Paris system.2nd edition(2022) برای بزرگنمایی عکسها کلیک را روی ان نگه دارید..... ■■■【1】Cytopreparatory Techniques Fig. 1.1 Paris 2.0 International survey of urine preparation types Fig. 1.2 ThinPrep® liquid-based preparation technique Fig. 1.3 High-grade urothelial carcinoma. (ThinPrep® preparation, voided urine, Papanicolaou stain, high magnification) Fig. 1.4 Hologic ThinPrep® 5000® Processor Fig. 1.5 Thermo ScientificTM CytospinTM preparation technique Fig. 1.6 Thermo ScientificTM CytospinTM instrument Fig. 1.7 Negative for high-grade urothelial carcinoma. (CytospinTM preparation, bladder washing, Papanicolaou stain, high magnification) Fig. 1.8 Negative for high-grade urothelial carcinoma. (Direct smear, bladder washing, Papanicolaou stain, high magnification) Fig. 1.9 BD TotalysTM preparation technique Fig. 1.10 BD TotalysTM Slide Prep instrument Fig. 1.11 High-grade urothelial carcinoma. (BD TotalysTM SurePath® preparation, bladder washing, Papanicolaou stain, high magnification) Fig. 1.12 Negative for high-grade urothelial carcinoma. (Millipore® filter preparation, bladder diversion, Papanicolaou stain, high magnification) Fig. 1.13 High-grade urothelial carcinoma. (Cell block preparation, bladder washing, hematoxylin & eosin stain, high magnification) Fig. 1.14 Low-grade urothelial carcinoma with fibrovascular cores. (a) Millipore® filter prepa- ration, bladder washing, Papanicolaou stain, low magnification. (b) Cell block preparation, bladder washing, hematoxylin & eosin stain, low magnification Fig. 1.15 Centrifugation sediment cell block preparation technique Fig. 1.16 Metastatic adenocarcinoma. (a) Cell block preparation, bladder washing, hematoxylin & eosin stain, high magnification. (b) Cell block preparation, bladder washing, Kreyberg mucin histochemical stain, high magnification Fig. 1.17 CellientR automated cell block preparation technique ■■■【2】Specimen Adequacy Fig. 2.1 The adequacy algorithm shows The Paris System's recommendation for the proper rela- tionship between specimen source, cytological diagnosis, urine volume, urothelial cellularity, and obscuring features. Obscuring features include non-urothelial cells such as lubricant, acute inflam- mation, bacteria, vaginal contaminants, sperm, and crystals which, when copious, may obscure the finding and characterization of urothelial cells. "*": Cutoffs for appropriate benign urothelial cel- lularity should be validated for both instrumented and non-instrumented sources Fig. 2.2 Relationship of volume to the prevalence of malignant and suspicious diagnosis for demographically comparable populations. There were no suspicious samples in the lowest volume bin, and there was a nearly linear increase in the suspicious fraction up to the bin centered on 15 mL. A specimen was nearly twofold more likely to be suspicious when more than 15 mL was received than when less than 5 mL was received. The global maximum for the malignancy fraction was seen at 27.5 mL (range: 25–30 mL) which was also the location of a local maximum for the suspicious fraction. The global maximum for the suspicious curve was centered at 85 mL, and the difference between the global maximum (5.8, 95% CI: 5.6-5.9) and the local maximum at 27.5 mL (5.7, 95% CI: 5.5-5.9) was not statistically significant. Based on this analysis, we concluded that at least 30 mL is necessary to consider a urine fully adequate when processed with SurePath. (From Vandenbussche et al. [4] with kind permission of John Wiley & Sons) Fig. 2.3 Unsatisfactory/nondiagnostic specimen. (a) Acellular specimen showing only lubricant without the presence of urothelial cells (Bladder wash, TP, medium mag.). (b) Scantly cellular specimen with obscuring blood (voided urine, TP, medium mag.). (c) Scantly cellular specimen with obscuring inflammation in a patient with a papillary lesion observed on cystoscopy (bladder wash, TP, medium mag.) ■■■ 【3】Negative for HGUC Fig. 3.1 Superficial urothelial (umbrella) cells. (a) The cytoplasm of large superficial cells is frothy and abundant, resulting in a low N/C ratio. Nuclei have pale, finely granular chromatin and prominent nucleoli. Multinucleation is common, especially in instrumented samples. (Washing, TP, medium mag.). (b) In addition to superficial (umbrella) cells, clusters of smaller cells are seen (arrows). The nuclei are darker and slightly smaller than the superficial cells, but the nuclear shapes are round, nuclear membranes are smooth, and architecture is uniform. N/C ratios are high but, in the context of the other criteria, should not be considered atypical. (Washing, TP, medium mag.). (c) Umbrella cells are the most superficial cells in the bladder, creating an "umbrella" over all other urothelial cells. Their nuclear and cytoplasmic character is the same as other superficial cells, but additionally, they possess a thickened cytoplasmic edge that doesn't go all around the cell. (Washing, CS, medium mag.) Fig. 3.2 Intermediate urothelial cells. These cells have a "fried egg" appearance and resemble the parabasal squamous cells seen in Pap test specimens, causing them to also be described as "parabasal-type" or "parabasal-like" cells. They are usually found singly or in small, loose clusters (as seen here). Note the low N/C ratios, oval-shaped nuclei with regular borders, and bland chro- matin pattern. The nuclei also are uniform in size. (Voided, SP, high mag.) Fig. 3.3 Deep urothelial cells. This sheet is essentially a monolayer of uniform cells with round nuclei and uniformly pale chromatin. N/C ratios are high, a reflection of the deep, more basal position of these cells in the urothelial layer. (Washing, TP, medium mag.) Fig. 3.4 Benign squamous cells. Two benign squamous cells line up below an umbrella cell with three nuclei. The presence of squamous cells in voided urine may come from external genitalia, including the vagina. In a catheterized patient, their origin is usually in an area of metaplasia in the trigone. (VU, TP, medium mag.) Fig. 3.5 Benign glandular cells - endometriosis. Glandular cells in a urinary tract specimen may be native to the urinary collecting system, or external to it. The larger cells are urothelial or squa- mous. The cluster of small dark cells originated in an endometriosis of the ureter. The patient was presenting with hematuria and pain coincident with her menstrual periods. (Ureteral brushing, CS, high mag.) Fig. 3.6 Cystitis cystica/glandularis. (a) Glandular cells from the lining of the bladder can origi- nate from a focus native to the urothelium, metaplasia from an inflammatory focus (cystitis cystica/ glandularis), or from a glandular neoplasm, either primary or secondary. Unless the cytomorphol- ogy suggests a neoplasm, glandular cells are considered benign. (Washing, TP, high mag.). (b) Benign glandular cells. The nuclei are uniform in size and shape, with a bland chromatin pattern, and the cells maintain a columnar architecture. (Washing, SP, high mag.). (c) Cystitis cystica may appear as a single layer of glandular cells. They closely resemble endocervical cells and could be from a case of endocervicosis. This mucosal strip was from a focus of cystitis cystica. (Washing, TP, high mag.). (d) Another tight glandular group, a BUTF, demonstrates nuclear compression by relatively large cytoplasmic vacuoles. Regardless of their origin, these cells fulfill the criteria of benignity, making the diagnosis of NHGUC appropriate. (Washing, TP, high mag.). (e) Benign glandular cells. The glandular cells are numerous in this field, and the formation of a hyperchro- matic