (arrow) (hematoxylin and eosin stain). (B) Only the mesothelial cell is immunoreactive for cytokeratins Fig. 4.4 Eosinophilic Pleural Effusion. Numerous eosinophils in pleural fluid are more commonly associated with benign conditions such as a pneumothorax (as in this case) or hemothorax (Papanicolaou stain) Fig. 4.5 Lymphocytic Pleural Effusion. The specimen consists almost exclusively of small lymphocytes with round nuclei and con- densed chromatin. This finding is nonspecific (Papanicolaou stain) Fig. 4.6 Metastatic Thymoma, Type B2 (Pleural Effusion). (A) The specimen looks like a nonspecific lymphocytic effusion, but the patient had a history of a thymoma (Papanicolaou stain). (B) The cell block confirms the presence of numerous small lymphocytes (hematoxylin and eosin stain). (C) Numerous lym- phocytes are positive for terminal deoxytransferase, a marker of thymic lymphoid cells. (D) A cluster of cells shows strong immunoreactivity for p63, a marker of squamous differentiation that is usually negative in mesothelial cells Fig. 4.7 Rheumatoid Pleuritis. (A) Scattered multinucleated histiocytes and clumped granular debris in the background are characteristic of pleural fluids in patients with rheumatoid pleuritis (Papanicolaou stain). (B) A pleural biopsy has the appearance of an unfolded rheumatoid nodule, with epithelioid histiocytes, giant cells, and fibrinoid debris lining the pleural space (hematoxylin and eosin stain) Fig. 4.8 Hematoxylin Body (Lupus Pleuritis). The lobes of the nucleus are pushed against the side of the neutrophil by a large, homo- geneous, intracytoplasmic body (Romanowsky stain) Fig. 4.9 Cell Block Lacunae (Pleural Fluid). In cell block sections, malignant cells are often situated in an empty space (lacuna); the rea- son for this artifact is unknown. It is commonly seen with adenocarci- nomas, rarely with lymphomas and melanoma (hematoxylin and eosin stain) Fig. 4.10 Malignant Mesothelioma (Pleural Fluid). (A) Solid, morule-like spheres, some of them elon- gated, are composed of cells that resemble normal mesothelial cells. A fluid composed of many large clusters is virtually always malignant (Papanicolaou stain). (B) A branching pattern is seen in some cases. Note the knobby contours (Papanicolaou stain). (C) In many mesotheliomas, the nuclear-to-cytoplasmic ratio of normal mesothelial cells is recapitulated (Papanicolaou stain). (D) In other cases, the nuclear-to- cytoplasmic ratio is significantly increased (Papanicolaou stain) Fig. 4.11 Malignant Mesothelioma (Pleural Fluid). In some cases, the characteristically long microvilli can be appreciated with routine light microscopic preparations (hematoxylin and eosin stain) Fig. 4.12 Malignant Mesothelioma (Pleural Fluids). In some cases, cell block sections show that clusters of malignant cells surround a collagenous core (hematoxylin and eosin stain) Fig. 4.13 Malignant Mesothelioma, Unusual Variants. (A, B) Rarely, mesotheliomas show striking cyto- plasmic vacuolization ("clear cell type"). (C, D) Some mesotheliomas are comprised of small cells, but the term "small cell mesothelioma" is discouraged to avoid confusion with small cell carcinoma of the lung (A and C, Papanicolaou stain; B and D, hematoxylin and eosin stain) Fig. 4.14 Reactive Mesothelial Cells vs Mesothelioma. (A) Reactive mesothelial cells can show some variation in nuclear size and nuclear membrane irregularity (Papanicolaou stain). (B) Mesotheliomas usually show greater cytomegaly, but this can be difficult to assess on a case-by-case basis (Papanicolaou stain) Fig. 4.15 Malignant Mesothelioma. The clonal chromosomal deletions typical of mesothelioma can be interrogated by immunohistochemistry and fluorescence in situ hybridization (FISH). (A) Immunohistochemistry for BAP1 protein. Loss of nuclear staining, as seen here, is highly specific for malig- nancy when the cells are known to be mesothelial. Note the nuclear staining of background histiocytes and lymphocytes, an important internal control. (B) FISH of pleural fluid shows a normal cell on the right and a mesothelioma cell on the left. The preparation has been incubated with probes for the centromeric region (green) and the deleted region (red) of chromosome 9. Both cells show two centromeric regions, but the mesothelioma cell is missing a segment of the short arm of chromosome 9. (Image B Courtesy Dr. Paola Dal Cin, Brigham and Women's Hospital, Boston, MA.) Fig. 4.16 Immunoprofile of Malignant Mesothelioma. (A) Mesothe- liomas show nuclear and cytoplasmic staining for calretinin. (B) There is usually nuclear immunoreactivity for WT1 Fig. 4.17 Immunoprofile of Metastatic Adenocarcinomas. (A) Most adenocarcinomas are immunoreac- tive for one or more of the carcinoma markers like claudin-4 (shown here). Positive claudin-4 immunoreac- tivity is usually strong and occurs along the cell membrane, in a continuous or punctate pattern. (B) Most adenocarcinomas of the lung are immunoreactive for TTF-1, as are most thyroid cancers Fig. 4.18 Epithelioid Hemangioendothelioma of the Lung (Pleural Fluid). This tumor is a good mimic of mesothelioma because the cells form large aggregates and have round, centrally placed nuclei and abundant cytoplasm (hematoxylin and eosin stain) Fig. 4.19 Primary Effusion Lymphoma. (A) The malignant cells are large, with thick nuclear membranes, irregularly distributed chromatin, and prominent nucleoli. Apoptotic bodies are present (Papanicolaou stain). (B) The presence of human herpes virus 8 (HHV-8), demon- strated here by immunohistochemistry, is a sine qua non of primary effusion lymphomas Fig. 4.20 Adenocarcinoma of the Lung (Pleural Fluid). Clusters of very large, highly atypical cells like these are easily spotted and identi- fied as malignant. In the absence of a known primary, special stains are helpful to identify the primary site (Papanicolaou stain) Fig. 4.21 Adenocarcinoma of the Lung (Pleural Fluid). In cases like this, malignant cells can be more difficult to recognize as such because they are dispersed as isolated cells. Careful examination reveals mark- edly enlarged nucleoli, irregular nuclear contours, and a cytoplasmic texture that is frothier and less dense than that of most mesothelial cells (Papanicolaou stain) Fig. 4.22 Ductal Carcinoma of the Breast (Pleural Fluid). (A) Ductal breast cancers often exfoliate as large spheres of malignant cells (Papanicolaou stain). (B) The hollow nature of the spheres in apparent on cell block sections (hematoxylin and eosin stain) Fig. 4.23 Adenocarcinoma of the Stomach (Pleural Fluid). Large numbers of isolated signet ring cells are characteristic of many gastric cancers (Papanicolaou stain) Fig. 4.24 Clear Cell Carcinoma of the Kidney (Pleural Fluid). Large cells with round nuclei, prominent nucleoli, and abundant granular and vacuolated cytoplasm are typical of renal cell carcinoma, clear cell type (Papanicolaou stain) Fig. 4.25 Metastatic Papillary Carcinoma of the Thyroid (Pleural Fluid). This large irregular cluster of malignant cells is associated with a psammoma body. The thyroid origin can be confirmed by positive immunoreactivity for thyroglobulin, TTF-1, and PAX8 (Papanicolaou stain) Fig. 4.26 Pseudomyxoma Peritonei (Peritoneal Fluid). (A) Extracellular mucin is present in abundance and stains blue or purple with the Papanicolaou stain. Malignant cells are often not seen; the few cells in this field are mostly histiocytes (Papanicolaou stain). (B) In this case, rare strips of neoplastic epithelium were identified in cell block sections (hematoxylin and eosin stain) Fig. 4.27 Lobular Carcinoma of the Breast (Pleural Fluid). (A) These malignant cells are extremely difficult to recognize because they resemble histiocytes or mesothelial cells (Papanicolaou stain). (B) A mucicarmine stain reveals focal intracytoplasmic mucin. (C) A positive immunostain for estrogen receptor (ER) not only identifies the presence of metastatic breast cancer, it may also guide treatment Fig. 4.28 Ductal Carcinoma of the Breast (Pleural Fluid). (A) Cell block section shows numerous malig- nant cells. This pleural recurrence occurred 4 years after treatment of the primary invasive tumor (hema- toxylin and eosin stain). (B) Immunostaining for HER2 reveals uniform strong membrane staining in >30% of the malignant cells. The patient's original breast excision had two breast cancers, one that was HER2- negative and the other HER2-positive Fig. 4.29 Squamous Cell Carcinoma of the Cervix (Pericardial Fluid). Nonkeratinizing squamous cell cancers shed large spheres of malignant cells (A, Papanicolaou-stained cytocentrifuge Preparation. B, Hematoxylin and eosin-stained cell block preparation) Fig. 4.30 Squamous Cell Carcinoma of the Lung (Pleural Fluid). (A) The malignant cells have coarsely textured chromatin and plate-like cytoplasm (Papanicolaou stain). (B) Some of the malignant cells are isolated rather than clustered. Compare the large malignant cell in the center with the two mesothelial cells on either side (Papanicolaou stain) Fig. 4.31 Small Cell Carcinoma of the Lung (Pleural Fluid). (A) Some of the small malignant cells are isolated, and others are molded together in clusters. The mesothelial cell on the right provides a size com- parison (Papanicolaou stain). (B) Similar features are seen with air-dried, Romanowsky-stained prepara- tions. In this image, a macrophage in the lower left provides a size comparison Fig. 4.32 Melanoma (Pleural Fluid). (A) Nonpigmented melanoma cells are usually isolated, not clustered, and resemble mesothelial cells (Papanicolaou stain). (B) Less often, they aggregate into large clusters (Papanicolaou stain) Fig. 4.33 Diffuse Large B-Cell Lymphoma (Peritoneal Fluid). The lymphoma cells have predominantly round nuclei with prominent nucleoli. Note the karyopyknosis and karyorrhexis, characteristic of most lymphomas (Papanicolaou stain) Fig. 4.34 Lymphoblastic Lymphoma. Because lymphoblastic lymphoma cells are only slightly larger than normal lymphocytes, they are easily misdiagnosed. They are recognized by their more finely dis- persed chromatin texture, better appreciated on air-dried preparations (Romanowsky stain) Fig. 4.35 Non-Hodgkin Lymphoma. In equivocal cases, immunostains for immunoglobulin light chains, performed on cytocentrifuge preparations, can be helpful. Here the malignant lymphoid cells are immuno- reactive for k light chains (A) and negative for λ (B) Fig. 4.36 Hodgkin Lymphoma (Pleural Fluid). The classic Reed- Sternberg cell is a large, multinucleated cell with very prominent ("owl's eye") nucleoli (Papanicolaou stain) Fig. 4.37 Multiple Myeloma (Pleural Fluid). (A) The fluid is com- posed mostly of malignant plasma cells with abundant cytoplasm and eccentrically placed nuclei (Romanowsky stain). (B) The malignant cells are immunoreactive for CD138 Fig. 4.38 Extramedullary Hematopoiesis of Pleura (Pleural Fluid). (A) This patient had a recent diag- nosis of a squamous cell carcinoma of the lung and developed a pleural effusion. The sample contained scattered megakaryocytes, some with hyperlobulated and complex nuclei, typical of patients with myelo- proliferative neoplasms. A history of primary myelofibrosis was uncovered in the electronic medical record (Papanicolaou stain). (B) A hyperlobulated nucleus with thread-like connections between lobes is apparent (hematoxylin and eosin stain). (C) Megakaryocytes are immunoreactive for CD61. (The fluid was negative for metastatic squamous cell carcinoma.) Fig. 4.39 (A) Epithelioid Angiosarcoma (Peritoneal Fluid). The patient had a history of squamous cell carcinoma of the cervix. The new diagnosis of an intra-abdominal angiosarcoma was made on this fluid and confirmed by positive staining for the vascular markers ERG and CD31. (B) Pleomorphic rhabdo- myosarcoma (peritoneal fluid). The malignant cells are noncohesive. Binucleation, eccentrically placed nuclei, and dense cytoplasm are typical of rhabdomyosarcoma. The cells were negative for keratin but positive for desmin (Papanicolaou stain) Fig. 4.40 Adult Granulosa Cell Tumor (Ascites). (A) The malignant cells are uniform and bland and resemble benign mesothelial cells. The arrangement of cells in large clusters is suspicious, as is the promi- nence of nuclear grooves and focal follicle formation (Papanicolaou stain). (B) Comparison with the original histologic sections was helpful in establishing the diagnosis (hematoxylin and eosin stain) ■■■【5】Peritoneal Fig. 5.1 Mesothelial Cells. Normal mesothelial cells in peritoneal washings are often arranged in cohesive, sometimes folded, sheets. Isolated mesothelial cells are present in the background (Papanicolaou stain) Fig. 5.2 Mesothelial Cells (Cell Block). In cell block sections, a sheet of mesothelial cells is transected and looks like a string of pearls. When it curls around on itself, it has a pseudoglandular appearance (hema- toxylin & eosin stain) Fig. 5.3 Mesothelial Cells. (A) Benign mesothelial cells usually have round or oval nuclei, but in some cases there are irregularities in nuclear contour. Note the spaces ("windows") that separate adjacent cells, a common finding (Papanicolaou stain). (B) Benign mesothelial cells sometimes have grooved or even lobulated nuclei, in extreme cases resembling the petals of a flower ("daisy cells"). This finding has no diagnostic significance (ThinPrep, Papanicolaou stain). (Figure 5.3B courtesy Charles D. Sturgis, MD, Cleveland Clinic, Cleveland, OH.) Fig. 5.4 Collagen Ball. These spheres of collagen are surrounded by flattened mesothelial cells. (A) Papanicolaou stain; (B) hematoxylin & eosin-stained cell block section Fig. 5.5 Histiocytes. Histiocytes are either isolated or in groups, as seen here. They have indistinct cell borders (no "windows"), granu- lar or vacuolated cytoplasm, and occasionally folded nuclei. A short strip of mesothelial cells is also present on the cell block section. (A) Papanicolaou stain; (B) hematoxylin & eosin-stained cell block Fig. 5.6 Reactive Mesothelial Cells (Ovarian Torsion). The meso- thelial cells are enlarged, with irregular nuclei and prominent nucleoli. Exploratory laparotomy revealed torsion of the right ovary with intra- peritoneal adhesions Fig. 5.7 Endosalpingiosis. (A) The psammoma body has concentric lamination and is surrounded by cuboidal cells with small nucleoli and vacuolated cytoplasm. Cilia are not identified (Papanicolaou stain). (B) The surface of the resected ovary shows benign ciliated glandular cells associated with psammoma bodies. There was no evidence of tumor (hematoxylin & eosin stain) Fig. 5.8 Serous Adenofibroma of the Ovary. (A) A psammoma body is surrounded by evenly spaced mesothelial cells with minimal nuclear atypia (Papanicolaou stain). (B) The resected ovary shows a serous adenofibroma involving the ovarian surface, with an occasional psammoma body (arrow; hematoxylin & eosin stain) Fig. 5.9 Endometriosis. (A) A cluster of cells has scalloped borders and contains nuclear fragments. Individually, the cells resemble mesothelial cells, but the nuclear debris suggests that they are degener- ating endometrial cells. Such clusters are often recognized as endometrial cells only in retrospect, after reviewing cell block sections or correlating with laparoscopic or histologic evidence (Papanicolaou stain). (B) The cell block from the same case as (A) shows endometrial glands surrounding a core of degenerated endometrial stromal cells (hematoxylin & eosin stain). (C) Occasionally, the cell block of peritoneal washings from a patient with endometriosis shows diagnostic tissue fragments composed of intact endometrial-type glands and stroma (hematoxylin & eosin stain). (D) Endometriosis, like many Müllerian malignancies, is positive for PAX8 Fig. 5.10 High-Grade Serous Carcinoma of the Ovary. (A) The malignant cells are often arranged in large, irregularly shaped three-dimensional clusters of crowded cells (Papanicolaou stain). (B) Higher mag- nification reveals crowded large cells with round, dark nuclei, large nucleoli, and pale vacuolated cyto- plasm. Mitoses are often present (Papanicolaou stain) Fig. 5.11 High-Grade Serous Carcinoma of the Peritoneum. These tumors are morphologically indistinguishable from high-grade serous carcinomas of the ovary (Papanicolaou stain) Fig. 5.12 Serous Borderline Tumor. (A) Some neoplastic cells exfoliate as large branching micropapillary clusters with smoothly contoured or slightly scalloped edges. The centers are occupied by microcalcifica- tions (Papanicolaou stain). (B) A smaller cluster of cuboidal cells surrounding a cracked psammoma body from the same case demonstrates the minimal atypia characteristic of the serous borderline tumor. Biopsy specimens showed implants of identical cells on the omentum and peritoneum. Compare with Fig. 5.7: the cytologic distinction between endosalpingiosis and a borderline tumor is often very difficult (Papanicolaou stain) Fig. 5.13 Serous Borderline Tumor. Cell block sections are helful because they may show papillary structures lined by atypical cells with stratification and tufting, features that are characteristic of these tumors (hematoxylin & eosin stain) Fig. 5.14 Mucinous Adenocarcinoma of the Appendix Mimicking an Ovarian Mucinous Adenocarcinoma. The tumor cells are columnar, with elongated nuclei and a high nuclear to cytoplasmic ratio. The patient presented with pseudomyxoma peritonei and was found to have bilateral ovarian metas- tases. (A) Papanicolaou stain; (B) hematoxylin & eosin-stained cell block Fig. 5.15 Dysgerminoma of the Ovary. (A) The cells are large and relatively noncohesive, with a round, vesicular nucleus. There may be a single prominent nucleolus or multiple, irregular nucleoli (Papanicolaou stain). (B) In cell block sections, the cells can be aggregated. Cytoplasm is moderately abundant and clear (hematoxylin & eosin stain) Fig. 5.16 Embryonal Carcinoma of the Ovary. The cells are large and pleomorphic, with vesicular nuclei, prominent, irregular, and multiple nucleoli, and pale cytoplasm (Papanicolaou stain) Fig. 5.17 Endometrial Carcinoma, Endometrioid Type. The cells are enlarged, crowded, and have coarsely textured chromatin. Because well-differentiated endometrial cancers have round nuclei and only mild atypia, they can be difficult to distinguish from reactive meso- thelial cells. The absence of intercellular windows is a helpful feature (Papanicolaou stain) Fig. 5.18 Endometrial Carcinoma, Endometrioid Type. (A) Cell block sections occasionally show well- formed neoplastic glands. A mitotic figure is present (hematoxylin & eosin stain). (B) Cell block sections may show squamous morule formation by the neoplastic cells (hematoxylin & eosin stain) Fig. 5.19 Endometrial Carcinoma, Clear Cell Type. High-grade endometrial carcinomas such as the clear cell type have large nuclei and prominent nucleoli. Abundant clear cytoplasm is characteristic of but not specific for clear cell cancers (Papanicolaou stain) Fig. 5.20 Mesothelial Cell Atypia Caused by Chemotherapy. Features include multinucleation and marked anisonucleosis but only slight hyperchromasia. Cytoplasm is abundant (Papanicolaou stain) ■■■【6】Cerebrospinal Fig. 6.1 Ommaya Reservoir. (A) The ommaya reservoir consists of a pouch connected to a cannula with distal perforations. (B) When implanted, the pouch is subcutaneous, and the cannula ends in one of the lateral ventricles. A needle penetrates the pouch to instill medication and withdraw cerebrospinal fluid for examination of response to treatment Fig. 6.2 Tumor Involvement of Cerebrospinal Fluid (CSF) Pathways. (A) The arrows indicate a focus of astrocytoma cells that have disrupted the ependymal lining (hematoxylin & eosin stain). (B) The normally delicate subarachnoid membrane is filled and expanded by metastatic breast cancer cells, encasing the spinal cord. CSF was positive for malignant cells in both cases (hematoxylin & eosin stain) Fig. 6.3 Normal Cerebrospinal Fluid (CSF). Lymphocytes and monocytes are the usual components of a normal CSF (A, Papanicolaou stain; B, Romanowsky stain) Fig. 6.4 Choroid Plexus/Ependymal Cells. These cells are rare in cerebrospinal fluid; even when present, their number is usually small. They may be isolated or arranged in small clusters. Note the dis- persed chromatin texture of the nuclei and the abundant cytoplasm (Papanicolaou stain.) Fig. 6.5 Brain Tissue. These fragments, obtained from a ventricular tap, have a fibrillary texture and con- tain normal glial cells. Some fragments may contain neurons and capillaries (Papanicolaou stain.) Fig. 6.6 Neuron. Many neurons have an angular shape, a round nucleus, and a prominent nucleolus. Some have lipofuscin pigment (A, Papanicolaou stain; B, Romanowsky stain.) Fig. 6.7 Germinal Matrix. (A) In neonates, the small, dark, densely packed cells of the germinal matrix lie beneath the ependyma. Choroid plexus is seen on the right (hematoxylin & eosin stain). (B) When the ependyma is injured, clusters of small cells, accompanied by macrophages, are seen in cerebrospinal fluid (Romanowsky stain.) Fig. 6.8 Chondrocyte. Rarely seen in cerebrospinal fluid, chrondro- cytes have a pyknotic nucleus and are surrounded by a shell of extracel- lular mucopolysaccharide matrix that stains purple with the Papanicolaou stain. The adjacent cells are macrophages (Papanicolaou stain) Fig. 6.9 Bone Marrow. If the needle penetrates a vertebral body, immature erythroid and myeloid elements from normal bone marrow are sampled, as seen here (Romanowsky stain) Fig. 6.10 Macrophages. Macrophages have abundant cytoplasm and are seen in benign and malignant conditions. (A) Subarachnoid hemorrhage (Romanowsky stain). (B) Chronic shunt infection (Papanicolaou stain) Fig. 6.11 Plasma Cells (Lyme disease). Cerebrospinal fluid from patients with aseptic meningitis, as in this case of Lyme meningi- tis, can be markedly hypercellular, with plasma cells as a prominent component. Such specimens resemble a lymphoproliferative disorder (Romanowsky stain) Fig. 6.12 Acute Bacterial Meningitis. (A) There are numerous neutrophils and diplococci in this example of pneumococcal meningitis (Romanowsky stain). (B) Occasional rods are seen within a neutrophil and macrophage in this example of Listeria monocytogenes meningitis (Romanowsky stain) Fig. 6.13 Eosinophils. Except for a traumatic tap, eosinophils are an abnormal finding in cerebrospinal fluid. A parasitic infection should be considered (Romanowsky stain) Fig. 6.14 Aseptic Meningitis (Viral). An increased number of lymphocytes is present, including occa- sional so-called atypical lymphoid cells: enlarged cells with large nuclei, some of which have irregular contours, more finely dispersed chromatin, and prominent nucleoli. Note that the predominant cell type is still the small mature lymphocyte. (A) Papanicolaou stain. (B) Romanowsky stain. (C) In most cases of aseptic meningitis the lymphoid infiltrate is mostly T cells (Immunocytochemistry for CD3, cytocentrifuge preparation) Fig. 6.15 Cloverleaf ("Floret") Cells (Aseptic Meningitis Due to Infection by Human Immunodeficiency Virus-1). CSF samples occa- sionally contain lymphocytes with this unusual appearance. Cloverleaf lymphocytes are a nonspecific finding and can be seen in a variety of nonneoplastic conditions, but in larger numbers they raise the possibil- ity of a lymphoid malignancy (Papanicolaou stain) Fig. 6.16 Cryptococcal Meningitis. (A) The organisms have a muco- polysaccharide capsule. Note the characteristic thin-necked budding (arrow; Papanicolaou stain). (B) Some organisms are cup-shaped, trapping air and producing a refractile artifact (arrow; Papanicolaou stain) Fig. 6.17 Toxoplasma Meningoencephalitis. Toxoplasma gondii is a small bow-shaped organism with a single tiny nucleus. It can be intra- cellular or extracellular (Inset) (Papanicolaou stain) Fig. 6.18 Astrocytic Neoplasm. (A) The large cell has an oval nucleus, cytoplasmic blebs, and a long cytoplasmic extension (Romanowsky stain). (B) An immunostain for GFAP is positive, confirming the glial nature of this neoplasm Fig. 6.19 Adenocarcinoma of the Lung. (A) The malignant cells have large hyperchromatic nuclei and abundant cytoplasm. Note the eccen- tric placement of nuclei, a characteristic feature of some lung adeno- carcinomas (Papanicolaou stain). (B) The large malignant cells are admixed with lymphocytes, neutrophils, and monocytes (Romanowsky stain) Fig. 6.20 Small Cell Carcinoma of the Lung. The small cells have dispersed chromatin, indistinct nucleoli, and scant cytoplasm. Nuclear molding is prominent (Romanowsky stain) Fig. 6.21 Ductal Carcinoma of the Breast. The malignant cells of this grade 3 ductal cancer are round, large, and highly variable in size. Cytoplasmic blebs are commonly seen (Romanowsky stain) Fig. 6.22 Lobular Carcinoma of the Breast. These malignant cells have round or semilunar nuclei, and some have prominent nucleoli (Romanowsky stain) Fig. 6.23 Melanoma. (A) Melanoma cells tend to be isolated or only loosely aggregated. The two cells shown here are amelanotic (Romanowsky stain). (B) Melanin pigment is finely granular in malignant cells (Papanicolaou stain) Fig. 6.24 Acute Lymphoblastic Leukemia (ALL) and the Leukemic Variant of Burkitt Lymphoma. Depending on the subtype, the blasts of ALL may have several different appearances, which are best appreci- ated on air-dried preparations. (A) L1 blasts are small, with predomi- nantly round nuclei and scant cytoplasm. (B) L2 blasts are larger, with irregular nuclei and more abundant cytoplasm. (C) L3 blasts have coarse chromatin, dark blue cytoplasm, and small lipid vacuoles. In the World Health Organization classification, this is considered a leukemic variant of Burkitt lymphoma and not ALL. (A-C, Romanowsky stain) Fig. 6.25 Acute Myelomonocytic Leukemia (AML M4). In cerebro- spinal fluid from patients with leukemia, it is usually sufficient simply to identify the presence of blasts; further typing (myeloid vs. lymphoid and their subtypes) is done on peripheral blood and bone marrow speci- mens (Romanowsky stain) Fig. 6.26 Diffuse Large B-Cell Lymphoma. Tumor cells are dispersed as isolated cells with irregular nuclei, coarsely textured chromatin, and scant to abundant cytoplasm. Pyknosis (arrowhead) and karyorrhexis are common and can be prominent. A small, benign lymphocyte is also present (arrow; Papanicolaou stain) Fig. 6.27 Follicular Lymphoma. The malignant cells are relatively small and have irregular nuclear con- tours. The cells show monotypic expression of immunoglobulin light chains. (A) Romanowsky stain. (B) x expression. (C) λ expression Fig. 6.28 Flow Cytometric Analysis of Cerebrospinal Fluid (Non-Hodgkin Lymphoma). There is a pop- ulation of CD19-positive B cells that are (A) Negative for x and (B) Positive for 2. light chains Fig. 6.29 Primary Leptomeningeal Lymphoma. Five large, atypical lymphoid cells are present in this field, one with a prominent nuclear cleave. (Two benign lymphocytes are smaller, with darker nuclei.) In some cases of primary central nervous system lymphoma, the malig- nant B cells are outnumbered by small reactive T Cells, and the find- ings mimic aseptic meningitis. (Compare with Fig. 6.14B.) In this case there was a high clinical suspicion of lymphoma because the patient had cranial nerve findings (diplopia and facial droop). A portion of the sample was sent for flow cytometry, which showed immunoglobulin light chain restriction by the large cells (Romanowsky stain) Fig. 6.30 Medulloblastoma. The tumor cells are small, with hyper- chromatic nuclei and scant cytoplasm. Nuclear molding is prominent. (A) Papanicolaou stain. (B) Romanowsky stain Fig. 6.31 Poorly Preserved Lymphocytes and Monocytes Mimicking Medulloblastoma. Particularly in cerebrospinal fluid samples older than 48 hours, lymphocytes and monocytes undergo degeneration; they cluster together uncharacteristically and even show nuclear molding (Romanowsky stain) Fig. 6.32 Glioblastoma. The malignant cells are highly pleomorphic, with hyperchromatic nuclei and abundant cytoplasm (Papanicolaou stain) Fig. 6.33 Ependymoma. The tumor cells have a round, eccentrically placed nucleus (Papanicolaou stain) Fig. 6.34 Atypical Teratoid/Rhabdoid Tumor. This large rhabdoid cell has a dense cytoplasmic "body" that pushes the nucleus to the side. A lymphocyte, two monocytes, and some red blood cells are also present (Romanowsky stain) Fig. 6.35 Choroid Plexus Papilloma. The tumor cells are arranged in large, three-dimensional clusters of uniform cuboidal cells with a round or oval nucleus (Papanicolaou stain.) Fig. 6.36 Germinoma. The malignant cells are large, with a round nucleus and a prominent nucleolus (Papanicolaou stain) ■■■【7】Gastrointestinal Fig. 7.1 Candida (Esophageal Brushings). Infection by Candida species is recognized by identifying ovoid yeast forms, elongated pseudohyphae, or both (Thin Prep, Papanicolaou stain) Fig. 7.2 Herpes Simplex Infection (Esophageal Brushings). (A) Multinucleation, molding of nuclei, mar- gination of chromatin to the periphery of the nucleus, and a ground-glass chromatin pattern are diagnostic features (ThinPrep, Papanicolaou stain). (B) Some nuclei have a Cowdry A type inclusion (arrow) (ThinPrep, Papanicolaou stain) Fig. 7.3 Repair and Reactive Changes. (A) Repair (gastric brushings). A slight flowing or streaming pattern is noted. The cells have enlarged pale nuclei with regular nuclear borders, finely dispersed chromatin, and one or more prominent nucleoli. Mitoses are present (arrow) (smear, Papanicolaou stain). (B) Reactive Changes (esophageal brushings). Nuclei are enlarged but round and regular, with prominent nucleoli. There is nuclear crowding, but polarity is maintained, and the cells are cohesive (smear, Papanicolaou stain) Fig. 7.4 Radiation-Induced Changes (Esophageal Brushings). Cellular and nuclear enlargement, multinucleation, and vacuolization of cytoplasm are characteristic (ThinPrep, Papanicolaou stain) Fig. 7.5 Barrett's Epithelium with Goblet Cells. A single large cyto- plasmic vacuole expands the apical portion of the cytoplasm and dis- places the nucleus, shaping it into a crescent against the basal cell membrane (ThinPrep, Papanicolaou stain) Fig. 7.6 Low-Grade Dysplasia in Barrett's Epithelium. (A) This columnar epithelium is notable for mucin depletion, an increased nuclear-to-cytoplasmic ratio, and marked nuclear crowding, but there is little nuclear atypia (smear, Papanicolaou stain). (B) Nuclear crowding and stratification are prominent, and there is focal loss of nuclear polarity in this strip of low-grade dysplasia (Thin Prep, Papanicolaou stain) Fig. 7.7 High-Grade Dysplasia in Barrett's Epithelium. Irregularly aggregated, crowded cells with enlarged nuclei of varying sizes are present without evident necrosis. The findings are suspicious for malig- nancy, but the biopsy showed only high-grade dysplasia (ThinPrep, Papanicolaou stain) Fig. 7.8 Adenocarcinoma of the Esophagus. The findings are similar to those in Fig. 7.7, but the abnormal cells were more numer- ous, and dyshesion was prominent elsewhere on the slide (ThinPrep, Papanicolaou stain) Fig. 7.9 Well-Differentiated SQC of the Esophagus. Two spindled- shaped, keratinized malignant squamous cells with dense orange cytoplasm and hyperchromatic nuclei show markedly abnormal chro- matin distribution. Degenerated cells with pyknotic nuclei are in the background (Thin Prep, Papanicolaou stain) Fig. 7.10 Poorly Differentiated SQC of the Esophagus. Squamous differentiation is not discernible in this group of cells with scant cyto- plasm. The nuclei show markedly abnormal chromatin distribution and prominent nucleoli (ThinPrep, Papanicolaou stain) Fig.7.11 Leiomyoma of the Esophagus. (A) The cells have spindle-shaped nuclei (Thin Prep, Papanicolaou stain). (B) Cell block sections reveal abundant eosinophilic cytoplasm (hematoxylin and eosin stain). (C) Leiomyomas are strongly and diffusely immunoreactive for desmin. (D) Leiomyomas may contain scattered interstitial cells of Cajal-bipolar cells with long, slender cytoplasmic processes (DOG1 Immunostain) Fig. 7.12 Helicobacter Pylori (Gastric Brushings). Numerous faintly basophilic S-shaped rods are entrapped in mucus (smear, Papanicolaou stain) Fig. 7.13 Atypical Mycobacteria (Duodenal Brushings). An isolated histiocyte with abundant foamy cytoplasm is present. The presence of numerous acid-fast bacilli was confirmed with the acid-fast stain (smear, Papanicolaou stain) FIG. 7.14 Signet-Ring Cell Carcinoma (Gastric Brushings). Signet- ring carcinoma cells resemble histiocytes because of their vacuoliza- tion, but the nuclei are too large and nucleoli too prominent (ThinPrep, Papanicolaou stain) FIG. 