crowded group may be alarming. It is easiest to identify their columnar morphology at the edges or in the singly dispersed cells. Note how the nuclei are all relatively similar in size, in addi- tion to maintaining their apical cytoplasm. (Washing, SP, high mag.). (f) Benign glandular cells. In this separate field, the glandular cells are mostly individually dispersed and some appear more cercariform than columnar. The cells have similarly sized, oval-shaped nuclei with bland chroma- tin. This cytomorphologic pattern has significant overlap with that of a LGUN but without a fibro- vascular core. Fortunately, there are no features of HGUC, so a diagnosis of NHGUC is not challenging to make. (Washing, SP, intermediate mag.) Fig. 3.6 (continued) Fig. 3.7 Renal tubular cells (RTC). (a) RTCs can be very small, the size of histiocytes. When aggregated as in this group, a cast should be considered. There are usually variable amounts of cellular degeneration (voided, SP, high mag.). (b) This larger fragment represents a tubular cast. The renal tubular cells vary from small with scant cytoplasm to larger and vacuolated. The patient was in renal failure. (Voided, SP, high mag.). (c) RTC within this cast demonstrate small nuclei with relatively abundant cytoplasm. The material supporting the RTC in the cast is protein. The patient was in renal failure.(Voided, CS, high mag.) Fig. 3.8 Cellular degeneration secondary to stasis. When cells sit in the urinary tract for long periods of time, they begin to degenerate. Many of the cells here have small, dark pyknotic nuclei but retain a large amount of cytoplasm. The cells have granular cytoplasm and some cells have irregular cytoplasmic vacuoles. More severely degenerated cells have lost their nuclear-cytoplasmic interface. The dark nuclei may be concerning for urothelial carcinoma; however, specimens with degenerated HGUC cells will often contain some larger cells, and the nuclei will be larger in size than those seen here. (Catheterized, SP, intermediate mag.) Fig. 3.9 Degeneration. (a) Specimens may contain a large number of degenerated cells, which can give the impression of a proliferative or neoplastic process. Examination of each individual cell in this field is reassuring, as the cells contain dark yet very small nuclei and maintain their N/C ratios. Many are RTCs (voided urine, SP, high mag.). (b) This degenerated benign cell has chromatin that appears smudged and homogenous. The N/C ratio is low and the cytoplasm is vacuolated (voided urine, SP, high mag.). (c) These degenerated cells are enlarged and dark, but the nuclear-cytoplasmic interface is becoming lost in the cell on the right. The nuclei of both cells contain a condensed ball of chromatin. These cells are too far degenerated for assessment. (Voided urine, SP, high mag.). (d) At low magnification, this cell may appear to have a high N/C with a prominent nucleolus, but the cytoplasm is vacuolated and the nuclear-cytoplasmic interface cannot be clearly demarcated. The specimen diagnosis should not include consideration of this cell, given the severity of its degenera- tion. (Voided urine, SP, high mag.) Fig. 3.9 (continued) Fig. 3.10 Degeneration of benign cells compared to high-grade urothelial cells. (a) Melamed-Wolinska bodies. These intracytoplasmic round red inclusions are not indicative of malignancy. (Voided, TP, high mag.). (b) HGUC cells are often degenerated, limiting a definitive diagnosis of malignancy. Here, two cells have pyknotic nuclei which cause the cells to have decreased N/C ratios. However, the chromatin is very dark, and the nuclei are still larger than the nuclei of adjacent benign cells an indication that these cells may have an abnormally high content of DNA. The nuclear borders are highly irregular, but the chromatin pattern cannot be assessed due to the hyperchromasia caused by degeneration. (Voided, SP, high mag.). (c) These umbrella cells are relatively well-preserved but appear smaller than usually well-preserved versions. Smaller forms have N/C ratios that approach 0.5 and can be visually striking at low magnifications. However, they maintain their granular cytoplasm, distinctive nucleoli, and marginated chromatin, reassuring features that help identify them as umbrella cells. (Voided, SP, high mag.) Fig. 3.11 Benign urothelial tissue fragment (BUTF). (a) Voided BUTF can be seen in voided urines and do not mandate a diagnosis of AUC. In this fragment, nuclei are uniform in size and shape, evenly spaced, and with finely granular chromatin. (Voided, SP, high mag.). (b) Instrumented from renal pelvis. Cell fragments from the renal pelvis should be cautiously considered. In this case, the diagnosis rendered was "suspicious for low-grade neoplasm." The excision of the kidney revealed only urothelial hyperplasia overlying a subepithelial hemangioma. Retrospective review recognized the uniform nuclear size and round shape. The resemblance to a papillary lesion was likely the result of instrumentation. (Renal pelvic washing, CS, high mag.). (c) BUTF. This fragment contains cells with oval-shaped nuclei and mildly irregular nuclear contours. However, the nuclei are similar in size, and the chromatin pattern is bland, with the nuclei containing one to two small chromocenters rather than coarse/clumpy chromatin. (Bladder washing, SP, high mag.). (d) BUTF. While the N/C ratios in these papillary fragments may seem elevated, examination of cells lying flat at the edges reveals a reassuring amount of cytoplasm. This architecture is not concerning unless a fibrovascular core is present. (Bladder washing, SP, high mag.) Fig. 3.11 (continued) Fig. 3.12 BUTF in voided urine. (a) This patient was found to have a bladder mass which was subsequently biopsied and identified as a leiomyoma. It is uncertain whether the mass may have contributed to the natural exfoliation of the BUTF seen in this initial voided urine specimen. While the nuclei are oval and have mildly irregular nuclear contours, the nuclei are similar in size and have a bland chromatin pattern. (Voided urine, SP, high mag.). (b) Additional field containing a BUTF in the same patient. (Voided urine, SP, high mag.) Fig. 3.13 Atypical urothelial tissue fragment (AUTF) adjacent to HGUC cell. The cells in this urothelial tissue fragment display atypical features: irregular nuclear membranes, increased N/C ratios, coarse chromatin, and anisonucleosis. It is difficult to assess N/C ratios and chromatin pat- tern in a three-dimensional tissue fragment; thus, one may have an increased threshold to make a diagnosis of AUC or SHGUC based on a tissue fragment alone. The more concerning cell is to the bottom right of the AUTF, which has all the qualitative features of HGUC. This patient had HGUC on follow-up biopsy. (Bladder washing, SP, high mag.) Fig. 3.14 Low-grade urothelial neoplasm (LGUN). (a) A monotonous population of neoplastic cells fills the field, almost forming a sheet. However, the presence of vascular structures containing flattened endothelial cell nuclei indicates that this is a papillary lesion. The neoplastic cells have bland chromatin and are small in size. This finding falls under the NHGUC diagnostic category (renal pelvic washing, Cytospin, medium mag.). (b) At higher magnification, one can appreciate the bland chromatin pattern of the neoplastic cells. The nuclei are oval-shaped and have minimal irregularity in their nuclear contours. These features are not compatible with HGUC category (renal pelvis washing, Cytospin, high mag.). (c) This papillary fragment contains an endothelial- lined fibrovascular core. Numerous monomorphic neoplastic cells line the core, and detached neo- plastic cells can also be seen nearby in the background. The N/C ratio of these cells (which is less than 0.5) can be more clearly assessed using the detached cells rather than the cells within the three-dimensional papillary fragment (renal pelvis washing, Cytospin, high mag.). (d) In a separate field, small fragments of neoplastic cells can be seen which lack the fibrovascular core. They lack features of HGUC and have significant overlap with benign urothelial tissue fragments. Thus, the cytomorphologic features of individual LGUN cells and tissue fragments are nonspecific (renal pelvis washing, Cytospin, high mag.) Fig. 3.14 (continued) Fig. 3.15 LGUN. A true papillary tissue fragment contains a fibrovascular core, as seen in this field, and indicates the presence of a papillary urothelial neoplasm. Neoplastic cells line the fibrovascular core. Many cells can also be seen in the background, which have been forcibly removed from the papillary structure during the washing procedure. The cells have monomorphic nuclei and N/C ratios that approach 0.5. They lack the irregular nuclear contours, coarse chromatin, and hyperchromasia that would be seen in HGUC (bladder washing, Cytospin, medium mag. [a] and high mag. [b]) Fig. 3.16 LGUN. In this field, the neoplastic cells are predominantly attached to the fibrovascular stalk. The cells have oval-shaped nuclei with mild nuclear contour irregularities and hypochromasia; they lack coarse chromatin (bladder washing, Cytospin, high mag) Fig. 3.17 LGUN. The N/C ratios of these dispersed single cells are clearly below 0.5. The cells possess a few small chromocenters and lack the "clumpy" chromatin seen in HGUC (bladder washing, Cytospin, high mag) Fig. 3.18 Urothelium with nephrolithiasis (BUTF). A BUTF in a voided urine may be the result of one or several among numerous causes. In this patient, nephrolithiasis was the reason. Cellular changes are mild when compared to those in the photos to follow. The absence of any fibrovascular stalk eliminates a diagnosis of LGUN. (Voided, SP, high mag.) Fig. 3.19 Urothelium with nephrolithiasis (AUTF). (a) A sheet of urothelium consists of relatively uniform cells with moderately hyperchromatic nuclei. Even though the nuclear chromatin is darker than normal, the presence of a bladder stone is reason enough for the changes. Because of the history and presence of only mild atypia, this sample was placed in the NHGUC category. (Voided, SP, medium mag.). (b) Compare the cells in the center of the field with those to the right, especially considering the nuclear chromatin and nuclear shapes. The central cells are hyperchromatic and the shapes vary. Inflammation is seen in the background. Without the history of nephrolithiasis, these cells would indicate a diagnosis of AUC. If there were any consideration of a urothelial lesion in addition to lithiasis, a note or a diagnosis of AUC is appropriate. (Washing, CS, medium mag.). (c) Most often, direct evidence of stones is not so dramatic as in this photograph. Variation in cells in the background can be appreciated. (Washing, SP, low mag.). (d) A small fragment of hyperchromatic urothelial cells is adjacent to an X-shaped crystalloid. The nuclei of the cells in the fragment have slightly irregular borders, and the N/C ratios are difficult to assess within a tissue fragment. The presence of crystals and/or crystalloids can account for mild atypia in urothelial tissue fragments, as seen here, and prevent classification into the AUC category. (Voided urine, SP, high mag.) Fig. 3.19 (continued) Explanatory Note Urolithiasis was first noted as a cause of false-positive diagno- ses by Papanicolaou. The clinical history, if available, is valuable to avoid a false- positive diagnosis. As described above, BUTF may be seen in instrumented urines and sometimes in voided urine from patients with stones. Urothelial carcinoma and squamous cell carcinoma have been associated with renal calculi with and without associated infection [23, 24]. Whether this association represents a causal relation- ship is not clear Fig. 3.20 Herpes simplex virus (HSV). Herpes criteria are similar to those seen in other cytologic preparations, with the three Ms: (nuclear) molding, (chromatin) margination, and multinucleation. HSV rarely infects the urinary tract and when seen in urinary tract specimens may arise from contaminating extraurinary sites (voided urine, SP, high mag.) Fig. 3.21 Polyomavirus - classic (a), spider web (b-c), benign case (d-f). (a) Classic polyoma (BK) cytopathic effect includes enlargement of the nucleus and nuclear chromatin homogenization and/or chromatin margination. The shape of the nucleus is always round or oval with a very smooth outline. The cell cytoplasm may be absent or, in the case of these cells, form degenerating tails ("comet cells"). In this case, the chromatin appears somewhat "clumpy" which may initially cause concern for HGUC. However, all the other features suggest this is simply BK cytopathic effect (voided, SP, high mag.). (b) Dissolution of the nuclear chromatin is also a characteristic of poly- omavirus infection. The size and shape of the nucleus are the same as the classic features. (Voided, SP, high mag.). (c) If the focal plane is changed, then a spider web of the cytoskeleton comes into view. (Voided, SP, high mag.). (d) The assortment of pale and darker cells is striking on low mag- nification. (Washing, TP, low mag.). (e) Closer view will demonstrate the reasons for the dark cells observed on low magnification. Almost all the cells display glassy nuclear inclusions diagnostic of polyomavirus (washing, TP, high mag.). (f) The BK-infected cells in this field demonstrate positive nuclear staining for SV40 by immunocytochemistry. In most instances, a morphologic assessment is sufficient for the diagnosis of BK infection; furthermore, infection with BK (and SV40 positiv- ity) does not exclude HGUC. (Voided urine, SV40 immunocytochemistry, high mag.) Fig. 3.21 (continued) Fig. 3.22 Schistosoma haematobium (image courtesy of Greta Neethling, Tygerberg Academic Hospital, South Africa). (a) Intact Schistosoma haematobium ovum. The ovum has the character- istic terminal spine, which distinguishes it from other schistosomes. However, S. haematobium is the only schistosome that involves the urinary tract. The intact ovum contains the schistosome miracidium. The faint-staining nuclei within the miracidium is one way to distinguish the ova from similarly shaped crystals. (Voided urine, conventional smear, high mag.). (b) Hatching Schistosoma haematobium. The ovum hatches, releasing the miracidium which is infectious to snails. The hatching can occur after excretion or within the urinary tract. (Voided urine, conventional smear, high mag.). (c) Hatching Schistosoma haematobium. Alternative view. (Voided urine, conventional smear, high mag.). (d) Naked Schistosoma haematobium miracidium. Note the internal nuclear staining and cilia lining the edges of the miracidium. (Voided urine, conventional smear, high mag.). (e) Empty Schistosoma haematobium ova. The only structures that may be seen are the empty ova in a background of inflammation and granular debris. These may be more difficult to distinguish from vegetable material or crystals. The presence of the terminal spine and inflamma- tory response, together with patient history of being from an endemic area, prompts the diagnosis. (Voided urine, conventional