7.15 Well-Differentiated Neuroendocrine (Carcinoid) Tumor (Duodenal Brushings). The monomorphic cells have a moderate amount of cytoplasm and a salt-and-pepper chromatin pattern. A few cells have a plasmacytoid appearance (smear, Papanicolaou stain) Fig. 7.16 Diffuse Large B-Cell Lymphoma (Endoscopic FNA of a Gastric Mass). Scattered isolated large atypical cells with scant cyto- plasm are seen. The nuclei have vesicular chromatin with one or a few prominent nucleoli. Necrotic debris and apoptotic bodies are present in the background (smear, toluidine blue and eosin stain) Fig.7.17 Lymphoma of Mucosa-Associated Lymphoid Tissue Type (Gastric Brushings). Scattered monomorphic lymphocytes are seen, without intermixed neutrophils or plasma cells (smear, Papanicolaou stain) Fig. 7.18 GIST (Ultrasound-Guided Endoscopic Fine-Needle Aspiration of a Gastric Mass). (A) The cells have an oval or elongated nucleus with finely textured chromatin and inconspicuous nucleoli (smear, Papanicolaou stain). (B) The cells are immunoreactive for c-kit, with some showing a characteristic dot-like cytoplasmic pattern (arrow) Fig.7.19 Microsporidia. Aggregates of tiny, brightly eosinophilic rod- shaped or ovoid organisms are seen in the apical portion of glandular epithelial cells (Thin Prep, Papanicolaou stain) Fig. 7.20 Cryptosporidia (Gastric Brushings). Small round baso- philic bodies dot the surface of glandular epithelial cells (smear, Papanicolaou stain) Fig. 7.21 Ampullary Adenoma. (A) Brushings show strips of dysplastic epithelium notable for crowded nuclei, mucin depletion, and an increased nuclear-to-cytoplasmic ratio. Some nuclei have drifted from their basal location toward the cell apex (i.e., there is loss of polarity). Although the nuclei are enlarged and elongated, they are relatively uniform in size, and nucleoli are inconspicuous (Thin Prep, Papanicolaou stain). (B) The same cytomorphologic features are recapitulated in the ampullary mass biopsy (hematoxylin and eosin stain) Fig. 7.22 High-Grade Squamous Intraepithelial Lesion (Anal Pap). Cells show nuclear enlargement, nuclear membrane irregular- ity, and coarse chromatin, analogous to the changes seen in cervical specimens (Thin Prep, Papanicolaou stain) ■■■【8】FNA technique Fig. 8.1 FNA Equipment. The syringe holder (A) and other items (B) are small enough to fit into a basket. They can be quickly assembled on a small amount of counter space. (B and C courtesy Sara Monaco, MD, University of Pittsburgh Medical Center, Shadyside Hospital.) Fig. 8.2 The "One-Smear" Preparation Method. (A) A single smear is made by applying a spreader slide perpendicular to the slide with the aspirated material and (B) rotating the spreader slide until (C) it comes in contact with the bottom slide and slightly compresses the expelled material. (D) The spreader slide is gently and quickly pulled back, maintaining contact with the bottom slide Fig. 8.3 The "Two-Smear" Preparation Method. (A) Two identical smears are made by holding the slide that has the specimen horizontally, with its frosted side up. A second slide is positioned over it, frosted side down. (B) The two slides are gently pressed together to compress the material. (C) The slides are smoothly pulled apart Fig. 8.4 Splitting Abundant Material for Multiple Smears. (A) One edge of the spreader (top) slide engages the bottom slide containing the aspirated material at right angles, below the level of the aspirated droplet. (B) The spreader slide is lowered (rotated) until it contacts the bottom slide and slightly com- presses the expelled material. (C) The two slides are separated. Some material will have transferred to the spreader slide. (D) After setting aside the first bottom slide, a clean slide is picked up and the spreader slide engaged at right angles to the clean, bottom slide. (E) A is smear made by rotating (lowering) the spreader slide until it contacts the bottom slide and compresses the material. (F) The spreader slide is smoothly pulled back over the material. This process can be repeated to make multiple smears Fig. 8.5 Retrieving Material from the Needle Hub. (A) The needle is detached from the syringe and pushed into a needle safety device or rubber top of a blood draw tube. (B) The needle hub is positioned over the middle of a glass slide. (C and D) The hub is lifted and dropped repeatedly onto the slide while the blood draw tube is rocked side to side in a coordinated fashion Fig. 8.6 Rapid on-site evaluation allows appropriate triage of the material for ancillary studies. FISH, Fluorescence in situ hybridization. (Modified figure courtesy Sara Monaco, MD, University of Pittsburgh Medical Center, Shadyside Hospital.) Fig. 8.7 Vacuum Suction Without a Syringe Holder. Suction can be created without a syringe holder by pulling the plunger back with the thumb (A) or the index finger (B) Fig. 8.8 Ultrasound-Guided Fine Needle Aspiration, Perpendicular Technique. (A) Operator's view- point: the hand holding the ultrasound probe can be stabilized by resting the third, fourth, and fifth fingers and/or wrist on the patient's body. The needle entry point into the body is 0.5 to 1.0 cm from the edge of the probe. (B) The needle tip appears as a bright dot on the screen (arrow). (C) Once the needle is in the nodule, vacuum is generated in the syringe and sampling begins Fig. 8.9 Ultrasound-Guided Fine Needle Aspiration, Parallel Technique. (A) Operator's viewpoint: the hand holding the ultrasound probe can be stabilized by resting the wrist on the patient's body. The needle entry point is 0.5 to 1.0 cm from the edge of the probe. (B) The needle tip and shaft are visualized on the screen (arrows). (C) Once the needle is in the nodule, the plunger is withdrawn to generate suction and sampling begins ■■■【9】Breast Fig. 9.1 Nipple Discharge Cytology. (A) Benign nipple discharge. Histiocytes (foam cells) have a kidney bean-shaped nucleus and abundant vacuolated cytoplasm (Papanicolaou stain). (B) Suspicious nipple discharge. The sample contains very atypical cells with enlarged nuclei. The subsequent biopsy showed a high-grade comedocarcinoma (Papanicolaou stain) Fig. 9.2 Apocrine Metaplasia. Apocrine cells have distinct cytoplasmic borders, a centrally located nucleus, and a prominent nucleolus. The abundant granular cytoplasm is gray-purple with a Romanowsky- type stain (A) and green with the Papanicolaou stain (B) Fig. 9.3 Benign Ductal Epithelium (Nonproliferative Fibrocystic Changes). A tightly cohesive cluster of ductal epithelial cells without atypia is noted adjacent to apocrine metaplastic cells (Papanicolaou stain) Fig. 9.4 Granular Cell Tumor. Tumor cells have a low nuclear-to- cytoplasmic ratio because of an abundance of granular cytoplasm (hematoxylin and eosin stain) Fig. 9.5 Ductal Proliferative Lesion Without Atypia. Note the inter- spersed myoepithelial cells, which stand out like sesame seeds on a bun (Papanicolaou stain) Fig. 9.6 Ductal Proliferative Lesion with Atypia. In contrast to Fig. 9.5, there is less regular nuclear spacing, more overlapping, and more prominent nuclear atypia, with a suggestion of cribriform spaces. Such proliferative lesions cannot be categorized precisely by fine-needle aspiration. Histologic examination revealed atypical ductal hyperpla- sia bordering on noncomedo ductal carcinoma in situ (Papanicolaou stain) Fig. 9.7 Suspicious for Malignancy. The cells are loosely cohesive, with marked nuclear pleomorphism, prominent nucleoli, and a dirty background. Such specimens cannot be distinguished from invasive carcinoma by fine-needle aspiration. Histologic examination revealed comedo-type ductal carcinoma in situ (Papanicolaou stain) Fig. 9.8 Fibroadenoma, Low Magnification. The specimen is hypercel- lular, with many folded sheets and antler-horn clusters (Papanicolaou stain) Fig.9.9 Fibroadenoma. (A) Branching antler-horn clusters are the predominant arrangement of cells. There are rare stripped naked nuclei and bipo- lar cells in the background, but they are not prominent in this case, making it difficult to distinguish from a ductal proliferative process (Romanowsky stain). (B) Clusters of tightly cohesive cells with minimal nuclear atypia are characteristic of fibroadenomas (Romanowsky stain) Fig. 9.10 Fibroadenoma. Clusters of epithelial cells in a background of numerous stripped, elongated naked nuclei are characteristic of fibroadenomas. When stromal cells are absent, the diagnosis is more difficult (Papanicolaou stain) Fig. 9.11 Fibroadenoma. Note the presence of nuclear atypia and prominent nucleoli. The tightness of the cluster is an important clue for avoiding an overdiagnosis of malignancy (Papanicolaou stain) Fig. 9.12 Pregnancy/Lactation. (A) Numerous stripped ("naked") nuclei are seen. (B) Cells in loose clusters can also be seen. Nuclei are round or oval, with prominent nucleoli (Thin Prep, Papanicolaou stain) Fig. 9.13 Fat Necrosis. Necrotic fat is recognized by the absence of fat cell nuclei. In the early stage there is neutrophilic infiltration, as seen here; later stages demonstrate numerous foamy macrophages (lipo- phages) (Papanicolaou stain). (Courtesy Dr. Andrew Field, St. Vincent's Hospital, Sydney, Australia.) Fig. 9.14 Cryptococcal Infection. There are numerous intracellular yeast forms within macrophages (hematoxylin and eosin stain) Fig. 9.15 Lipid-Rich Carcinoma. The cells are finely vacuolated and resemble histiocytes, but there is nuclear atypia and an increased nuclear-to-cytoplasmic ratio (Papanicolaou stain) • Fig. 9.16 Radiation Change. The cells show pronounced nuclear enlargement with concomitant cytomegaly. The nuclear-to-cytoplas- mic ratio is thus maintained (ThinPrep, Papanicolaou stain) Fig. 9.17 Recurrent Carcinoma after Radiation Treatment. In con- trast to Fig. 9.16, the nuclei are irregular in contour, and the nuclear-to- cytoplasmic ratio is increased (ThinPrep, Papanicolaou stain) Fig. 9.18 Gynecomastia. Cohesive flat sheets are identical to those of fibroadenoma and ductal proliferative processes (Papanicolaou stain) Fig. 9.19 Atypical Papillary Neoplasm. An excisional biopsy showed that this lesion was an intraductal papilloma. Note the complex branch- ing structure (Papanicolaou stain) Fig. 9.20 Suspicious Papillary Neoplasm. In contrast to Fig. 9.19, this lesion proved to be a papillary carcinoma. They are very similar cytologically; the definitive diagnosis is best deferred to an excisional biopsy (Papanicolaou stain) Fig. 9.21 Invasive Micropapillary Carcinoma. Well-differentiated neoplasms like this invasive micropapillary carcinoma can be very dif- ficult to diagnose (Thin Prep, Papanicolaou stain) Fig. 9.22 Phyllodes Tumor. (A) Similar cytologically to a fibroadenoma, a phyllodes tumor has greater cellularity. (B) The difference between stromal and epithelial cells is subtle and can be obscured in a liquid- based preparation (ThinPrep, Papanicolaou stain) Fig. 9.23 Phyllodes Tumor. (A) Epithelial clusters in a phyllodes tumor resemble those of fibroadenoma but may be more crowded (Romanowsky stain). (B) Stromal clusters can be very cellular (Papanicolaou stain) Fig. 9.24 Phyllodes Tumor. Very atypical stromal and epithelial cells are noted. The background is necrotic. Although cytologically more alarming than the lesion in Fig. 9.23, this tumor was benign, and the previous one was malignant (Thin Prep, Papanicolaou stain) Fig. 9.25 Ductal Carcinoma. A major criterion for the diagnosis of ductal carcinoma is a highly cellular specimen. Even at low magnifica- tion, nuclear atypia is prominent (Romanowsky stain) Fig. 9.26 Ductal Carcinoma. The specimen is very cellular, and the cells are dispersed both as isolated cells and as loosely cohesive clus- ters (Papanicolaou stain) Fig. 9.27 Ductal Carcinoma. Many of the isolated cells of ductal cancers are comet-shaped, with a nucleus that protrudes from the cytoplasm. Whether or not there is marked nuclear atypia, a protu- berant nucleus suggests carcinoma (Thin Prep, Papanicolaou stain) Fig. 9.28 Ductal Carcinoma. Note the pronounced nuclear pleomorphism and atypia, apparent with both the Romanowsky (A) and Papanicolaou (B) stains Fig. 9.29 Ductal Carcinoma. The tumor cells are buried in a back- ground of marked acute inflammation. In samples with abundant acute inflammation, a careful search must be conducted to exclude malig- nant cells (Papanicolaou stain) Fig. 9.30 Lobular Carcinoma. (A) A loose, single-file arrangement is apparent. (B) Large, solitary intracy- toplasmic vacuoles are present, imparting a signet-ring cell appearance (Papanicolaou stain) Fig. 9.31 Lobular Carcinoma in Situ. The cells are present in loosely cohesive sheets (Papanicolaou stain) Fig. 9.32 Lobular Carcinoma in Situ. In contrast with Fig. 9.31, the cells are dispersed, and signet-ring cell forms are noted. Such a case is likely to be overdiagnosed as invasive lobular carcinoma (Papanicolaou stain) Fig. 9.33 Medullary Carcinoma. The cells are very large, with promi- nent nucleoli and frequent mitoses (hematoxylin and eosin stain) Fig. 9.34 Medullary Carcinoma. Lymphocytes and plasma cells are often noted in the background (hematoxylin and eosin stain) Fig. 9.35 Mucinous Carcinoma. At low magnification, numerous tightly cohesive clusters are dispersed in a mucinous background (Papanicolaou stain) Fig. 9.36 Mucinous Carcinoma. Branching capillary structures in a mucinous background suggest the diagnosis (arrows). Isolated cells can be seen in addition to cellular balls (Papanicolaou stain) Fig. 9.37 Mucinous Carcinoma. At higher magnification, the low- grade, round, regular nuclei are noted (Papanicolaou stain) ·Fig. 9.38 Tubular Carcinoma. Cells in tightly cohesive clusters often have rigid borders. Nuclear atypia is minimal, and isolated cells are usually not seen (Papanicolaou stain) Fig. 9.39 Tubular Carcinoma. Clusters of cells typically come to a sharp point (comma or cornucopia formations). By contrast, fibroadenomas tend to have more rounded and less rigid outlines (Papanicolaou stain) Fig. 9.40 Metaplastic Carcinoma. Isolated highly atypical spindle cells are noted (Romanowsky stain) Fig. 9.41 Apocrine Carcinoma. A variant of ductal carcinoma, apo- crine carcinoma is also typified by marked cellularity, nuclear atypia, and many isolated cells (Papanicolaou stain) Fig. 9.42 Apocrine Carcinoma. Note the abundant granular cyto- plasm, pronounced nuclear atypia, and prominent nucleoli, which are round and centrally located (Papanicolaou stain) Fig. 9.43 Adenoid Cystic Carcinoma. Tightly cohesive clusters of cells with round, uniform nuclei are noted. Basement membrane globules (arrows) are pale with the Papanicolaou stain (ThinPrep, Papanicolaou stain) Fig. 9.44 Adenoid Cystic Carcinoma. The basement membrane globules (arrows) appear as pale areas within dense cell clusters (ThinPrep, Papanicolaou stain) Fig. 9.45 Adenoid Cystic Carcinoma. Nuclear immunoreactivity for p63 is a useful adjunct test when considering this diagnosis (ThinPrep) Fig. 9.46 Postradiation Angiosarcoma. (A) Very atypical isolated cells are noted, some with a cell-in- cell pattern (Papanicolaou stain). (B) The cells are round to spindle-shaped, with an eccentric nucleus and prominent nucleolus (Romanowsky stain; case courtesy Dr. James E. Orr, Presence Resurrection Medical Center, Chicago, IL.) Fig. 9.47 Breast Implant-Associated Anaplastic Large Cell Lymphoma. (A) Large atypical lymphoid cells have prominent nucleoli (cytocentrifuge preparation, Romanowsky stain). (B) The excised implant reveals neoplastic cells surrounding the capsule (hematoxylin and eosin stain) Fig. 9.48 Metastatic Squamous Cell Carcinoma. (A) The loosely cohesive aggregate of markedly atypi- cal cells resembles a poorly differentiated breast carcinoma (Papanicolaou stain). (B) Malignant keratinized squamous cells raise the possibility of an extramammary tumor. This was a metastasis from a squamous carcinoma of the vulva (Papanicolaou stain) Fig. 9.49 Metastatic Small Cell Carcinoma of the Lung. Metastatic small cell carcinoma might be mistaken for lobular carcinoma, but there is greater nuclear atypia and pleomorphism, less cytoplasm, and very pronounced nuclear molding. (A) Papanicolaou stain. (B) Romanowsky stain ■■■【10】Thyroid Fig. 10.1 (A) Transverse sonogram of a thyroid nodule. The tip of a needle (thin arrows) is in the middle of a nodule (large