smear, high mag.) Fig. 3.22 (continued) Fig. 3.23 Radiation changes. Patients may receive radiation treatment to the urinary tract to treat a primary malignancy or areas of the urinary tract may become radiated due to treatment of extra- urinary malignancies, such as cervical cancer. The changes seen are similar to those seen at other anatomic sites: nucleomegaly with a corresponding increase in cytoplasm, multinucleation, and cytoplasmic vacuolization. (Voided urine, SP, high mag.) Fig. 3.24 Granulomatous reaction following BCG immunotherapy. (a) Multinucleation in superficial urothelial cells is common. In contrast, Langhans-type giant cells resulting from fused macrophages are multinucleated but have their smaller and slightly hyperchromatic nuclei clustered at one pole of the cytoplasm. Clinical history revealed recent BCG instillation following diagnosis of bladder cancer. (Voided, CS, high mag.). (b) In addition to Langhans giant cells, granulomata can be found in urine following BCG immunotherapy. These granulomata are no different from those in any other body site, complete with monocytes, lymphocytes, and histiocytes in a tight mélange. (Washing, TP, high mag.) Fig. 3.25 Seminal vesicle cells. Seminal vesicle cells are unusual and may provide confusion with HGUC cells because of their large size and nuclear hyperchromasia. Two clues to their identity include intracytoplasmic yellow lipofuscin pigment (arrow) and accompanying sperm. (Washing, TP, high mag.) Explanatory Note Seminal vesicle cells have an abnormal DNA content and potentially are a pitfall for DNA-based adjuvant tests [41]. When seminal vesicle cells are recognized by the presence of yellow pigment and mature spermatozoa in the back- ground, there is no need to call the urine specimen AUC Fig. 3.26 Enteric cells from a urinary diversion post-cystectomy. (a) One superficial urothelial cell is present to conveniently compare with the small round cells in the figure. All are of the same size and have small punctate nuclei. These are typical of degenerated enteric cells. (Catheterized, TP, medium mag.). (b) Following a cystectomy, a diversionary pouch is constructed, lined by cells from the portion of the intestine used. They usually are single and closely resemble histiocytes. Sometimes they cluster, which can present a diagnostic dilemma. Careful focusing will reveal the small nuclei, dissimilar to HGUC. (Catheterized, SP, medium mag.) Fig. 3.27 Urinary diversion specimen. (a) Urinary diversion specimens usually contain numerous small degenerated cells in a background of granular debris. The degenerated cells arise from the intestinal segment used for diversion. The cells have dark, yet very small, nuclei and granular cytoplasm. (Catheterized, SP, low mag.). (b) A separate field shows the benign degenerated cells with apoptotic bodies. These patients usually have a history of aggressive HGUC and are at high risk for recurrence. HGUC cells would be larger than the small benign degenerated cells seen in diversion specimens. This field contains strictly benign degenerated cells, though some three- dimensional areas of cellular piling could appear atypical at lower magnification (catheterized, SP, high mag.) Fig. 3.28 Guar bean. (a) The vegetable cells that comprise this structure have a distinctive appearance, with pink-staining geometrically shaped nuclei. Guar bean is a component of adhesive material used on skin around a urostomy stoma. (Catheterized, SP, high mag.). (b) An additional view of vegetable material derived from guar bean in a patient with a urostomy. While the material is visually striking, its appearance is unlikely to be confused for a malignant process.(Catheterized, SP, medium mag.) ■■■【4】 AUC Fig. 4.1 Diagnostic ideal: in the ideal testing situation, the values derived from a test, be they numeric or a morphologic impression, would clearly separate the non-diseased population from a diseased population Fig. 4.2 Diagnostic reality: in the usual testing situation, some benign states yield values or fea- tures that overlap with those found in a diseased population Fig. 4.3 Diagnostic reality: the area of overlap between benign states and diseased states consti- tutes a region of diagnostic uncertainty and provides a conceptual representation of the domain of atypia Fig. 4.4 Benign urothelial cells. The top left corner shows benign superficial urothelial cells (umbrella cells), and the bottom right corner has benign intermediate/basal type urothelial cells. Although the non-superficial urothelial cells have a high N/C ratio, they have a smooth nuclear contour and do not show nuclear enlargement, placing them in the "negative" category. The follow- up diagnosis was benign. (Bladder washing, TP, high mag.) Fig. 4.5 Benign urothelial cells. Intermediate urothelial cells display slight nuclear enlargement and prominent chromocenters. There is no nuclear hyperchromasia, clumped chromatin or nuclear contour irregularity. These changes are consistent with the "negative" category. The follow-up diagnosis was benign. (Bladder washing, TP, high mag.) Fig. 4.6 Atypical urothelial cells (AUC). Two groups of urothelial cells are shown. The group on the top left is orderly, composed of intermediate type urothelial cells with smooth nuclear contours, and no features of atypia. The group on the bottom right is disorganized; urothelial cells have high N/C ratio and nuclear contour irregularity. Nuclear chromasia is similar in both groups. Due to the cytologic atypia seen in the group on the bottom, this case should be categorized as AUC. (Voided urine, TP, medium mag.) Fig. 4.7 Atypical urothelial cells (AUC). A group of atypical urothelial cells with variable N/C ratios and nuclear contour irregularity. The absence of hyperchromasia and the presence of degenerated clumped chromatin preclude a diagnosis of SHGUC. (Bladder washing, TP, high mag.) Fig. 4.8 Atypical urothelial cells (AUC). Atypical urothelial cells with high N/C ratio, enlarged nuclei (compared to the neighboring benign urothelial cells), and mild nuclear contour irregularities. The chromatin is uniform and hypochromatic, precluding a diagnosis of SHGUC. (Bladder Washing, TP, high mag.) Fig. 4.9 Atypical urothelial cells (AUC). (a) Atypical urothelial cells with high N/C ratio, enlarged nuclei (compared to the neighboring benign urothelial cells), and mild nuclear contour irregulari- ties. (Bladder washing, TP, medium mag.). (b) Another image of the same case shows irregular nuclear contours in a group of urothelial cells that have degenerative cellular changes. The cellular changes are worrisome, but the degree of degeneration and lack of marked atypia precludes a definitive diagnosis. (Bladder washing, TP, medium mag.) Fig. 4.10 Atypical urothelial cells (AUC). Urothelial cells display high N/C ratio, anisonucleosis, nuclear contour irregularities, and alteration of nuclear polarity. The chromatin is finely granular with minimal hyperchromasia. This patient had renal urolithiasis on follow-up. These are reactive changes and retrospectively categorize this sample as NHGUC. (Renal pelvis washing, TP, high mag.) Fig. 4.11 Atypical urothelial cells (AUC). (a) Urothelial cells display increased N/C ratio, nuclear enlargement, and mild hyperchromasia. (Renal pelvis washing, TP, high mag.). (b) The follow-up nephrectomy showed a low-grade urothelial carcinoma by histology, causing a filling defect on imaging. (Nephrectomy surgical sample, H&E, medium mag) Fig. 4.12 Atypical urothelial cells (AUC). Urothelial cells have increased N/C ratio, enlarged nuclei, and conspicuous nuclear contour irregularities. The chromatin is coarse and clumped. In some of the urothelial cells, the N/C ratio is <0.5, and there are degenerative changes (such as fray- ing of the cytoplasm), but due to the hyperchromasia and coarse chromatin pattern, a diagnosis of AUC was rendered. Follow-up revealed a high-grade urothelial carcinoma of the kidney. (Bladder washing, TP, high mag.) Fig. 4.13 Atypical urothelial cells (AUC). Urothelial cells with high N/C ratio and nuclear hyper- chromasia. These three figures display all the atypical urothelial cells that are present in the speci- men. (a) Atypical urothelial cells (AUC) (upper left). Urothelial cells display irregular nuclear contours and cytoplasmic vacuolization, consistent with degenerative changes. (b) Aggregate of cells (lower left) have markedly irregular nuclear contours and variation in nuclear size. In com- parison to the neighboring squamous cells, there is mild nuclear hyperchromasia. There are cellu- lar degenerative changes, such as partial loss of the cytoplasm and loss of crisp nuclear detail. (c) Small aggregate of atypical cells adjacent to squamous cells (right). The urothelial cell nuclei also show degeneration, but the one cell with the high N/C ratio is worrisome. The patient is a 36-year- old woman with recurrent urolithiasis and no history of urothelial carcinoma. Her age and history are low-risk factors for bladder cancer; however, without a history of renal calculi, these cytologic features warrant the diagnosis AUC. (Voided, TP, high mag.). The follow-up was benign Fig. 4.14 Atypical urothelial cells (AUC). The urothelial cell shown here has a high N/C ratio, nuclear enlargement, and prominent nucleoli. Chromatin is pale and slightly coarse, but the chro- matinic rim is thin and uniform. Compared to the nucleus of the neighboring inflammatory cells, the nucleus of the atypical urothelial cell is much larger. Follow-up with cystoscopy and urinary bladder biopsy within 6 months showed urothelial mucosa with reactive changes, likely due to inflammation. (Bladder washing, TP, high mag.) Fig. 4.15 Atypical urothelial cells (AUC). Urothelial cells show high N/C ratio, nuclear enlarge- ment, and hyperchromasia. Some have prominent nucleoli. The nuclear contours are relatively regular. The paucity of the atypical cells precluded a HGUC diagnosis. There are more than five abnormal urothelial cells, and while they do not all show a N/C ratio >0.7, due to the presence of the other criteria mentioned above, a diagnosis of SHGUC may also be appropriate for this case. The follow-up showed high-grade urothelial carcinoma in the urinary bladder. (Bladder washing, TP, high mag.) Fig. 4.16 Atypical urothelial cells (AUC). Urothelial cells with high N/C ratio, mild nuclear enlargement, and hyperchromasia with some degenerative changes in the cytoplasm. The follow- up showed high-grade urothelial carcinoma of the bladder. (Bladder washing, TP, high mag.) Fig. 4.17 Atypical urothelial cells (AUC). A single urothelial cell with high N/C ratio, nuclear enlargement, hyperchromasia, and irregular nuclear contours with some degenerative cytoplasmic changes. Compare this cell to the surrounding benign urothelial cells with low N/C ratio and regu- lar chromatin pattern. Since this was the only atypical urothelial cell in the case, either an AUC or a SHGUC diagnosis would be appropriate for this case. The patient was lost to follow-up. (Bladder washing, TP, high mag.) Fig. 4.18 Atypical urothelial cells (AUC). (a) A cohesive group of urothelial cells with high N/C ratio, mild nuclear enlargement, and hyperchromasia on a Cytospin preparation. The chromatin pattern is mostly uniform. (Bladder washing, Cytospin, high mag.). (b) Follow-up showed a low- grade urothelial carcinoma on biopsy (urinary bladder biopsy, H&E, medium mag.) Fig. 4.19 (a–c) Atypical urothelial cells (AUC). (a) Single cells and groups of urothelial cells with high N/C ratio and nuclear enlargement are depicted. (b-c) Compared with nearby unbrella cells there are single urothelial cells with high N/C rtio and nuclear enlargement. However, the chromatin is smooth and there is a lack of nuclear contour irregularity. The patient was post-BCG therapy, and the follow-up urinary bladder biopsy showed reactive epithelial changes. (Catheterized urine, Cytospin, high mag.) ■■■【5】Suspicious for HGUC Fig. 5.1 SHGUC. One single abnormal well- preserved intermediate urothelial cell displays an eccentric nucleus with increased N/C ratio, hyperchromasia, irregular clumpy chromatin, and mildly irregular nuclear membrane. (Voided urine, TP, high mag) Fig. 5.2 SHGUC. Rare but abnormal well- preserved intermediate urothelial cells show increased N/C ratios, hyperchromasia, and irregular nuclear membranes. (Catheterized urine, CS, high mag) Fig. 5.3 SHGUC. A few abnormal intermediate urothelial cells, many of which are well-preserved and feature an increased N/C ratio, hyperchromasia, irregular clumpy chromatin, and severely irregular nuclear membranes. In this example in which pleomorphism is present, a diagnosis of HGUC may also be appropriate. (Catheterized urine, CS, med. mag) Fig. 5.4 SHGUC. A cell cluster composed of six abnormal well-preserved intermediate urothelial cells displays increased N/C ratios, hyperchromasia, clumpy chromatin, and irregular nuclear membranes. Note that despite similar nuclear characteristics, there is a range of N/C ratios from 0.5 to 0.8. An HGUC diagnosis may be appropriate in this case, especially in the presence of a previous history of HGUC. (Catheterized urine, CS, high mag) Fig. 5.5 SHGUC. Few intermediate urothelial cells exhibit an increased N/C ratio, hyperchromasia, and irregular nuclear membranes in the absence of clear chromatin details. (Cystoscopic urine, CS, high mag) Fig. 5.6 SHGUC. One severely abnormal urothelial cell (left) has an increased N/C ratio and coarse and clumpy chromatin but regular nuclear membranes. Also present is a degenerated atypical cell (top) that does not fulfill the criteria for SHGUC. (Cystoscopic urine, CS, high mag) Fig. 5.7 SHGUC. One single abnormal well- preserved intermediate urothelial cell has an increased N/C ratio, hyperchromasia, irregular clumpy chromatin, and smooth regular nuclear membranes. Note the severe hyperchromasia in comparison to the normal intermediate urothelial cells (right). (Catheterized urine, CS, high mag) Fig. 5.8 SHGUC. One abnormal well-preserved intermediate urothelial cells has increased N/C ratio, severe hyperchromasia, irregular nuclear membranes but no easily evaluable chromatin pat- tern. The background contains smaller degenerated cells with hyperchromatic nuclei, red cell membranes, and necrotic debris, suggesting an invasive lesion. The follow-up biopsy was invasive high-grade urothelial carcinoma (voided urine, CS, high mag) Fig. 5.9 SHGUC. Rare but abnormal well- preserved intermediate urothelial cells display increased N/C ratios, moderate hyperchromasia, irregular chromatin patterns, and irregular nuclear membranes. (Voided urine, SurePath,med mag) Fig. 5.10 AUC. Cell clusters of well-preserved intermediate urothelial cells demonstrate variable N/C ratios and hyperchromasia. The degree of hyperchromasia is mild in comparison to the normal intermediate cell nucleus (upper right). In addition, the cells do not show clumpy chromatin pattern or irregular nuclear membranes which preclude the assignment of a SHGUC diagnosis. (Voided urine, TP, high mag) Fig. 5.11 AUC. Abnormal intermediate urothelial