arrow). (Courtesy Dr. Carol Benson, Brigham and Women's Hospital, Boston, Massachusetts, USA.) (B) Ultrasound gel. Ultrasound gel has a purple, mesh-like or spiderweb-like appearance. If not wiped off the skin before aspiration, it can cover large areas of the slide surface and interfere with cellular evaluation (Papanicolaou stain) Fig. 10.2 Macrophages. These cells have abundant cytoplasm that may be filled with hemosiderin or red blood cell fragments. They are a nonspecific finding, seen in both benign and malignant thyroid nodules (Papanicolaou stain) Fig. 10.3 Benign Follicular Nodule. (A) The fine-needle aspirate contains tissue fragments containing intact macrofollicles (Papanicolaou stain). (B) Macrofollicles often break into fragments and appear as sheets of various sizes. Although colloid is scant in this case, a predominantly macrofollicular architecture can be inferred from these fragments (Papanicolaou stain) Fig. 10.4 Benign Follicular Nodule. (A) The follicular cells comprising this unfolded macrofollicle are evenly spaced. Pale green-blue colloid has escaped from the follicle (Papanicolaou stain). (B) Normal follicular cells Fig. 10.5 Colloid (Benign Follicular Nodule). Colloid can congeal into opaque, irregularly shaped hyaline chunks with hard edges that are clearly visible on smears and liquid-based preparations (Papanicolaou stain) Fig. 10.6 Colloid (Benign Follicular Nodule). (A) On smears, watery colloid often covers the entire slide as a thin, translucent film (pink in this image) and is often admixed with blood (Papanicolaou stain). (B) On liquid-based preparations, watery colloid appears as torn, translucent sheets resembling tissue paper (Papanicolaou stain) Fig. 10.7 Focal Hürthle Cell Metaplasia, Multinodular Goiter. Hürthle cells are a common finding in some cases of multinodular goiter. The cells are large and polygonal and have abundant, finely granular cytoplasm. Variation in nuclear size, as seen here, is common in nonneoplastic Hürthle cell proliferations and does not signify neoplasia (Papanicolaou stain) Fig. 10.8 Cyst Lining Cells. Reactive follicular cell changes are often seen adjacent to areas of cystic degeneration. They have a characteristic pulled-out appearance that mimics reparative epithelium (Papanicolaou stain) Fig. 10.9 Chronic Lymphocytic (Hashimoto) Thyroiditis. (A) Lymphoid cells are the predominant fea- ture. Most are small, mature lymphocytes (Papanicolaou stain). (B) The heterogeneity of the lymphoid cells is better appreciated with air-dried preparations (Romanowsky stain) Fig. 10.9, cont'd (C) Dendritic-lymphocytic aggregates are often present. Dendritic cells have a large vesicular nucleus and conspicuous nucleolus (arrow) (Papanicolaou stain). (D) Hürthle cells with abundant cytoplasm are usually identified in clusters. Note the scattered lymphoid cells (Romanowsky stain) Fig. 10.10 Subacute Thyroiditis. (A) The most conspicuous finding is an abundance of multinucleated giant cells with bizarre shapes (Papanicolaou stain). (B) Granulomas are often few in number. The nuclei of epithelioid histiocytes have a variety of elongated and curved shapes. Cytoplasm is abundant, clear, and poorly demarcated (Papanicolaou stain) Fig. 10.11 Amyloid Goiter. Like colloid, amyloid forms opaque masses with irregular, sharp edges. Amyloid is deposited in the interstitium in patients with amyloid goiter; hence, aspirated amyloid fragments often contain entrapped fibroblasts (Papanicolaou stain) Fig. 10.12 Black Thyroid. Follicular cells contain abundant coarse, brown cytoplasmic granules (Papanicolaou stain) Fig. 10.13 Radioactive lodine Effect. Follicular cells show marked variation in cellular and nuclear size, sometimes with conspicuous cytoplasmic vacuolization (Papanicolaou stain) Fig. 10.14 Suspicious for a Follicular Neoplasm. (A) A neoplasm should be suspected whenever a specimen is composed predominantly of microfollicles (Papanicolaou stain). (B) The cells of some follicular neoplasms are crowded haphazardly into cords or ribbons (trabeculae) (Papanicolaou stain) Fig. 10.15 Suspicious for a Follicular Neoplasm, Hürthle Cell Type. The sample is at least moderately cellular and composed exclusively of Hürthle cells (Papanicolaou stain) Fig. 10.16 Mimics of a Hürthle Cell Neoplasm. (A) Metastatic renal cell carcinoma to the thyroid. The abundant cytoplasm of clear cell renal cell carcinomas mimics that of a Hürthle cell neoplasm, but it is thinner and more fragile-appearing than Hürthle cell cytoplasm (Papanicolaou stain). (B) Parathyroid carcinoma. Some parathyroid neoplasms have abundant oncocytic cytoplasm. The patient presented with hyperparathyroidism; a positive immunostain for parathyroid hormone on the cell block preparation was helpful for diagnosis (Papanicolaou stain) Fig. 10.17 Papillary Thyroid Carcinoma, Classical Type. In classical papillary thyroid carcinoma, papillae with fibrovascular cores are often seen (Papanicolaou stain) • Fig. 10.18 Papillary Thyroid Carcinoma, Classical Type. In some cases, papillae are absent, and the neoplastic cells are arranged in crowded sheets. Psammoma bodies are present (Papanicolaou stain) Fig. 10.19 (A) Papillary thyroid carcinoma, follicular variant. (B) Follicular neoplasm (follicular ade- noma). Some papillary carcinomas are comprised entirely of microfollicles and mimic a follicular neoplasm, but the pale chromatin of a papillary carcinoma (A) is different from the coarse chromatin granularity of a follicular neoplasm (B) (Papanicolaou stain) Fig. 10.20 Papillary Thyroid Carcinoma. The neoplastic cells have pale, powdery chromatin. Other important nuclear changes are the circular, sharply defined intranuclear pseudoinclusion (arrow) and the nuclear groove (arrowhead). Note that the pseudoinclusion has the same color and consistency as the surrounding cytoplasm; a purely white hole is usually an artifact (Papanicolaou stain) Fig. 10.21 Papillary Thyroid Carcinoma Variants. (A) Oncocytic variant. The neoplastic cells of this variant have abundant granular cytoplasm resembling Hürthle cell cytoplasm. Note the intranuclear pseu- doinclusions (holes) (Papanicolaou stain). (B) Tall cell variant. The cells are large and have abundant elon- gated ("tall") cytoplasm. Nuclear features typical of papillary carcinoma, including numerous intranuclear holes, are apparent (Papanicolaou stain) Fig. 10.22 Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP). (A) NIFTP is often a predominantly microfollicular proliferation. Nuclear features of papillary carcinoma are incomplete or only focally present (inset). This FNA was interpreted as suspicious for papillary carcinoma. (B) The resected nodule shows good demarcation from the surrounding thyroid (hematoxylin and eosin stain) Fig. 10.23 Poorly Differentiated Thyroid Carcinoma. (A) The architectural pattern is variable and may include crowded groups, microfollicles, and numerous isolated cells. The isolated malignant cells resemble those of medullary thyroid carcinoma (Papanicolaou stain). (B) Some tumors have a greater degree of nuclear atypia (Papanicolaou stain) Fig. 10.24 Anaplastic Thyroid Carcinoma. (A) Tumor cells are dispersed as isolated epithelioid cells. Nuclei are large and hyperchromatic, and multinucleated tumor giant cells are present (Papanicolaou stain). (B) Some tumors have a predominantly sarcomatoid appearance (Romanowsky stain) Fig. 10.25 Primary Thyroid Lymphomas. (A) Diffuse large B-cell lymphoma. The large dispersed cells can mimic an anaplastic carcinoma. Lymphoglandular bodies are helpful and point to a lymphoid rather than epithelial neoplasm (Romanowsky stain). (B) Hodgkin lymphoma. Reed-Sternberg cells can be prominent and mimic the cells of anaplastic carcinoma (Papanicolaou stain) Fig. 10.26 Squamous Cell Carcinoma. A pleomorphic malignancy in the thyroid that is comprised of keratinized cells is considered a squamous cell carcinoma, but it has the same clinical behavior as an anaplastic carcinoma (Papanicolaou stain) Fig. 10.27 Medullary Thyroid Carcinoma. (A) Smears show numerous isolated cells and small blobs of amyloid (arrows) (Papanicolaou stain). (B) Air-dried Romanowsky-stained preparations show fine red cyto- plasmic granules, a helpful diagnostic feature. (C) Some medullary carcinomas have prominent intranuclear pseudoinclusions (Papanicolaou stain). (D) The malignant cells are strongly immunoreactive for calcitonin Fig. 10.28 Extranodal Marginal Zone B-Cell Lymphoma of the Thyroid. The neoplastic lymphoid cells are uniformly small to medium-sized, and there's a prominent population of cells with irregularly shaped nuclei and prominent nucleoli (Papanicolaou stain) Fig. 10.29 Atypia of Undetermined Significance. (A) Cytologic atypia. The follicular cell nuclei are enlarged and irregular in contour, but precise classification is challenging because of obscuring blood and clotting elements (Papanicolaou stain). (B) Architectural atypia. This sample is comprised mostly of microfollicles but is sparsely cellular and thus does not fulfill criteria for "suspicious for a follicular neoplasm" (Papanicolaou stain) Fig. 10.30 Parathyroid Adenoma. Smears are often highly cellular, and the cells are arranged in groups that resemble microfollicle fragments or, as see here, trabeculae. Colloid is absent (hematoxylin and eosin stain) ■■■【11】Salivary gland Fig. 11.1 Salivary Gland Crystalloids. (A) Tyrosine crystalloids are clustered in flower-like arrangements (hematoxylin-eosin stain). (B) Amylase crystalloids, needle-shaped or plate-like, are occasionally encoun- tered in salivary gland FNAS, usually in association with inflammatory conditions (Romanowsky stain; cour- tesy Dr. David Kaminsky, Palm Springs Pathology Services, Palm Springs, CA) Fig. 11.2 Normal Salivary Gland. (A) Normal acinar cells are aggregated in grape-like bunches (arrow) with admixed adipose tissue and an occasional flat sheet of ductal cells (arrowheads; Romanowsky stain). (B) Acinar cells have a round nucleus and abundant microvacuolated cytoplasm (Papanicolaou stain) Fig. 11.3 Sialolithiasis with Acute Sialadenitis. Stone fragments (arrow)-blue, irregularly shaped, jagged structures of varying sizes-are diagnostic of sialolithiasis. The presence of numerous neutrophils signifies an accompanying acute sialadenitis (Romanowsky stain) Fig. 11.4 Chronic Sialadenitis. (A) Sparsely cellular preparations show clusters of basaloid ductal cells that resemble the cells of a basaloid neoplasm. Granular debris and lymphocytes (some crushed) are scat- tered in the background (Papanicolaou stain). (B) A histologic specimen shows marked fibrosis, chronic inflammation, acinar atrophy, and residual ductal elements (hematoxylin and eosin stain) Fig. 11.5 Lymphoepithelial Sialadenitis. (A) Lymphoid cells, predominantly small lymphocytes, are usually abundant (Papanicolaou stain). (B) Lymphoepithelial islands are characteristic, composed of reactive epithelial cells in sheets admixed with lymphocytes (Papanicolaou stain) Fig. 11.6 Squamous Epithelial-Lined Cyst Compared with Squamous Cell Carcinoma. (A) A benign squamous-lined epithelial cyst contains nucleated and anucleate squamous cells with minimal nuclear atypia. These findings are nonspecific (Papanicolaou stain). (B) In contrast, keratinizing squamous cell carcinoma has marked nuclear atypia, bizarre cell shapes, and necrosis (Papanicolaou stain) Fig. 11.7 Mucus-Containing Cyst. Extracellular mucin, with or without histiocytes, is a nonspecific finding. This example proved to be a mucocele, but identical findings can be seen in a low-grade mucoepidermoid carcinoma (Romanowsky stain) Fig. 11.8 Pleomorphic Adenoma. (A) Pale-blue matrix, embedded spindle-shaped myoepithelial cells, and tubules of ductal cells are identified at low power (Papanicolaou stain). (B) Air-dried preparation accen- tuate the matrix, which stains a bright magenta and has a characteristic fibrillar texture with frayed edges ("troll hair"). Isolated plump spindle-shaped and plasmacytoid myoepithelial cells are scattered about (Romanowsky stain) Fig. 11.9 Pleomorphic Adenoma with Adenoid Cystic-Like Foci. (A) A lucent cylinder is present in a background of myoepithelial cells (Papanicolaou stain). (B) Immunocytochemistry can resolve uncertainty in challenging cases. This cell block preparation from a pleomorphic adenoma shows nuclear overexpression of PLAG1 Fig. 11.10 Pleomorphic Adenomas with Atypia. (A) There is marked nuclear size variation in an other- wise typical pleomorphic adenoma (Romanowsky stain). (B) A cell block reveals scattered cells with an enlarged nucleus and prominent nucleolus (hematoxylin and eosin stain). When few and far between, such cells are not concerning for malignancy. More extensive atypia, as in these cases, merits the interpretation "pleomorphic adenoma with atypia." Fig. 11.11 Myoepithelial Cell-Rich Neoplasms. (A) Loosely cohesive, spindle-shaped myoepithelial cells are the sole constituents of this aspirate. (B) A cell block from a different case shows an exclusive population of plump myoepithelial cells with eosinophilic cytoplasm (hematoxylin and eosin stain). (Inset) HMGA2 immunoreactivity on a cell block preparation distinguishes a myoepithelial-rich pleomorphic adenoma from other spindle cell neoplasms Fig. 11.12 Basaloid Neoplasms. (A) There is a pure population of uniform basaloid cells: "basaloid" because of their scant cytoplasm. A more specific interpretation than basaloid neoplasm is not pos- sible (Romanowsky stain). (B) A lattice-like network of basaloid cells surrounds coalescing extracellular matrix globules. This pattern is nonspecific and seen in a variety of matrix-containing basaloid neoplasms (Romanowsky stain). Histologic examination of both specimens revealed a basal cell adenoma Fig. 11.13 Basal Cell Adenoma, Membranous Type. (A) Clusters of basaloid cells are surrounded by a ribbon ("cuticle") of dense aqua-colored matrix material (arrow; Papanicolaou stain). (B) The ribbon of matrix is better seen in this high magnification image (Papanicolaou stain) Fig. 11.14 Pilomatricoma. (A) This benign subcutaneous skin tumor often arises in the head and neck and is composed mostly of basaloid cells (Papanicolaou stain). (B) An important diagnostic clue is the presence of ghost cells, often present in large tissue fragments (hematoxylin and eosin stain) Fig. 11.15 Warthin Tumor. (A) Sheets of oncocytes are present in a background of lymphocytes and granular debris (Papanicolaou stain). (B) At higher power, the abundant smooth, dense cytoplasm is apparent. The cytoplasm would appear finely granular (rather than smooth and dense) with an alcohol- fixed preparation. There is abundant granular debris in the background, and many lymphocytes show smearing artifact (Romanowsky stain). (C) The cell block shows the characteristically bilayered oncocytic epithelium lining a core of small lymphocytes (hematoxylin and eosin stain). (D) Squamous metaplasia with reactive atypia might be mistaken for squamous cell carcinoma (Papanicolaou stain) Fig. 11.15, cont'd Fig. 11.16 Oncocytoma. (A) The oncocytes of an oncocytoma are often arranged as cords (trabeculae) of variable thickness, and the cords may show a branching pattern, as seen here. Note the absence of lymphocytes and granular debris, as compared with a Warthin tumor (Papanicolaou stain). (B) Oncocytes have a round to oval nucleus and abundant finely granular cytoplasm (Papanicolaou stain) Fig. 11.17 Low-Grade Mucoepidermoid Carcinoma (MEC). (A) In a low-grade MEC, abundant back- ground mucin is often seen. Compared with a mucocele (see Fig. 11.7), cellularity is typically greater, and mucus cells (arrows) and intermediate cells (arrowheads) predominate (Papanicolaou stain). (B) At high power, mucus cells and intermediate cells (arrowheads) are accompanied by lymphocytes. Note the wisp of extracellular mucin (Papanicolaou stain). (C) In this low-grade MEC, the mucus cells are more difficult to recognize (arrows) because of the more numerous intermediate cells (arrowheads). Note the abundance of lymphoid cells (Romanowsky stain). (D) A cell with both squamoid and mucinous features (arrow) is a characteristic finding (Papanicolaou stain) Fig. 11.17, cont'd Fig. 11.18 High-Grade Mucoepidermoid Carcinoma (MEC). In high-grade MEC, squamoid cells pre- dominate, as shown in these two different