cells with increased N/C ratios and irregular nuclear membranes in the absence of nuclear hyperchromasia preclude a diagnosis of SHGUC. The follow-up diagnosis was LGUC. (Voided urine, TP, high mag) Fig. 5.12 AUC. Intermediate urothelial cells with increased N/C ratios and irregular nuclear mem- branes in the absence of nuclear hyperchromasia are insufficient criteria for a diagnosis of SHGUC. (Voided urine, TP, high mag) Fig. 5.13 AUC. One single and degenerated urothelial cell has an enlarged nucleus, with increased N/C ratio, mild hyperchromasia, and irregularly distributed clumpy chromatin. Note the presence of incomplete cytoplasm and poorly preserved chromatin details. A SHGUC diagnosis should not be rendered on degenerated cells only. However, atypical degenerated hyperchromatic cells are often seen in the background of cases diagnosed as SHGUC or HGUC. Consequently, the presence of degenerated atypical hyperchromatic cells warrants careful evaluation in order to rule out the presence of similar non-degenerated cells in which a SHGUC or a HGUC diagnosis can be rendered. (Voided urine, TP, high mag) Fig. 5.14 (a) AUC. One single and degenerated urothelial cell displays an increased N/C ratio, hyperchromasia, and irregularly distributed clumpy chromatin. Note the presence of incomplete cytoplasm and discontinuous nuclear membranes. In the presence of cellular degeneration, a SHGUC diagnosis should not be rendered. (Voided urine, TP, high mag.) (b) AUC. One single and degenerated urothelial cell shows increased N/C ratio, hyperchromasia, and irregularly distributed clumpy chromatin. Note the presence of incomplete cytoplasm and discontinuous nuclear mem- branes (Voided urine, TP, high mag) Fig. 5.15 NHGUC. Reactive urothelial cells often show increased N/C ratios as seen in the current example. However, hyperchromasia is absent, and the nuclei show fine regularly distributed chromatin with small visible nucleoli. Nuclear membranes are smooth and regular. (Voided urine, TP, high mag) Explanatory Notes Explanatory Note 1 Increased N/C ratio generally refers to an enlarged nucleus that occupies at least half of the surface of the cell provided the cell is not degener- ated and the cytoplasm is complete. The N/C ratio of the abnormal cell should exceed 0.7, although cases may have some abnormal cells having an N/C ratio between 0.5 and 0.7 Explanatory Note 2 Hyperchromasia refers to an increased density of the nuclear chromatin of abnormal urothelial cells as compared with that of normal umbrella or intermediate urothelial cells. The degree of hyperchromasia is moderate to severe; a mild difference in the chromatin density between the questionable urothelial cell assessed and the normal accompanying cells does not warrant a “suspicious” diag- nosis (Fig. 5.10). However, since there is a variant of HGUC with hypochromatic nuclei, all cellular criteria must be evaluated before the case category is chosen (see Chap. 6) Explanatory Note 3 In the absence of clear and evaluable chromatin details, the irregular clumpy chromatin pattern is not required in the presence of the other fea- tures (high N/C ratio, nucleomegaly, irregular nuclear membranes, hyperchromasia) (Figs. 5.5, and 5.8). Similarly, the presence of nuclear membrane irregularity is not required in the presence of the other features (increased N/C ratio, nucleomegaly, hyperchromasia, irregular clumpy chromatin) (Figs. 5.6, and 5.7) Explanatory Note 4 Intermediate urothelial cells with increased N/C ratio, nucleo- megaly, and mild hyperchromasia in the absence of evaluable chromatin details and irregular nuclear membranes should not be labelled as "suspicious" but as AUC instead. Similarly, cells with increased N/C ratio and irregular nuclear membranes in the absence of moderate or severe hyperchromasia should generally not be labelled as "suspicious" (Figs. 5.11, and 5.12) Explanatory Note 5 While the category of AUC includes a subset of cases showing cellular degeneration, a SHGUC diagnosis should not be rendered solely on degen- erated cells, although some of the severely atypical cells may be degenerated. Cellular degeneration is often present in voided specimens and can take the form of incomplete cytoplasm, poorly preserved chromatin details, or discontinuous nuclear membranes. The resulting altered cellular morphology can be problematic from the diagnostic standpoint for the following reasons Nuclei may look "blown-up" resulting in a falsely increased N/C ratio (Figs. 5.13, and 5.14) Cytoplasm may be incomplete which makes it difficult to assess the N/C ratio, often making it appear increased (Fig. 5.14) Nuclear membranes may seem irregular from dehydration Nuclei may look hyperchromatic as a feature of degeneration, and not as a result of an abnormal chromatin (Figs. 5.13, and 5.14) Explanatory Note 6 Although prominent nucleoli can be appreciated in HGUC cells, this finding is not consistently present, and therefore this criterion is not required for a diagnosis of SHGUC. In addition, visible to prominent nucleoli can be seen in reactive urothelial cells, which may have an increased N/C ratio border- ing on and sometimes exceeding 0.5; however, unlike cells in SHGUC or HGUC, such reactive cells exhibit regular nuclear membranes and fine chromatin (Fig. 5.15) ■■■【6】Positive for HGUC Fig. 6.1 HGUC demonstrating a wide range of cell sizes and shapes. Nuclear hyperchromasia is pronounced (voided urine, TP, low mag) Fig. 6.2 HGUC with numerous malignant cells displaying heterogeneity. The tumor cells vary in size and shape and are arranged in clusters and single cells. Necrosis is present in the background (voided urine, SP, low mag) Fig. 6.3 (a) Malignant cells are arranged in small groups and as single cells. Pleomorphism and background necrosis are also present (voided urine, SP, medium mag.). (b) Malignant cells with high N/C ratios and irregular nuclear membranes. The sample is stained lightly, so observers are cautioned to use benign cells in the background as stain intensity controls. Also, note the presence of lymphocytes, which can be used as a control for nuclear size (washing, TP, medium mag) Fig. 6.4 Loosely cohesive HGUC cells demonstrate high N/C ratios which are >0.7 (voided urine, TP, high mag) Fig. 6.5 An aggregate of hyperchromatic HGUC cells with high N/C ratios which are >0.7 (voided urine, TP, medium mag) Fig. 6.5 An aggregate of hyperchromatic HGUC cells with high N/C ratios which are >0.7 (voided urine, TP, medium mag) Fig. 6.6 A loosely cohesive group of HGUC cells with a wide range in size (voided urine, TP, high mag) Fig. 6.7 Hyperchromatic HGUC cells presenting as a cohesive group. The majority of tumor cells have high N/C ratios (bladder washing, TP, high mag) Fig. 6.8 Nuclear membrane irregularity and focal thickness of nuclear membranes are evident in this group of HGUC cells (bladder washing, TP, high mag) Fig. 6.9 HGUC cells with coarsely clumped nuclear chromatin, but with N/C ratios <0.7. However, all other features, including enlarged cell size, are seen in HGUC (voided urine, TP, high mag) Fig. 6.10 Coarse chromatin and nuclear membrane irregularity is present in HGUC cells (bladder washing, TP, high mag) Fig. 6.11 Nuclear membrane irregularity, hyperchromasia, coarse chromatin, and cytoplasmic vacuolation are present in HGUC. The vacuoles probably reflect degeneration but may also be found in cells with glandular differentiation. The follow-up biopsy confirmed the diagnosis of HGUC with glandular differentiation (bladder washing, TP, high mag) Fig. 6.12 