examples. Marked nuclear atypia is present. (A) Papanicolaou stain; (B) Romanowsky stain Fig. 11.19 Acinic Cell Carcinoma. (A) Thick masses of cells with acinar features cluster around blood vessels in a pseudopapillary fashion. Compared to the tight grape-like arrangement of normal acini (see Fig. 11.2), these cells form larger, expanded aggregates (Romanowsky stain). (B) Neoplastic cells have abundant delicate, granular cytoplasm and cytologically bland nuclei (Papanicolaou stain). (C) The loose arrangement of cells with abundant delicate, vacuolated cytoplasm can be appreciated (Romanowsky stain). (D) Acinic cell differentiation is often apparent in cell block preparations, which reveal the typical purple, granular cytoplasm of these cells (hematoxylin and eosin stain) Fig. 11.19, cont'd Fig. 11.20 Adenoid Cystic Carcinoma. (A) Numerous variably sized, magenta stromal spheres are evi- dent (Romanowsky stain). (B) With the Papanicolaou stain, the tumor cells are readily apparent, but the matrix material is pale and ghost-like (arrows, Papanicolaou stain). (C) The basaloid neoplastic cells are uniform in size (Papanicolaou stain). (D) The neoplastic cells are immunoreactive for MYB Fig. 11.20, cont'd Fig. 11.21 Adenoid Cystic Carcinoma. Basaloid cells surround spheres and finger-like projections of matrix, which has a "cookie-cutter"-like appearance due to its sharp edges (Romanowsky stain) Fig. 11.22 Adenoid Cystic Carcinoma, Solid Variant. Basaloid cells predominate in this aggressive variant. The identification of rare stromal spheres (arrow) is needed to make the diagnosis (Romanowsky stain) Fig. 11.23 Carcinoma Ex Pleomorphic Adenoma. (A) Carcinoma, typically high-grade, may be pre- dominantly myoepithelial as shown here. Residual pleomorphic adenoma is needed for definitive diagnosis but is often inapparent and only suggested by the presence of metachromatic stroma in the background (Romanowsky stain). (B) The distinction from other high-grade carcinomas like this myoepithelial carci- noma may be impossible but does not impact clinical management (Papanicolaou stain) Fig. 11.24 High-Grade Carcinoma (Salivary Duct Carcinoma). (A) Large, round nuclei with prominent nucleoli and nondescript cytoplasm are typical of a high-grade carcinoma (Papanicolaou stain). (B) A salivary duct carcinoma can be suspected when there is abundant necrosis (Romanowsky stain). (Inset) Strong nuclear staining for androgen receptor is characteristic of salivary duct carcinoma Fig. 11.25 Secretory Carcinoma. (A) Loosely cohesive cells have abundant vacuolated cytoplasm, a round nucleus, and a distinct nucleolus (Papanicolaou stain). (B) The cell block section reveals cribri- form architecture and intraluminal secretions (hematoxylin and eosin stain). (C) The tumor cells are immu- noreactive for mammaglobin. (D) Fluorescence in-situ hybridization is often performed with centromeric (green) and telomeric (red) probes that flank the ETV6 gene breakpoint. There is one normal chromosome (probes adjacent = yellow), but the split-apart green and red signals indicate a translocation on the other chromosome Fig. 11.26 Polymorphous Adenocarcinoma. (A) The neoplastic cells have a basaloid appearance and form large, sheet-like masses. Sharply circumscribed spheres of matrix are indistinguishable from those seen in adenoid cystic carcinoma (arrow) (Romanowsky stain). (B) The neoplastic cells have round to oval nuclei and lack atypia (Papanicolaou stain). (Case courtesy Dr. Luis Bettencourt Leça, Department of Pathology, Portuguese Oncology Institute, Porto, Portugal.) Fig. 11.27 Epithelial-Myoepithelial Carcinoma. (A) The neoplastic cells are crowded around vessels and dispersed in the background, many as bare nuclei. The majority are myoepithelial cells. Because the epithelial cells are less apparent, a biphasic population is not obvious. Note the finely dispersed gly- cogen in the background (Romanowsky stain). (B) The myoepithelial cells have clear, fragile cytoplasm (Papanicolaou stain) ■■■【12】Lymph node Fig. 12.1 Reactive Lymphoid Hyperplasia. Immunoblasts and plasmacytoid lymphocytes are inter- spersed throughout a smear dominated by small round lymphocytes, creating a polymorphous cell pic- ture. Lymphoglandular bodies are sprinkled between the cells (Romanowsky stain) Fig. 12.2 Reactive Lymphoid Hyperplasia. A capillary emanates diagonally from this follicular center fragment (dendritic-lymphocytic aggregate), which contains a mixture of dendritic cells and a hetero- geneous lymphocyte population. Note the dispersed lymphoglandular bodies (Romanowsky stain) Fig. 12.3 Reactive Lymphoid Hyperplasia. This dendritic-lymphocytic aggregate is a loose collection of small round lymphocytes and dendritic cells. The latter have pale nuclei with delicate cytoplasmic extensions (Papanicolaou stain) Fig. 12.4 Sarcoidosis. In sarcoidosis, the granulomas are tight aggregates of epithelioid histiocytes. The cells have oval or curved nuclei and abundant cytoplasm with indistinct borders (Romanowsky stain) Fig. 12.5 Acute Lymphadenitis. Neutrophils are mixed with small round lymphocytes. Note the chains of bacterial cocci (arrows) (Romanowsky stain) Fig. 12.6 Cat Scratch Disease. A discrete aggregate of epi- thelioid histiocytes is surrounded by large numbers of neutrophils (Romanowsky stain) Fig. 12.7 Mycobacterial Lymphadenitis. (A) There is necrotic material and degenerating nuclei (Romanowsky stain). (B) A stain for acid-fast bacilli shows many extracellular bacilli and a macrophage filled with organisms (Ziehl-Neelsen stain) Fig. 12.8 Rosai-Dorfman Disease. An enormous histiocyte has engulfed many small lymphocytes (Romanowsky stain) Fig. 12.9 Kikuchi Lymphadenitis. Histiocytes with contorted nuclei, including one with a C shape, contain ingested debris. These cells are significantly smaller than tingible-body macrophages (Romanowsky stain) Fig. 12.10 Infectious Mononucleosis. Many immunoblasts are mixed with small round lymphocytes and plasmacytoid lymphocytes (Romanowsky stain) Fig. 12.11 HIV Lymphadenitis. The FNA features are not specific, but HIV lymphadenitis can be sus- pected when (A) "giant" intact lymphoid follicles are seen (liquid-based preparation, Papanicolaou stain), and (B) numerous plasma cells and large lymphocytes are present (Romanowsky stain) in the appropriate clinical setting Fig. 12.12 Dermatopathic Lymphadenitis. (A) Several macrophages contain coarse granular pigment in this aspirate from an enlarged inguinal node adjacent to a large tattoo. A heterogeneous population of lymphocytes is also present (Romanowsky stain). (B) Macrophages containing melanin pigment are charac- teristic of dermatopathic lymphadenitis associated with primary inflammatory dermatoses. Nonpigmented histiocytes or dendritic cells and small lymphocytes are also seen (hematoxylin and eosin stain) Fig. 12.13 Silicone Lymphadenitis. This cluster of macrophages contains cells with multiple cytoplasmic vacuoles of varying size (liquid- based preparation, Papanicolaou stain) Fig. 12.14 Classic Hodgkin Lymphoma. (A) A classic binucleated Reed-Sternberg (RS) cell is present (Romanowsky stain). (B) Two conspicuous mononuclear RS cells are surrounded by lymphocytes. The RS nucleus at the right is lobulated, whereas the one to the left has only slight bosselation. Both have macronucleoli (Papanicolaou stain) Fig. 12.15 Nodular Lymphocyte Predominant Hodgkin Lymphoma. The characteristic cell is the LP or "popcorn" cell, which has a large, highly convoluted nucleus. Although there are two nice examples here, they are often difficult to find: one must hunt for them because they are vastly outnumbered by small lymphocytes and other nonneoplastic lymphoid cells (Romanowsky stain) Fig. 12.16 Follicular Lymphoma. (A) Note the nuclear irregularities and occasional clefted nucleus. Lymphoglandular bodies are numerous (Romanowsky stain). (B) FISH reveals a (14;18) translocation in the abnormal cell on the right. A green probe for IgH (immunoglobulin heavy chain) at 14q32 and a red probe for BCL2 at 18q21 come together to give a yellow signal when there is a translocation. Note that the green and red signals are far apart in the normal cell. (Dual color interphase fluorescence in situ hybrid- ization. Courtesy Paola dal Cin, PhD, Brigham and Women's Hospital, Boston, MA, USA). (C) Follicular lymphoma with signet-ring cells. Some cells have a single, large, optically clear cytoplasmic vacuole filled with immunoglobulin that create confusion with signet-ring-cell carcinoma (Romanowsky stain) Fig. 12.17 Marginal Zone Lymphoma. These small- and intermediate-size lymphocytes have irregu- lar nuclear contours, and occasional monocytoid cells are present (arrow). Lymphoglandular bodies are numerous (Romanowsky stain) Fig. 12.18 Small Lymphocytic Lymphoma. (A) The monomorphous neoplastic small lymphocytes have scant cytoplasm; some bare nuclei are present. The mostly round nuclei have very dense ("clotted") chro- matin. Lymphoglandular bodies are present in the background (Romanowsky stain). (B) "Soccer-ball-like" chromatin is more evident with alcohol-fixed smears. A few (large) paraimmunoblasts are also present (Papanicolaou stain) Fig. 12.19 Mantle Cell Lymphoma. (A) The smear shows an isomorphic population of small cells with round-to-oval nuclei and scant cytoplasm. Note the neutrophil at upper right for size comparison (Romanowsky stain). (B) FISH reveals a t(11;14) translocation in the abnormal cells on the right. A green probe for IgH (immunoglobulin heavy chain) at 14q32 and a red probe for the cyclin D1 gene come together to give a yellow signal when there is a translocation. Note that the green and red signals are far apart in the normal cells. (Dual color interphase fluorescence in-situ hybridization. Courtesy Paola dal Cin, PhD, Brigham and Women's Hospital, Boston, MA.) Fig. 12.20 Diffuse Large B-Cell Lymphoma (DLBCL). (A) A uniform population of lymphocytes with large, almost vesicular nuclei, obvious nucleoli, and a moderate amount of cytoplasm is admixed with neu- trophils and small lymphocytes (Papanicolaou stain). (B) By definition, the nucleus of DLBCL cells (black arrow) is at least the size of a histiocyte nucleus (black arrowhead on foam-cell nucleus); the background T-cell nuclei (red arrow) are much smaller (Romanowsky stain) Fig. 12.21 High-Grade B-Cell Lymphoma. A monomorphous popu- lation of intermediate-sized cells closely mimics Burkitt lymphoma; note the tingible-body macrophage at upper right. FISH evaluation showed both MYC and BCL2 translocations (not pictured) (Romanowsky stain) Fig. 12.22 Burkitt Lymphoma. (A) The intermediate-sized neoplastic lymphocytes have round nuclei, multiple indistinct nucleoli, blue cytoplasm, and small cytoplasmic vacuoles. Apoptotic bodies (arrows) are present (Romanowsky stain). (B) Detection of MYC translocation by FISH. Red and green fluorescent probes to regions flanking MYC are split apart. This occurs in all three of the common MYC transloca- tions. (Dual-color interphase fluorescence in situ hybridization. Courtesy Paola dal Cin, PhD, Brigham and Women's Hospital, Boston, MA.) Fig. 12.23 Plasmablastic Lymphoma. Large malignant cells are dis- persed in a noncohesive pattern. The eccentric position of the nucleus is the only "plasmacytic" feature. Because this image is virtually impos- sible to distinguish from a plasmablastic myeloma or melanoma, cor- relation with clinical history and ancillary testing are necessary for definitive diagnosis (Romanowsky stain) Fig. 12.24 Peripheral T-Cell Lymphoma, Unspecified. A picture of lymphocyte heterogeneity is pro- duced by this mixture of small, intermediate, and large cells. In other fields of the smear the large cells were more numerous, but taken in isolation this image is easily misinterpreted as representing reactive hyperplasia (Romanowsky stain) Fig. 12.25 Anaplastic Large Cell Lymphoma. Very large cells with marked variation in nuclear shape, including "donut" forms, are seen (Romanowsky stain) Fig. 12.26 Adult T-Cell Leukemia/Lymphoma. (A) The most distinctive cell is the floret cell, a large lymphocyte with multiple radiating nuclear lobes (Romanowsky stain), but (B) a wide range of neoplastic forms are typically seen, including large nucleolated cells (liquid-based preparation, Papanicolaou stain) Fig. 12.27 Lymphoblastic Lymphoma. A pure population of blasts is present with finely dispersed chromatin and nuclear molding. A mitotic figure is seen. Compare the size of the blasts with the neutrophil at the lower right (Romanowsky stain) Fig. 12.28 Posttransplant Lymphoproliferative Disorder, Polymorphic Type. (A) The smear shows a polymorphic population of small lymphocytes, plasmacytoid lymphocytes, plasma cells, and centrocytes (Romanowsky stain). (B) In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER), performed on cell block sections, shows a positive reaction in many of the lesional cells Fig. 12.29 Myeloid Sarcoma. (A) At low and medium magnification, blasts mimic lymphoma cells. Recognition of these cells as myeloid is often precluded when a tumor lacks cytoplasmic granules (Romanowsky stain). (B) Myeloid blasts are also difficult to identify as such with the Pap stain, even if they show characteristic (but nonspecific) folded nuclear membranes and dispersed chromatin (liquid-based preparation, Papanicolaou stain). (C) Blasts are more easily recognized with Romanowsky stains if the characteristic chromatin pattern, nucleoli, cytoplasmic granules (upper left), and accompanying granulo- cytic/eosinophilic forms are all present (Romanowsky stain) Fig. 12.30 Small Cell Carcinoma. When cell clusters are sparse and there is smearing of cell nuclei in a background of necrotic debris, the smears mimic lymphoma. Fragments of cytoplasm from necrotic cell "ghosts" masquerade as lymphoglandular bodies (Papanicolaou stain) Fig. 12.31 Merkel Cell Carcinoma. Meager cytoplasm and round nuclei with finely granular chromatin instead of nucleoli characterize these malignant cells. Smear background shows fragments of cells in various stages of necrosis that can be confused for large lymphoglandular bodies (Papanicolaou stain) Fig. 12.32 Human Papillomavirus (HPV)-Associated Squamous Cell Carcinoma. (A) The neoplastic cells form large crowded sheets of immature cells (Romanowsky stain). (B) Nuclei are round to oval, and cytoplasm is scant. Cell borders are indistinct and intercellular bridges are not apparent (Papanicolaou stain). (C) An immunostain for p16 shows positive nuclear and cytoplasmic staining. (D) In situ hybridization for HPV 16 and 18 RNA is positive Fig. 12.33 Nasopharyngeal Carcinoma. These neoplastic cells have a large round-to-oval nucleus, a large nucleolus, and abundant cytoplasm with indisctinct cell borders; small lymphocytes are in the back- ground (Papanicolaou stain). The malignant cells show nuclear staining for Epstein Barr virus-encoded ribonucleic acids by in situ hybridization (inset) Fig. 12.34 Malignant Melanoma. Large nonpigmented cells are distributed in a noncohesive pattern. Tiny cytoplasmic bubbles (best seen with Romanowsky stains) and binucleated cells with wide spacing between the mirror-image nuclei are clues to the diagnosis (Romanowsky stain) Fig. 12.35 Seminoma. Partially vacuolated detached strips of cyto- plasm create a striking "tigroid" background. Large germ cells are mixed with small lymphocytes (Romanowsky stain) Fig. 12.36 Follicular Dendritic Cell Sarcoma. Delicate cytoplasmic processes extend from these clustered cells with smooth, ovoid nuclei (Romanowsky stain) ■■■【13】Liver Fig. 13.1 Normal Hepatocytes. (A) Hepatocytes have abundant granular cytoplasm, a round and regular nucleus (or two), and a prominent nucleolus. They are arranged as a ribbon of two cells' width. Lipofuscin, the normal "wear and tear" pigment, is present (arrow) (Papanicolaou stain). (B) Lipofuscin appears green- ish with the Romanowsky stains. A pseudoinclusion is present (Romanowsky stain) Fig. 13.2 Bile. Bile pigment is not usually seen unless there is bile stasis. With the Romanowsky stains, bile pigment is a dense, dark greenish-black pigment in the cytoplasm of hepatocytes (arrow). This case is from a patient with cirrhosis (Romanowsky stain) Fig. 13.3 Steatosis. This patient had a long-standing history of alco- hol abuse, and diffuse nodularity