HGUC cells exhibiting nuclear hyperchromasia, nuclear membrane irregularity, coarse chromatin, and atypical mitoses. The N/C ratios vary, from low to very high (bladder washing, TP, high mag) Fig. 6.13 Loosely cohesive HGUC tumor cells with a very wide range of N/C ratios. The nuclear features are helpful in confirming the diagnoses of malignant cells with an N/C ratio lower than 0.7 (voided urine, TP, high mag) Fig. 6.14 A majority of malignant cells with N/C ratio lower than 0.7 but classic features of HGUC. An N/C ratio of at least 0.7 is a benchmark for diagnosing HGUC, present in rare tumor cells in this loosely cohesive group (voided urine, TP, high mag) Fig. 6.15 Malignant cells can be large with abundant cytoplasm, creating a low N/C ratio. All other features of HGUC are present. Note the tumor necrosis clinging to the cells (bladder washing, TP, high mag) Fig. 6.16 A multinucle- ated malignant cell with abundant cytoplasm, possibly the result of degeneration (voided urine, SP, high mag) Fig. 6.17 A single malignant cell with very low N/C ratio. The nuclear features are consistent with HGUC. If less than five similar cells are present in the specimen, then the diagnosis of the sample should be SHGUC (voided urine, TP, high mag) Fig. 6.18 Hypochromatic HGUC tumor cells are rarely present as a solitary finding. High N/C ratios and nuclear membrane irregularity are also present to confirm the diagnosis (voided urine, CS, medium mag) Fig. 6.19 Hypochromatic HGUC tumor cells predominate along with rare hyperchromatic HGUC cells (voided urine, CS, medium mag) Fig. 6.20 Degenerated tumor cells with cytoplasmic vacuolation and frayed cell membranes (bladder washing, TP, medium mag) Fig. 6.21 Degenerated tumor cells with irregular nuclear membranes and pyknosis (bladder washing, TP, medium mag) Fig. 6.22 A few cells show classic features of HGUC adjacent to tumor cells with squamous differentiation (Bladder washing, TP, high mag.) Fig. 6.23 The squamous cells have hyperchromatic nuclei with clumped chromatin. The cytoplasm is dense, keratinized, and orangeophilic. A keratinized tad-pole cell with a Herxheimer spiral is also present. Keratin flakes and necrosis are present in the background (bladder washing, TP, high mag) Fig. 6.24 Mucin-filled goblet cells with hyperchromatic nuclei and coarse chromatin are present in HGUC with glandular differentiation (bladder washing, TP, high mag) Fig. 6.25 Scattered single malignant cells with mucin-filled cytoplasm (arrow) are representative of glandular differentiation (bladder washing, TP, medium mag) Fig. 6.26 Tightly packed three-dimensional micropapillary clusters with hyperchromasia, high N/C ratio, and some vacuolated cells in a case of micropapillary HGUC (voided urine, TP, medium mag) Fig. 6.27 Large, discohesive hyperchromatic malignant cells with abundant and thick cytoplasm and an eccentrically placed nucleus represent a plasmacytoid HGUC (bladder washing, TP, high mag) ■■■【7】Cytology of Upper Urinary Tract Fig. 7.1 HGUC arising in the renal pelvis. (a) This field is cellular and contains cells of different sizes and varied N/C ratios. A cluster of three particularly large cells can be seen in the top center. Despite having minimal nuclear contour irregularities, the N/C ratios of these cells exceeds 0.7 and the cells possess coarse chromatin, features concerning for HGUC. (Renal pelvis washing, SP, medium mag.). (b) At higher magnification, the coarse chromatin pattern of these larger cells can be better appreciated. Some of the smaller cells in the background also have high N/C ratios and coarse chromatin and are also likely malignant. A mitotic figure (arrow) can be seen, a finding that is not entirely specific for HGUC. (Renal pelvis washing, SP, high mag.). (c) Despite having a very low N/C ratio, this huge cell has all the other features of malignancy: hyperchromasia, coarse chromatin, and irregular nuclear contours. The abundant cytoplasm is likely a form of degenerative change. (Renal pelvis washing, SP, high mag.). (d) The corresponding biopsy reveals papillary HGUC. Note the full thickness of atypical urothelial cells on this papilla, demonstrating hyperchromasia, nuclear enlargement, anisonucleosis, and irregular nuclear contours. (Renal pelvis biopsy, H&E, high mag) Fig. 7.2 HGUC with prominent cercariform cell formation. (a) The specimen is cellular and con- tains numerous dispersed single atypical cells. At this magnification, great variation in nuclear size can be seen. (Renal pelvis washing, SP, low mag.). (b) At higher magnification, the atypical cells can be identified as malignant. They have coarse chromatin and variable N/C ratios. Some cells have cytoplasmic tails, forming so-called cercariform cells. This feature is seen more often in washing specimens containing papillary urothelial neoplasms of any grade and is not specific to HGUC. (Renal pelvis washing, SP, medium mag) Fig. 7.3 Small fragments of HGUC. (a) This three-dimensional fragment contains cells with hyperchromatic nuclei and minimal cytoplasm. While HGUC cells tend to be discohesive, frag- ments of HGUC may be seen in instrumented specimens. Even here, the cells at the edges appear discohesive. (Renal pelvis washing, TP, medium mag.) (b) A separate fragment of HGUC cells from the same case demonstrates striking anisonucleosis. The cells have highly irregular nuclear contours and the chromatin is too dark to assess for the coarse, clumpy chromatin often seen in HGUC. However, this level of hyperchromasia is just as concerning as the presence of clumpy chromatin. (Renal pelvis washing, TP, high mag) Fig. 7.4 HGUC in a pelvic washing with cell-in-cell forms. (a and b) The HGUC cells in these two representative fields are present singly and in small fragments. Both fields show examples of a HGUC cell's cytoplasm enveloping a neighboring HGUC cell. This phenomenon has been described as "clasping" (when the neighboring cell does not appear entirely enveloped) and "cell- in-cell" (when the neighboring cell is completely enveloped). Other terms used include "cell can- nibalism" and "hugging." While this finding can be seen in HGUC, the finding is not specific and can occasionally be seen with benign, reactive processes. (Renal pelvis washing, Cytospin, medium mag) Fig. 7.5 HGUC. (a) In this ureteral washing specimen, the HGUC cells have features of malig- nancy: high N/C ratios, coarse chromatin, and slightly irregular nuclear contours. The cells do not demonstrate significant anisonucleosis, which is often seen in other specimens with HGUC but is not required for a definitive diagnosis of malignancy. (Ureteral washing, SP, medium mag.) (b) The presence of atypical keratinized cells can indicate squamous differentiation in a HGUC. In this renal pelvic washing specimen, the keratinized cells have bland-appearing nuclei but brilliant orange cytoplasm. Overtly malignant cells are seen in small- to medium-sized non-keratinized fragments adjacent to the keratinized fragment. While their morphology is compatible with urothe- lial carcinoma, squamous cell carcinoma can metastasize to the kidney from the lung. If uncer- tainty exists as to whether this is a HGUC, the "Other" diagnostic category may be used. (Renal pelvis washing, SP, high mag) Fig. 7.6 Suspicious for HGUC. (a) There are five atypical urothelial cells in the center of the field. While some of these cells meet the cytomorphologic criteria for HGUC, a higher threshold is rec- ommended for making a diagnosis of HGUC in upper tract specimens as compared to lower tract