was noted on computed tomogra- phy. Fine-needle aspiration demonstrated abundant fatty changes (Papanicolaou stain) Fig. 13.4 Echinococcal Cyst. (A) Fragments of the laminated mem- brane of the cyst appear as parallel, acellular striations and are diag- nostic (hematoxylin and eosin-stained cell block). Inset: Some cysts contain mostly acellular debris without scolices. A diligent search uncovers the pale dagger-like hooklets, which do not stain with the Papanicolaou stain (Papanicolaou stain). (B) Rarely, an intact scolex and numerous hooklets are identified (Papanicolaou stain). (Case B courtesy Dr. Edward B. Stelow, University of Virginia School of Medicine, Charlottesville, VA.) Fig. 13.5 Focal Nodular Hyperplasia. (A) Findings include benign hepatocytes, indistinguishable from those of normal liver (Romanowsky stain). (B) In some cases, there may be numerous benign ductal cells. This constellation of findings is nonspecific, however (Papanicolaou stain) Fig. 13.6 Hepatic Adenoma. Anisonucleosis and binucleation are no different from that seen with normal hepatocytes. (A, smear, Romanowsky stain; B, cell block, hematoxylin and eosin stain) Fig. 13.7 Hemangioma. (A) Smears show occasional tangles of spindle-shaped cells that are difficult to classify (Papanicolaou stain). (B) The diag- nosis is easier with cell block sections, where the vascular architecture is more readily apparent (hematoxylin and eosin stain) Fig. 13.8 Angiomyolipoma of the Liver. The myoid cells have indis- tinct cell borders and, grouped together, resemble the epithelioid histiocytes of a granuloma. Note the prominent component of extra- medullary hematopoiesis, including a megakaryocyte on the right (Papanicolaou stain) Fig. 13.9 The Spectrum of Hepatocellular Carcinoma. (A) Well- differentiated tumors are clearly of hepatocyte derivation but can be difficult to distinguish from benign hepatocytes (Papanicolaou stain). (B) Poorly differentiated tumors show little if any hepatocellular differ- entiation; they resemble poorly differentiated cholangiocarcinomas and metastatic carcinomas (Papanicolaou stain) Fig. 13.10 Hepatocellular Carcinoma. A markedly cellular preparation with abundant naked nuclei is characteristic of many hepatocellular carcinomas (Romanowsky stain) Fig. 13.11 Hepatocellular Carcinoma (Trabecular Type). (A) Thick (>2 cells across) trabeculae are a characteristic feature of the classic hepatocellular carcinoma with a prominent trabecular pattern. Note the increased nuclear-to-cytoplasmic ratio of the neoplastic hepatocytes and the flat endothelial cells with spindle-shaped nuclei that wrap the trabecu- lae (Papanicolaou stain). (B) Thickened trabeculae are cut across in cell block sections. Note the prominence of the wrapping endothelial cells, a helpful diagnostic feature (hematoxylin and eosin stain) Fig. 13.12 Hepatocellular Carcinoma (Acinar Type). (A) The cords of neoplastic cells are arranged in acini. Note the increased nuclear- to-cytoplasmic ratio, a key feature in the diagnosis of hepatocellular carcinoma (Papanicolaou stain). (B) Acini are easily appreciated in cell block preparations (hematoxylin and eosin stain) Fig. 13.13 Hepatocellular Carcinoma. Prominent transgressing vessels are characteristic of hepatocellular carcinoma (Papanicolaou stain) Fig. 13.14 Reticulin for Distinguishing Benign From Malignant Hepatocellular Proliferations. (A) Benign Liver. The reticulin stain sharply outlines the normal, two-cell-thick hepatic cords. (B) Hepatocellular Carcinoma. The reticulin strands are attenuated and outline large, chunky masses of neoplastic cells (A and B, retic- ulin stain) Fig. 13.15 Hepatocellular Carcinoma. Glypican-3 is a useful marker that distinguishes benign from malignant hepatocytes: benign hepatocytes are virtually always negative, whereas most hepatocellular carci- nomas show cytoplasmic and membranous staining (immunostain for glypican-3) Fig. 13.16 Hepatocellular Carcinoma. Bile stains dark green-brown and is a useful marker of hepatocyte differentiation (Papanicolaou stain) Fig. 13.17 Hepatocellular Carcinoma, Poorly Differentiated. A, Bizarre, atypical forms including spindle cells with intracytoplasmic globules are noted (smear, Romanowsky stain). (B) Pronounced nuclear atypia and numerous mitoses are seen (cell block, hematoxylin and eosin stain) Fig. 13.18 Hepatocellular Carcinoma, Clear Cell Variant. (A) As with many hepatocellular carcinomas, abundant bare nuclei are present. The cells have been disrupted, and the abundant spilled cytoplasmic glycogen gives a mottled appearance to the background that is reminiscent of the "tigroid" background seen with another glycogen-rich tumor, the semi- noma (see Fig. 2.48) (Romanowsky stain). (B) Intact clear cells are better seen in the cell block sections (hematoxylin and eosin stain) Fig. 13.19 Hepatocellular Carcinoma, Fatty Change Variant. The malignant cells are distended by sharply outlined, large fat vacuoles (Romanowsky stain) Fig. 13.20 Immunomarkers of Hepatocytic Differentiation. The markers illustrated here help distinguish hepatocellular carcinoma (HCC) from cholangiocarcinoma and metastatic carcinoma. (All images are of HCCs.) (A) Immunoreactivity with polyclonal antibodies to carcinoembryonic antigen leaves the malignant cells unstained but outlines the bile canaliculi as short, discontinuous linear thread and small lumina. (B) Most HCCs are immunoreactive for HepPar1. (C) Most HCCs show cytoplasmic immunoreactivity for TTF- 1. (D) Most HCCs show cytoplasmic and sometimes nuclear reactivity for ARG-1 Fig. 13.21 Fibrolamellar Hepatocellular Carcinoma. (A) Large, atypical hepatocytes are accompanied by fibrous tissue. (B) The malignant cells have abundant granular cytoplasm and intracytoplasmic hyaline globules (arrows) (Papanicolaou stain) Fig. 13.22 Cholangiocarcinoma. (A) The tumor cells are in crowded sheets. Haphazard cellular arrangement and glandular differentiation are apparent (Papanicolaou stain). (B) Anisonucleosis and nuclear membrane irregularity are present (Romanowsky stain) Fig. 13.23 Hepatoblastoma. The embryonal pattern is illustrated here, exemplified by crowded, overlapping cells with prominent nucle- oli. The patient was a 7-month-old baby girl with a large liver mass and a markedly elevated serum AFP level. (Case courtesy Dr. Martha Pitman, Massachusetts General Hospital, Boston, MA.) Fig. 13.24 Metastatic Colonic Carcinoma. (A) Colorectal cancer cells often have a "picket fence" arrangement and are associated with a dirty, necrotic background (cell block, hematoxylin and eosin stain). (B) The columnar, picket-fence arrangement is apparent on smears as well. Nuclei are enlarged and ovoid (smear, Papanicolaou stain) Fig. 13.25 Metastatic Prostatic Carcinoma. (A) Acinar structures are characteristic of prostate cancers (cell block, hematoxylin and eosin stain). (B) Immunoreactivity for prostate-specific antigen confirms the diagnosis (cell block) Fig. 13.26 Metastatic Carcinoid Tumor. (A) The tumor cells are monomorphic and arranged in loose clusters. This appearance should raise the possibility of a neuroendocrine tumor (Romanowsky stain). (B) The cell block shows cords and trabeculae of cells with a granular chromatin pattern (hematoxylin and eosin stain) Fig. 13.27 Metastatic Small Cell Carcinoma. (A) Note the abundant small blue cells with scant cyto- plasm and pronounced molding. Nuclear crush artifact is prominent (Romanowsky stain). (B) The cells are isolated and arranged in loosely cohesive clusters. The nuclear-to-cytoplasmic ratio is very high, nuclear molding is seen, and the chromatin is finely granular without nucleoli (Papanicolaou stain) Fig. 13.28 Metastatic Urothelial Carcinoma. The tumor cells are iso- lated and in small clusters. A cercariform cell (upper right) is a clue that the primary is a urothelial carcinoma (Papanicolaou stain) Fig. 13.29 Metastatic Melanoma. Melanin is more finely granular than bile. Melanoma cells are usually isolated rather than clustered. The nucleoli of melanoma cells are usually prominent and solitary (Papanicolaou stain) Fig. 13.30 Metastatic Gastrointestinal Stromal Tumor. (A) There are cohesive groups of spindle-shaped cells. Nuclear atypia is minimal in this case (Papanicolaou stain). (B) The spindle-cell proliferation is also apparent on cell block sections. The tumor cells were immunoreactive for CD117 (c-kit) (not shown) (hematoxylin and eosin stain) Fig. 13.31 Metastatic Leiomyosarcoma. Fascicles of neoplastic spindle cells have cigar-shaped nuclei and homogenous cytoplasm (Papanicolaou stain). (Case courtesy Dr. Edward G. Bernacki Jr., Beaumont Health System, Royal Oak, MI.) ■■■【14】Pancreas Fig. 14.1 (A) This whole-mount image illustrates the tissue yield with a fork-tipped core needle biopsy of a desmoplastic stroma-dominant ductal carcinoma. (B) A rare focus of invasive carcinoma is noted at high magnification, allowing for a definitive diagnosis of malignancy (A and B, hematoxylin and eosin stain) Fig. 14.2 Normal Pancreatic Acinar Cells. (A) Acinar cells are polygonal cells with abundant granular cytoplasm and an eccentrically placed, round nucleus (Papanicolaou stain). (B) Organoid clustering of acini around vascular connective tissue, like "grapes on a vine," is a characteristic architectural feature (Papanicolaou stain) Fig. 14.3 Normal Pancreatic Ductal Cells. Normal ductal cells are often arranged in large, cohesive sheets with evenly spaced nuclei that impart a uniform, honeycomb-like appearance (Papanicolaou stain) Fig. 14.4 Duodenal Epithelial Cells. Duodenal enterocytes are non- mucinous epithelial cells in large sheets. The sheets are studded with occasional goblet cells that impart a "fried egg" appearance (arrows) (Romanowsky stain) Fig. 14.5 Gastric Epithelial Cells. Surface gastric foveolar cells have mucinous cytoplasm; large sheets may display intact crypts (Papanicolaou stain) Fig. 14.6 Acute Pancreatitis. Benign-appearing ductal and acinar cells are associated with fat necrosis and inflammation (Papanicolaou stain) Fig. 14.7 Autoimmune Pancreatitis. (A) Cellular stromal fragments containing inflammatory cells are a clue to the diagnosis (Papanicolaou stain). (B) A fork-tipped core biopsy demonstrates a dense lymphoplas- macytic infiltrate (hematoxylin and eosin stain) Fig. 14.8 Reactive (Benign) Ductal Cell Atypia. Nuclear enlargement, crowding, and prominent nucleoli are evident, but there is little variation in nuclear size (Papanicolaou stain) Fig. 14.9 Ductal Adenocarcinoma. (A) The uneven distribution of nuclei in the sheet ("drunken honey- comb") and the variation in nuclear diameter (anisonucleosis) exceeding a ratio of 4:1 are characteristic features (Papanicolaou stain). (B) "Foamy-gland" adenocarcinoma is deceptively bland due to the abun- dance of mucinous cytoplasm and the resulting low nuclear-to-cytoplasmic ratio (Papanicolaou stain). (C) Cell block preparations may demonstrate cribriform glands with nuclear atypia (hematoxylin and eosin [H & E] stain). (D) Cell blocks can also show invasive glands or cells in a desmoplastic stroma (H&E stain) Fig. 14.10 Ductal Adenocarcinoma. High-grade carcinoma shows more overt features of malignancy, with marked nuclear pleomorphism, hyperchromasia, and irregular nuclear membranes (Papanicolaou stain) Fig. 14.11 SMAD4 Loss as a Helpful Marker of Ductal Adenocarcinoma. (A) The loss of SMAD4 expression in these atypical cells supports the diagnosis of adenocarcinoma. (B) Elsewhere in the cell block from this case, benign gastric foveolar cells act as an internal control by showing normal nuclear SMAD4 expression Fig. 14.12 Ductal Carcinoma Variants. (A) Adenosquamous carci- noma is composed of a combination of malignant glandular and squa- mous cells. The malignant squamous component, which sometimes predominates, is characterized by dense, sometimes orangeophilic cytoplasm; the glandular component manifest as cells with vacu- olated, mucinous cytoplasm (Papanicolaou stain). (B) Undifferenti- ated carcinomas consist of large epithelioid or spindle-shaped cells (Romanowsky stain) Fig. 14.13 Undifferentiated Carcinoma with Osteoclast-Type Giant Cells. The tumor cells are mononuclear, spindle-shaped or epithelioid cells associated with prominent benign osteoclast-type giant cells (A, Papanicolaou stain; B, hematoxylin and eosin stain) Fig. 14.14 Pancreatic Neuroendocrine Tumor. (A) Tumor cells are dispersed as isolated cells and bare nuclei (Papanicolaou stain). (B) Some cells are arranged in a pseudorosette (Papanicolaou stain). (C) Finely stippled ("salt and pepper") chromatin, occasional binucleation, and a plasmacytoid appearance (arrow) are characteristic (Papanicolaou stain) Fig. 14.15 (A) "Lipid rich" Pancreatic Neuroendocrine Tumor and its Mimics. Abundant vacuolated cytoplasm is a hallmark of the "lipid-rich" pancreatic neuroendocrine tumor; care must be taken to distin- guish it from metastatic renal cell carcinoma and other mimics (Romanowsky stain). (B) Metastatic Renal Cell Carcinoma. Polygonal cells with round central nuclei, prominent nucleoli, and punched out cytoplasmic vacuoles are characteristic (Romanowsky stain). (C) Ectopic Adrenal Cortical Tissue. Adrenal corti- cal cells have abundant microvacuolated cytoplasm. The cells are fragile: note the bare nuclei and spilled vacuoles. (D) Ectopic Adrenal Cortical Tissue. Immunostains (here SF1) help to confirm the adrenal cortical nature of the nodule Fig. 14.16 High-Grade Pancreatic Neuroendocrine Tumor. (A) Mono- morphic plasmacytoid cells are present, some showing degenerative changes. (B) The Ki-67 (MIB-1) proliferation index of this tumor was estimated at 50% to 60%, placing it in the high-grade (G3) category Fig. 14.17 Acinar Cell Carcinoma. (A) Acinar cell carcinomas reca- pitulate acinar architecture, but the sharp "grapelike" clustering of nor- mal acini is blunted, resulting in solid, irregularly shaped cell clusters (Romanowsky stain). (B) Acinar cell carcinoma cells are fragile; spilled zymogen granules from disrupted cytoplasm are characteristic and help distinguish this tumor from a neuroendocrine tumor (Romanowsky stain) Fig.14.18 Solid-Pseudopapillary Neoplasm. (A) Tumor cells surround a thick stalk (Romanowsky stain). (B) Cell block sections highlight the pseudopapillary architecture (hematoxylin and eosin stain). (C) Tumor cells have finely granular chromatin and an indistinct nucleolus (Papanicolaou stain). (D) Tumor cells show nuclear immunoreactivity for B-catenin Fig. 14.19 Pancreatoblastoma. The diagnostic feature is the squamoid corpuscle (arrow) (Papanicolaou stain) Fig. 14.20 Pseudocyst. Granular debris, histiocytes, and yellow hematoidin-like pigment are characteristic features of pseudocyst fluid (Papanicolaou stain) Fig. 14.21 Serous Cystadenoma. (A) The neoplastic cells are benign nonmucinous cells with round to oval nuclei (Papanicolaou stain). (B) A cell block demonstrates the cuboidal lining of the microcysts (hema- toxylin and eosin stain). (C) A PAS stain demonstrates red cytoplasmic granules. (D) The neoplastic cells are immunoreactive for inhibin Fig. 14.22 Lymphoepithelial Cyst. (A) Mature squamous cells are abundant; lymphocytes can be scant (Papanicolaou stain). (B) Cholesterol crystals can be prominent (Romanowsky stain) Fig. 14.23 Intraductal Papillary Mucinous Neoplasm. (A) Thick, colloid-like mucin is indicative of a neoplastic mucinous cyst and not gastrointestinal contamination (Papanicolaou stain). (B) Flat sheets of columnar mucinous cells with distinct cytoplasmic borders are characteristic, but virtually impossible to distinguish from normal gastric mucosa (compare with Fig. 14.5) (Papanicolaou stain). (C) Pseudostratification and moderate nuclear atypia ("intermediate-grade dysplasia") is classified as low- grade dysplasia (Papanicolaou stain). (D) Small size (smaller than a 12-um duodenal enterocyte), abnor- mal chromatin, and scant residual mucinous cytoplasm characterize the cells of high-grade dysplasia (Papanicolaou stain) Fig. 14.24 Ectopic Spleen. (A) Preparations reveal dense, cohesive tissue fragments and numerous dis- persed small lymphocytes (Romanowsky stain). (B) Most of the cells are small round lymphocytes. Note the abundant lymphoglandular bodies, indicative of a lymphoid lesion (Romanowsky stain). (C) Cell block sec- tions reveal venous sinusoids (hematoxylin and eosin stain). (D) The diagnosis can be confirmed by demon- strating immunoreactivity of the venous sinusoidal cells for CD8, a characteristic feature of splenic tissue ■■■【15】Kidney&Adrenal Fig. 15.1 Glomerulus. (A) Glomeruli are densely cellular structures with scalloped edges. Note the characteristic capillary loops (arrow; Papanicolaou stain). (B) The segmentation of the glomerulus is sometimes apparent (Romanowsky stain) Fig. 15.2 Proximal Tubular Cells. Proximal tubular cells have abundant granular cytoplasm and poorly demarcated cell membranes (A, Papanicolaou stain; B, Romanowsky stain) Fig. 15.3 Distal Tubular Cells. Distal tubular cells are smaller and have less cytoplasm (A, Papanicolaou stain; B, Romanowsky stain) Fig. 15.4 Oncocytoma. (A) Smears show noncohesive cells with abundant granular cytoplasm and well- demarcated cell membranes. Nucleoli are evident (Papanicolaou stain). (B) Well-demarcated cell membranes are also apparent with air-dried smears (Romanowsky stain). (C) Circumscribed cell nests are characteristic of these tumors, best seen with cell block sections and core biopsies (hematoxylin and eosin stain). (D) An apical staining pattern with the Hale's colloidal iron stain is sometimes encountered with oncocytomas Fig. 15.5 Angiomyolipoma. (A) Cohesive tissue fragments comprised of spindle-shaped smooth muscle cells are usually the predominant finding (Papanicolaou stain). (B) Occasionally, thick-walled blood vessels are seen (Romanowsky stain). (C) Nuclear atypia is commonly encountered in benign angiomyolipomas (Papanicolaou stain). (D) The tumor shows cytoplasmic immunoreactivity for HMB-45, a helpful marker in difficult cases Fig. 15.6 Metanephric Adenoma. (A and B) Smears show short tubules, cords, and tight balls of cells with scant cytoplasm (A, Papanicolaou stain; B, Romanowsky stain). (C) Cell block sections show numerous small tubules (hematoxylin and eosin stain). (D) The cells show strong nuclear reactivity for WT1 Fig. 15.7 Wilms Tumor. (A) This image illustrates only the blastemal component, which often predomi- nates. Blastema cells are small to medium-sized, round-to-ovoid cells with scant cytoplasm (Papanicolaou stain). (B) Blastema resembles small round cell tumors. Note the conspicuous cellular molding. Five cells in the upper right suggest a possible tubular arrangement (Romanowsky stain). (C) The presence of both blastema and epithelial (tubular) structures is better seen in this core biopsy. Note that the interface between the blastema and epithelial elements is poorly defined (hematoxylin and eosin stain). (D) The blastema and epithelial elements are almost always strongly positive for WT1 Fig. 15.8 Adult Cystic Nephroma/Mixed Epithelial and Stromal Tumor. (A) The epithelial cells are large and have prominent nucleoli (Papanicolaou stain). (B) A core biopsy demonstrates the cysts and the substantial stromal component (hematoxylin and eosin stain [H & E] stain). (C) The epithelial component shows cytologic atypia (H&E stain). (D) Shown here is immunoreactivity of the stromal component for progesterone receptor Fig. 15.9 Xanthogranulomatous Pyelonephritis. (A) Histocytes with abundant granular cytoplasm bear some resemblance to the cells of an oncocytic tumor (hematoxylin and eosin [H & E] stain). (B) The lesional cells are more easily recongizable as histiocytes on cell block sections (H&E stain). (C) The lesional cells are positive for CD68 Fig. 15.10 Renal Infarct Atypia. (A) Degenerated and regenerating renal tubular cells adjacent to the area of injury show marked atypia (Romanowsky stain). (B) There can be impressive anisonucleosis (Papanicoalou stain). (C) A cell block reveals normal tubular architecture with tubular necrosis and regeneration (hematoxylin and eosin [H & E] stain). (D) Infarcted glomeruli provide a clue to the underlying lesion (H&E stain) Fig. 15.11 Renal Cyst. Macrophages are a nonspecific finding (Papanicolaou stain) Fig.15.12 Cystic Renal Cell Carcinoma. (A) Fine-needle aspiration. There were only a few groups of cells with clear or granular cytoplasm on the slide. In the setting of a radiologically atypical cyst, this finding is suspicious for carcinoma. (B) Surgical resection. The tumor was almost entirely cystic. Malignant cells were found in the wall in only a few areas (hematoxylin and eosin stain) Fig. 15.13 Papillary Proliferation in Adult Polycystic Kidney Disease. A, Papillary proliferation is evident (Romanowsky stain). B, The cell block reveals oncocytic features and moderate atypia (hematoxylin and eosin stain) Fig. 15.14 Liesegang Rings in a Benign Renal Cyst. These sharply defined round crystal-like structures have a double-layered outer wall and radial striations. Often seen in association with benign renal cysts, they are a nonspecific finding (A, Papanicolaou stain; B, hematoxylin and eosin stain) Fig. 15.15 Clear Cell Renal Cell Carcinoma. (A) The tumor cells are in a broad sheet and have abundant clear and granular cytoplasm (Papanicolaou stain). (B) Fine cytoplasmic vacuoles and pink, strand-like material (arrow) are well seen with the Romanowsky stain. (C) Nuclei are often eccentri- cally placed (Papanicolaou stain). (D) The cytoplasm of this grade 4 tumor is more opaque, the cells are more dyshesive, and nucleoli are prominent (Romanowsky stain). (E) Cell block sections reveal the characteristic clear cell morphology (hematoxylin and eosin stain). (F) A karyotype reveals a 3p deletion (arrow) Fig. 15.16 Renal Cell Carcinoma, Morphologic Variants. (A) Sarcomatoid changes. The malignant cells are haphazardly arranged and very elongated (Papanicolaou stain). (B) Rhabdoid changes. The cells are large, with an eccentrically placed nucleus and a conspicuous focus of cytoplasmic condensation. Sarcomatoid and rhabdoid changes indicate a worse prognosis (Romanowsky stain) Fig. 15.17 Papillary Renal Cell Carcinoma. (A) Complex papillary architecture is apparent on smears. Note the large sphere (arrow), a characteristic finding. Foamy macrophages are scattered in the back- ground (Papanicolaou stain). (B) Foamy macrophages stuff the fibrovascular cores of the papillae and are often best seen on cell block sections (hematoxylin and eosin stain). (C) Note how round and monomor- phous the nuclei are in a low-grade papillary renal cell carcinoma (Papanicolaou stain). (D) Cytoplasmic hemosiderin is a common finding (Romanowsky stain). (E) A karyotype reveals trisomies of chromosomes 7 and 17 (arrows). (F) Fluorescence in situ hybridization shows trisomies of chromosomes 7 (green signal) and 17 (red signal) Fig. 15.18 Oncocytic Papillary Renal Cell Carcinoma, Typical Variant. (A) The tumor cells form complex papillary structures but are also dispersed as isolated cells (Romanowsky stain). (B) Cell block sections reveal papillae lined by a single layer of oncocytic cells (hematoxylin and eosin stain). The lesional cells were strongly positive for GATA3 (not shown) Fig. 15.19 Chromophobe Renal Cell Carcinoma, Typical Variant. (A) The tumor cells have a koilocytoid appearance, with abundant cytoplasm, prominent cell borders, binucleation, and dark nuclei that vary in size. Nucleoli are hard to see (Papanicolaou stain). (B) The fluffy, irregularly vacuolated cytoplasm has a moth-eaten appearance (Romanowsky stain). (C) In cell block sections, the tumor cells are arranged in an endless sheet (hematoxylin and eosin stain). (D) The Hale's colloidal iron stain shows a diffusely granular staining pattern Fig. 15.20 Tubulocystic Carcinoma. (A) The cells have abundant granular cytoplasm mimicking an oncocytoma but are arranged in sheets and are separated by windows (hematoxylin and eosin [H & E] stain). (B) Intracytoplasmic vacuoles are present (H&E stain) Fig. 15.21 MIT Family Translocation Renal Cell Carcinoma. (A and B) The cells have abundant clear and granular cytoplasm and irregular nuclei, mimicking a clear cell or chromophobe renal cell carcinoma (A, Papanicolaou stain; B, Romanowsky stain). (C) The core biopsy shows calcification (hematoxylin and eosin stain). (D) There is strong nuclear staining for TFE3 Fig. 15.22 Mucinous Tubular and Spindle Cell Carcinoma. Com- pressed tubules, spindle cells, and pale blue myxoid material are ap- parent in this cell block section (hematoxylin and eosin stain) Fig. 15.23 Urothelial Carcinoma. Cells with long unipolar cytoplasmic extensions and flared ends are called cercariform cells (Papanicolaou stain) Fig. 15.24 Metastatic Lung Cancer. These hyperchromatic crowded malignant cells are not typical of renal cell carcinoma. In a patient with a history of lung cancer, the findings are most consistent with a metastasis from that site. (A) Papanicolaou stain. (B) Hematoxylin and eosin-stained cell block Fig. 15.25 Metastatic Breast Cancer. There is abundant extracel- lular mucin, with clusters of malignant cells and occasional psam- moma bodies. The resemblance to the patient's colloid carcinoma of the breast, resected 13 years earlier, was striking (Papanicolaou stain) Fig. 15.26 Benign Adrenal Cortical Nodule/Adenoma. (A) Nuclei are stripped of cytoplasm and float in a sea of frothy cytoplasmic remnants (Papanicolaou stain). (B) Adjacent nuclei occasionally show mold- ing (arrow) and thus mimic small cell carcinoma (Romanoswky stain). (C) Intact cells have indistinct cell borders (Papanicolaou stain) Fig. 15.27 Adrenal Cortical Carcinoma. (A) The malignant cells are large and have intact cytoplasm (Romanowsky stain). (B) The myxoid variant has conspicuous extracellular mucin (Romanowsky stain). (C) Many tumors are highly pleomorphic and contain atypical mitoses (arrow). The mixture of clear and granular cytoplasm resembles that of a clear cell renal cell carcinoma (hematoxylin and eosin-stained cell block). (D) Adrenal cortical carcinomas show cytoplasmic immunoreactivity for inhibin Fig. 15.28 Pheochromocytoma. (A) In some cases there is marked anisonucleosis (Romanowsky stain). (B) Intranuclear cytoplasmic pseudoinclusions, a characteristic but nonspecific feature, are some- times seen (Papanicolaou stain) ■■■【16】Ovary Fig. 16.1 Follicle Cyst. In this histologic section, the follicle cyst is collapsed, and the cavity is slit-like. Follicle cysts are lined by one or several layers of granulosa cells. Mitotic activity (arrow) is common (hema- toxylin and eosin stain) Fig. 16.2 Follicle Cyst. Granulosa cells are clustered in loose aggre- gates (Papanicolaou stain) Fig. 16.3 Follicle Cyst. Granulosa cells have a round nucleus and a moderate amount of granular cytoplasm. Degenerated granulosa cells with pyknotic nuclei are a common finding, as are mitoses (arrow) (Papanicolaou stain) Fig. 16.4 Corpus Luteum Cyst. These cysts are lined by very large cells that have a small nucleus and abundant finely vacuolated cyto- plasm (Papanicolaou stain) Fig. 16.5 Endometriotic Cyst. (A) Cytologic preparations often show only macrophages with abundant intracytoplasmic hemosiderin (Papanicolaou stain). (B) In cell block sections, fragments containing endometrial glands and stroma are diagnostic (hematoxylin and eosin stain) Fig. 16.6 Simple Ovarian Cyst. This sheet of evenly arranged cuboidal cells resembles a sheet of mesothelial cells (Papanicolaou stain) Fig. 16.7 Detached Ciliary Tufts. These decapitated tips of ciliated cells are diagnostically very useful because they exclude a follicle cyst. They are seen in serous cysts, cystic teratomas, and hydrosalpinx (Papanicolaou stain) Fig. 16.8 Serous Cystadenoma. The cyst is lined by benign cili- ated cells that have a basally placed nucleus, terminal bar, and cilia (Papanicolaou stain) Fig. 16.9 Mucinous Cystadenoma. Admixed with macrophages are fragments of benign mucinous epithelium resembling gastric foveolar epithelium (Papanicolaou stain) Fig. 16.10 Mucinous Cystadenoma. Some mucinous cystadenomas contain intestinal-type goblet cells (Papanicolaou stain) Fig. 16.11 Serous Borderline Tumor. (A) The cells are arranged in a crowded sheet. There is mild to moderate atypia. (B) In this tight spherical aggregate, some cells have large cytoplasmic vacuoles. (C) Psammoma bodies are a common finding (Papanicolaou stain) Fig. 16.12 High-Grade Serous Carcinoma. The malignant cells often have large, round, and pleomorphic nuclei, and nucleoli are prominent (Papanicolaou stain) Fig. 16.13 Mucinous Carcinoma. (A) Some sheets of mucinous cells show only mild atypia (compare with Figs. 16.9, 16.10). (B) Other cells are markedly atypical, with little if any mucinous differentiation (Papanicolaou stain) Fig. 16.14 Endometrioid Carcinoma. (A) The cells have elongated nuclei and a narrow columnar shape. Some are arranged in pseudostratified strips and glands (Papanicolaou stain). (B) Cell block sections reveal endometrial-like glands with atypia (hematoxylin and eosin stain) Fig. 16.15 Mature Cystic Teratoma (Dermoid Cyst). (A) Mature nucleated and anucleate squamous cells and occasional glandular cells are present (Papanicolaou stain). (B) This cell block section contained several transected hair shafts, recognizable on the basis of their size, shape, and pigmentation (hema- toxylin and eosin stain) Fig 16.16 Dysgerminoma. (A) Tumor cells have a large round nucleus with a prominent nucleolus and clear cytoplasm (hematoxylin and eosin-stained cell block). They show nuclear immunoreactivity for the stem cell proteins SALL4 (B), Oct-3/4 (C), and NANOG (D) Fig. 16.17 Adult-Type Granulosa Cell Tumor. (A) The small to medium-sized cells are arranged in loose clusters. They are difficult to distinguish from normal granulosa cells (compare with Figs 16.2 and 16.3) (Papanicolaou stain). (B) Large fragments of tumor in cell block sections may show one of the characteristic architectural patterns, in this case the watered-silk pattern (hematoxylin and eosin-stained cell block) Fig. 16.18 Small Cell Carcinoma of the Ovary, Pulmonary Type. This tumor resembles the small cell carcinoma of neuroendocrine type of the lung. (A) Wright-Giemsa-stained smear; (B) hematoxylin and eosin-stained cell block section ■■■【17】Soft tissue Fig. 17.1 Lipoma. Benign lipomas have occasional capillaries, but they are not as numerous as in hibernomas (Papanicolaou stain) Fig. 17.2 Hibernoma. (A) Delicate capillaries (arrows) can be numerous and are closely associated with tumor cells that have distinct granular and multivacuolated cytoplasm (Papanicolaou stain). (B) Lipoblast- like cells are present, but the nuclei are small and lack atypia (Papanicolaou stain) Fig. 17.3 Spindle Cell Lipoma. (A) This tumor is characterized by a mixture of dispersed bland spindle cells and mature adipocytes (Romanowsky stain). (B) After some searching, long, ropy collagen fibers are identified, embedded in a myxoid background (Romanowsky stain) Fig. 17.4 "Floret" Cells. Multinucleated giant cells, some with nuclei in a wreathlike configuration (arrow), are a characteristic but nonspecific finding in pleomorphic lipomas (Papanicolaou stain). (Courtesy Dr. Henryk Domanski, Lund University Hospital, Lund, Sweden.) Fig. 17.5 Well-Differentiated Liposarcoma. The much-touted varia- tion in adipocyte size can be subtle and easily overlooked (compare with Fig. 17.1) (Papanicolaou stain) Fig. 17.6 Lipoblast. The enlarged, hyperchromatic nuclei of lipo- blasts are scalloped because of multiple impinging cytoplasmic lipid droplets (Papanicolaou stain) Fig. 17.7 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma. Atypical nuclei in deep-seated fatty lesions denote malignancy, even when classic lipoblasts are not readily identified (Papanicolaou stain) Fig. 17.8 Pleomorphic Liposarcoma. Clusters of pleomorphic cells, including numerous atypical lipo- blasts, are seen (Romanowsky stain) Fig. 17.9 Intramuscular Myxoma. (A) Many Intramuscular myxomas are paucicellular, comprised mostly of myxoid matrix. Rare macrophages and bland spindle cells are present (Papanicolaou stain). (B) Cellularity is more pronounced with a cellular myxoma. Stubby vessels can be seen, especially with the cellular myxoma (Romanowsky stain) Fig. 17.10 Myxofibrosarcoma. (A) The vascular component, when present, manifests itself as short curvilin- ear segments of thick-walled vessels with adherent matrix and pleomorphic tumor cells (Papanicolaou stain). (B) Pseudolipoblasts (arrow) contain acid mucins rather than lipid (Romanowsky stain) Fig. 17.11 Low-Grade Fibromyxoid Sarcoma. (A) Uniform, deceptively bland fibroblasts are embedded in a myxoid matrix (Papanicolaou stain). (B) Cytoplasmic MUC4 expression distinguishes low-grade fibro- myxoid sarcoma from its mimics Fig. 17.12 Myxoid Liposarcoma. (A) Discrete tissue fragments contain myxoid matrix, vessels, and tumor cells (Romanowsky stain). (B) Delicate branching "chicken-wire" capillaries are easily obtained by aspira- tion and are seen in abundance on smears (Papanicolaou stain). (C) The lipoblasts in myxoid liposarcomas resemble signet-ring cells and histiocytes and are often associated with the vessels (Romanowsky stain). (D) Fluorescence in situ hybridization is often performed with centromeric (red) and telomeric (green) probes that flank the CHOP (DDIT3) gene breakpoint. There is one normal chromosome (probes adjacent = yellow), but the split-apart green and red signals indicate a translocation on the other chromosome in the 4 tumor cells in this field. (Courtesy Dr. Paola Dal Cin, Brigham and Women's Hospital, Boston, MA.) Fig. 17.13 Dedifferentiated Liposarcoma, Myxofibrosarcoma-Like. These tumors may be myxoid, with complex, branching, thick-walled vasculature, and resemble a myxofibrosarcoma. True lipoblasts, as depicted in this case, are a helpful feature for the distinction from other myxoid lesions, but most dedif- ferentiated liposarcomas are nonlipogenic (Romanowsky stain) Fig. 17.14 Myxoinflammatory Fibroblastic Sarcoma. The occasional large ganglion-like or Reed- Sternberg-like cells in a background of otherwise bland spindle cells, vacuolated epithelioid cells, and inflammatory cells may lead to confusion with a high-grade sarcoma or Hodgkin lymphoma (Romanowsky stain) Fig. 17.15 Extraskeletal Myxoid Chondrosarcoma. (A) The extraskeletal myxoid chondrosarcoma has a distinctive fibrillary chondromyxoid matrix (Romanowsky stain). (B) Long cytoplasmic extensions link one cell to another, often conferring a lacelike appearance (Papanicolaou stain) Fig. 17.16 Leiomyosarcoma. (A) Spindle cells are packed in cohesive tissue fragments with well- circumscribed, rigid edges (Romanowsky stain). (B) Nuclei are hyperchromatic, with finely textured chromatin in lower-grade tumors and more coarsely clumped chromatin in the higher-grade neoplasms (Papanicolaou stain) Fig. 17.17 Schwannoma. (A) Smears often contain thick tissue fragments that appear densely cellular, erroneously suggesting a sarcoma (Papanicolaou stain). (B) The neoplastic cells have abundant filamentous cytoplasm and an oval, curved, or wavy nucleus (Romanowsky stain) Fig. 17.18 Malignant Peripheral Nerve Sheath Tumor. Although some of the elongated, wavy or fish- hook nuclei of benign nerve sheath tumors are present, in general, they give way to plumper forms with less pointed ends, with hyperchromatic nuclei and greater atypia (Papanicolaou stain) Fig. 17.19 Synovial Sarcoma. There is a distinctive pattern of dispersed cells alternating with cohesive cell clusters (Papanicolaou stain) Fig. 17.20 Synovial Sarcoma, Biphasic. Epithelial differentiation is recognized as only a vague palisad- ing of nuclei along the edges of tissue fragments or as clusters of more epithelioid-appearing cells among the spindle cells (Papanicolaou stain) Fig. 17.21 Synovial Sarcoma, Monophasic. (A) The oval to round nuclei are remarkably uniform, although rare elongated, blunt-ended, and bent forms are seen (Papanicolaou stain). (B) Fluorescence in situ hybridization is often performed with centromeric (SS18-c, green) and telomeric (SS18-t, red) probes that flank the SYT gene breakpoint. There is one normal chromosome (probes adjacent = yellow), but the split-apart green and red signals indicate a translocation on the other chromosome. (Courtesy Dr. Paola Dal Cin, Brigham and Women's Hospital, Boston, MA.) Fig. 17.22 Synovial Sarcoma, Poorly Differentiated Round-Cell Type. The tumor cells have a round cell morphology resembling that of a Ewing sarcoma. Mast cells are a characteristic feature (arrow) (Romanowsky stain). (Courtesy Dr. Bastiaan De Boer, Pathwest, QE II Medical Centre, Nedlands Perth, Australia.) Fig. 17.23 Solitary Fibrous Tumor. (A) Cellular fragments with a meshwork of irregular fascicles alternate with isolated spindle-shaped cells (Papanicolaou stain). (B) High magnification reveals collagen fibers cours- ing through the tumor (Papanicolaou stain). (C) Cell block preparations are very helpful for capturing the characteristic bland, monomorphic spindle-shaped cells insinuated between collagen bundles (hematoxylin and eosin stain). (D) Nuclear STAT6 expression is highly sensitive and specific for SFT Fig. 17.24 Desmoid Fibromatosis. (A) Long fascicular arrangements of spindle-shaped fibroblasts and scattered degenerated skeletal muscle fibers are characteristic (Papanicolaou stain). (B) Aberrant nuclear staining for B-catenin is seen in tumor cells but not in adjacent endothelial cells (arrow) Fig. 17.25 Nodular Fasciitis. (A) Smears can be cellular, with numerous myofibroblasts embedded in a myxoid matrix (Romanowsky stain). (B) Dispersed, polymorphic myofibroblasts are characteristic (Romanowsky stain). (C) The myxoid matrix is less conspicuous with the Papanicolaou stain. (D) Mitoses are not unusual (Romanowsky stain) Fig. 17.26 Inflammatory Myofibroblastic Tumor. (A) Spindle cells with plump nuclei, prominent nucleoli, and frequent cytoplasmic tails are arranged in loose clusters (Papanicolaou stain). (B) Up to half of all cases show cytoplasmic ALK expression, secondary to an ALK gene rearrangement Fig. 17.27 Tenosynovial Giant Cell Tumor. (A) Mononuclear histiocytoid cells are arranged in clusters. There is prominent intracytoplasmic hemosiderin, imparting a speckled, ladybug-like appearance to the cells (Papanicolaou stain). (B) Multinucleated giant cells are a prominent feature (Romanowsky stain) Fig. 17.28 Gout. (A) The sample is comprised of innumerable needle-shaped crystals in a background of granular debris (Papanicolaou stain). (B) Examination under polarized light demonstrates the crystals more clearly Fig. 17.29 Giant Cell Tumor of Soft Tissue. Mononuclear histiocytoid cells, often with vacuolated cyto- plasm, may look plasmacytoid, unipolar, or bipolar. They are accompanied by large and often bizarrely shaped multinucleated giant cells (Romanowsky stain) Fig. 17.30 Angiomatoid Fibrous Histiocytoma. Ball-like clusters of histiocytoid cells are commonly associated with capillaries lined by spindle-shaped endothelial cells Fig. 17.31 Ewing Sarcoma. (A) The tigroid background, characteristic light and dark cells, and the occasional cytoplasmic vacuoles are better appreciated with air-dried Romanowsky-stained preparations (Romanowsky stain). (B) Fluorescence in situ hybridization (FISH) with centromeric (red) and telomeric (green) probes that flank the EWS gene breakpoint show one normal chromosome (adjacent probes = yellow), but the split-apart green and red signals indicate a translocation on the other chromosome in all three cells. FISH cannot distinguish the EWS gene rearrangements in Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, angiomatoid fibrous histiocytoma, and extraskeletal myxoid chon- drosarcoma (as well as other tumors), but these tumors are morphologically and immunophenotypically distinct. (Courtesy Dr. Paola Dal Cin, Brigham and Women's Hospital, Boston, MA.) Fig. 17.32 Desmoplastic Small Round Cell Tumor. (A) This tumor differs morphologically from other round cell neoplasms because its cells retain some cohesiveness and are rarely dispersed as isolated cells (Papanicolaou stain). (B) Cell block sections reveal the desmoplastic stroma that surrounds nests of neoplastic cells (hematoxylin and eosin stain) Fig. 17.33 Alveolar Rhabdomyosarcoma. (A) In This field, the cells are relatively monomorphic (Romanowsky stain). (B) The cells are dispersed and generally larger and more uniformly round to polygo- nal than those seen in embryonal rhabdomyosarcoma (Romanowsky stain) Fig. 17.34 C/C-Rearranged Sarcoma. (A) Although the cells resemble those of Ewing sarcoma, they are more irregular and variable (Romanowsky stain). (B) Whereas Ewing sarcoma is usually strongly and diffusely positive for CD99, this sarcoma is often either negative or only weakly or focally reactive for CD99 Fig. 17.35 Epithelioid Sarcoma. (A) The dispersed epithelioid cells have eccentrically placed nuclei and dense cytoplasm with sharply defined cell borders (Romanowsky stain). (B) The cells are polygonal, round, or spindle shaped, and some have cytoplasmic vacuoles (Romanowsky stain). (C) Tumor cells are epi- thelial membrane antigen positive. (D) There is loss of nuclear INI1 expression, which is characteristic of epithelioid sarcoma. Note that the admixed normal endothelial cells and inflammatory cells have retained nuclear expression Fig. 17.36 Clear Cell Sarcoma of Soft Tissue. Cell borders are clearly defined. Binucleation and prominent nucleoli are present (Papanicolaou stain) Fig. 17.37 Alveolar Soft Part Sarcoma. Large polygonal cells have abundant granular cytoplasm, large nuclei, vesicular chromatin, smooth nuclear contours, and a prominent central, round nucleolus (Papanicolaou stain) Fig. 17.38 Pseudomyogenic Hemangioendothelioma. Plump spindle and epithelioid cells have round nuclei with vesicular chromatin and abundant cytoplasm, with cytoplasmic extensions and vacuoles resembling nodular fasciitis (Diff-Quik stain). (Courtesy Dr. Henryk Domanski, Lund University Hospital, Lund, Sweden.) Fig. 17.39 Granular Cell Tumor. Small nuclei within abundant granular cytoplasm result in a low nuclear- to-cytoplasmic ratio (Papanicolaou stain) Fig. 17.40 Undifferentiated High-Grade Pleomorphic Sarcoma. The bizarre tumor cells and necrotic background are nonspecific findings seen with any pleomorphic soft tissue neoplasm (Papanicolaou stain) Fig. 17.41 Pleomorphic Rhabdomyosarcoma. Numerous dispersed rhabdoid cells have eccentri- cally located nuclei, prominent nucleoli, abundant cytoplasm, and a perinuclear cytoplasmic density (Romanowsky stain) Fig. 17.42 Elastofibroma. Sharply defined, hypocellular fragments contain rare bland fibroblasts with curvilinear, rodlike elastic fibers (hematoxylin and eosin stain). (Courtesy Dr. Henryk Domanski, Lund University Hospital, Lund, Sweden.) Fig. 17.43 Amyloidoma. Fragments of waxy, amorphous material have sharply defined edges with embedded fibroblasts and capillaries (Papanicolaou stain) ■■■【18】Bone Fig. 18.1 Chondroblastoma. (A) The MRI shows a well-defined lytic lesion in the epiphyseal area of the distal femur. (B) Chondroblasts are uniform in size, with a round or polygonal shape. The nucleus is round to oval, with finely textured chromatin and frequent nuclear grooves (arrows) (Papanicolaou stain). (C) The chondroid matrix, embedded chondroblasts, and scattered osteoclast-like giant cells are nicely appreciated with cell block sections (H&E stain). (D) H3K36M is positive in the nuclei of the mononuclear chondroblasts but not the osteoclast-like giant cells Fig. 18.2 Chondromyxoid Fibroma. (A) Chondromyxoid fragments with embedded stellate to spindled cells are a typical feature (Romanowsky stain). (B) Micronodules of chondromyxoid tissue have a central hypocellular, myxomatous area (upper right) and peripheral hypercellular condensation (cell block, hematoxylin and eosin stain) Fig. 18.3 Enchondroma. Fragments of mature cartilage with small, uniform chondrocytes in lacunae are well appreciated with air-dried, Romanowsky-stained smears Fig. 18.4 Atypical Cartilaginous Tumor/Grade 1 Chondrosarcoma. (A) The proximal humerus shows an ill-defined lytic lesion with cortical destruction, soft tissue extension, and internal calcifications. (B) Extracellular chondroid material from an atypical cartilaginous tumor/grade 1 chondrosarcoma is indistin- guishable from that seen in enchondromas (Romanowsky stain). (C) Fragments of chondroid matrix and sparse cellularity are characteristic (cell block, hematoxylin and eosin [H&E] stain). (D) A permeative/infiltra- tive growth pattern helps distinguish a low-grade chondrosarcoma from an enchondroma and is better seen on core biopsy samples (H&E-stained core biopsy) Fig. 18.5 Grade 2 Chondrosarcoma. (A) Grade 2 and 3 chondrosarcomas yield cellular smears and prominent myxoid matrix (Romanowsky stain). (B) Cytologic atypia is apparent. The chondromyxoid matrix is paler and less conspicuous with alcohol-fixed smears (Papanicolaou stain) Fig. 18.6 Dedifferentiated Chondrosarcoma. Dedifferentiated chon- drosarcoma has a sarcomatous component that is indistinguishable from a spindle-cell/pleomorphic sarcoma. The scant chondromyxoid matrix seen here is relatively nonspecific but might spur a search for better differentiated areas (Romanowsky stain) Fig. 18.7 Giant Cell Tumor of Bone. (A) A large eccentric and purely lytic intramedullary lesion with sharp borders involves the epiphyseal-metaphyseal region of the distal femur. (B) Large clusters of mononuclear stro- mal cells are admixed with numerous osteoclast-like giant cells, many arranged at the periphery of the clusters of stromal cells (arrows) (Romanowsky stain). (C) The giant cells are distributed evenly within the stromal cells on cell block sections (hematoxylin and eosin stain). (D) H3G34W is positive in the mononuclear stromal cells, the true neoplastic cells in GCT of bone, but not in the osteoclast-like giant cells Fig. 18.8 Aneurysmal Bone Cyst (ABC). Diagnosing an ABC by cytomorphology alone is difficult because the findings are nonspecific: a myofibroblastic proliferation (A, Papanicolaou stain), with scattered osteoclast-like giant cells and reactive bone formation (B, core needle biopsy, hematoxylin and eosin stain) Fig. 18.9 Osteoblastoma. (A) A computed tomography scan shows a well-defined, expansile, and lytic lesion with internal ossification involving pedicle and lamina of a vertebra. (B) Uniform osteoblasts are round or triangular cells with an eccentrically located nucleus and abundant cytoplasm. (Courtesy Dr. Henryk Domanski, Lund University Hospital, Lund, Sweden.) Fig. 18.10 Osteosarcoma. (A) Osteoblastic Osteosarcoma. Cellular smears contain epithelioid or pleo- morphic malignant cells admixed with strands of osteoid (arrow) and occasional multinucleated tumor cells (Romanowsky stain). (B) Chondroblastic Osteosarcoma resembles high-grade chondrosarcoma. In this field, there is chondroid matrix (arrows) but no osteoid (Papanicolaou stain). (Courtesy Dr. Lisa Teot, Boston Children's Hospital, Boston, MA.) (C) Giant-cell Rich Osteosarcoma. Abundant osteoclast-like giant cells are admixed with malignant osteoblasts (Papanicolaou stain). (D) Low-grade Osteosarcomas yield scant cellularity, with scattered clusters of low-grade spindle cells (Romanowsky stain) Fig. 18.11 Chordoma. Clusters of large, round to cuboidal "physallif- erous" cells are embedded in a rich myxoid matrix (Romanowsky stain). Tumors cells show strong nuclear staining for brachyury (inset) Fig. 18.12 Adamantinoma. (A) Cellular smears are composed of clusters of cohesive overlapping round cells with scant cytoplasm (Papanicolaou stain). (B) A dual population of epithelial cells and fibrous stroma is evident on core needle biopsy (hematoxylin and eosin stain) Fig. 18.13 Plasmacytoma. (A) A Dispersed population of recognizably plasmacytoid cells is common. Binucleation is often seen (arrows) (Romanowsky stain). (B) Some plasmacytomas are rich in light chain amyloid; the neoplastic cells can be few and far between (cell block, hematoxylin and eosin stain) Fig. 18.14 Langerhans Cell Histiocytosis. (A) There is a well-defined lytic lesion of the occipital skull, without a zone of reactive sclerosis (computed tomography scan). (B) Neoplastic Langerhans cells can be epithelioid or elongated ("dendritic") in appearance. Many nuclei are markedly folded and grooved (arrows). The background is rich in eosinophils, lymphocytes, and histiocytes. (Inset) Neoplastic Langerhans cells are positive for CD1a Fig. 18.15 Metastatic Breast Cancer. (A) There is a sheet-like infiltrate of poorly differentiated epithelioid cells (hematoxylin and eosin-stained core biopsy). (B) The strong staining of some breast cancers for neuroendocrine markers can be misleading (synaptophysin immunostain, core biopsy). (Courtesy Dr. Susan Lester, Brigham and Women's Hospital, Boston, MA.)