specimens. Based on the overall clinical picture, an upper tract specimen may be quantitatively or qualitatively insufficient for HGUC. Direct communication with the clinical team in these circum- stances to convey the level of concern for HGUC may be useful. (Renal pelvis washing, SP, high mag.) (b) Several singly dispersed malignant cells are intermixed with fungal organisms, debris, and acute inflammatory cells. While some of the cells meet the cytomorphologic criteria for HGUC, other cells are obscured and degenerated. This specimen is at least suspicious for HGUC and a diagnosis of HGUC may be rendered depending on what is seen in other fields and the clini- cal scenario. (Nephrostomy tube, SP, high mag) Fig. 7.7 Fragment of HGUC from the ureter. Upper tract specimens are obtained through instru- mentation and thus fragments of HGUC, such as the one seen here, may be forcibly exfoliated during collection. This contrasts to the HGUC cells seen in voided urine specimens, which natu- rally exfoliate as predominantly single cells from the urothelial lining. Because the center of this fragment contains overlapping cells, it can be difficult to discern the morphology of each individ- ual cell. By looking at the edge of the fragment, the high N/C ratios and coarse chromatin can be better appreciated. (Ureter washing, SP, medium mag) Fig. 7.8 Hypochromatic HGUC cells. (a) Occasionally HGUC cells may appear paradoxically hypochromatic, a feature seen in many of the cells in this field. However, the malignant cells are very large and have elevated N/C ratios, nuclear contour irregularities, and chromatin coarseness. Because the chromatin stains faintly, these cells may be overlooked. (Renal pelvis washing, SP, medium mag.) (b) A higher magnification shows the atypical nature of these hypochromatic cells, with markedly atypical nuclear borders. The chromatin clumps are also small and difficult to dis- cern, even at this high magnification. Note that some cells with dark chromatin can be seen in the top right corner. (Renal pelvis washing, SP, high mag) Fig. 7.9 Examples of HGUC in fragments. (a) Tissue fragments containing HGUC cells. While the tissue fragments have a papillary configuration, they lack fibrovascular cores. Single HGUC cells with variable amounts of atypia can be seen in the background. (Renal pelvis washing, SP, medium mag.) (b) Separate field of (a) at higher magnification. The smaller fragment contains cells with more severe atypia than the cells seen in the lower, larger fragment and demonstrates hyperchromasia, coarse chromatin, anisonucleosis, and, for some of the cells, high N/C ratios. (Renal pelvis washing, SP, high mag.) (c) Numerous tissue fragments of variable sizes containing HGUC cells. HGUC cells can also be seen dispersed in the background. Examination at higher magnifica- tion is required to confirm the low power impression of HGUC. (Ureteral washing, SP, low mag.) (d) Well-preserved HGUC cells in a fragment, with coarse chromatin, hyperchromasia, and high N/C ratios. Instrumented specimens can obtain freshly exfoliated cells that have not been degenerating in the bladder. (Renal pelvis washing, SP, high mag) Fig. 7.10 HGUC cells adjacent to an LGUC fragment. Patients may have both LGUC and HGUC in the urinary tract, so it is most important to diagnose specimens based on features of HGUC rather than the identification of low grade urothelial neoplasms. This patient had LGUC and CIS in one ureter. The papillary lesion was identified by cystoscopy due to its papillary growth, but the CIS lesion was not identified until subsequent biopsy. This field contains a combination rarely seen - a papillary fragment of LGUC, identified by a fibrovascular stalk (arising from the right- hand bottom corner) with a monotonous population of attached neoplastic cells - and a small fragment of HGUC cells (left-hand bottom corner). (Ureteral washing, SP, medium mag) Fig. 7.11 Fragments of low-grade urothelial neoplasm without fibrovascular cores. (a-d) This patient was found to have a low-grade urothelial carcinoma on a concurrent biopsy. In this washing specimen, there are numerous neoplastic cells both in variably sized fragments (a-c) as well as dispersed single cells with cercariform features (d). The cells and their nuclei have an elongated, spindly appearance, possibly due to cautery artefact, which causes some fragments to resemble a spindle cell neoplasm (a–c). No features of HGUC can be identified. The cells have low N/C ratios and bland chromatin; the nuclei are all similar in size. In this case, it is appropriate to make a diag- nosis of NHGUC; the specimen provides a good example of how LGUN can be cellular and visu- ally striking in washing specimens. (Renal pelvis washings, TP, medium mag) Fig. 7.12 Benign urothelial tissue fragment. Instrumentation often forcibly exfoliates benign uro- thelial tissue fragments that may have cytomorphologic overlap with LGUN fragments. Benign urothelial tissue, however, does not form papillary fragments with fibrovascular cores. While some anisonucleosis can be spotted in this fragment, other features are benign. The cells have pale chro- matin and low N/C ratios. (Renal pelvis washing, Cytospin, medium mag) Fig. 7.13 Benign urothelial tissue fragments. (a) The nuclei of benign urothelial cells in frag- ments may appear slightly darker and have more irregular contours when compared to singly dis- persed urothelial cells. However, even at this magnification, one can see that these cells have abundant cytoplasm, supporting a benign diagnosis. (Renal pelvis washing, SP, medium mag.) (b) One benign feature in the small fragment at the top of the field is the presence of a "cytoplasmic collar," formed by centrally placed nuclei surrounded by a peripheral "collar" of granular cyto- plasm. This configuration represents the asymmetric unit membrane, a pathognomonic feature of superficial urothelium. Nuclei with prominent chromocenters and condensed rims of chromatin are characteristic of superficial cells and should not be mistaken for the hyperchromasia and coarse chromatin pattern seen in HGUC. (Renal pelvic washings, SP, medium mag) Fig. 7.14 Benign urothelial tissue fragments. (a) These are benign urothelial cells from a renal pelvis washing. Note the presence of multinucleated umbrella cells with abundant cytoplasm, single cells in the background with low N/C ratios and bland chromatin, and a three-dimensional benign urothelial tissue fragment at the bottom left-hand side of the field. (Renal pelvis washing, SP, medium mag.) (b) At higher magnification, the benign features of the tissue fragment seen in (a) can be appreciated. The cells have nuclei of approximately the same size and abundant, foamy cytoplasm that forms a peripheral cytoplasmic collar around the fragment. Most of the nuclei have two to three prominent chromocenters, which could be mistaken for a coarse chromatin pattern. However, the chromatin clumps are distributed similarly among the cells and do not vary in size. By contrast, the chromatin clumps in HGUC tend to be nonuniform in size and unevenly distrib- uted within the nucleus, with dissimilar chromatin patterns found among the carcinoma cells. (Renal pelvis washing, SP, high mag) Fig. 7.15 Benign urothelial tissue fragments demonstrating stone atypia. (a-d) These tissue frag- ments originated in a renal pelvis washing from a patient with nephrolithiasis. The fragments are of variable sizes; the larger three-dimensional fragments (d) make cytomorphology difficult to assess. Stones in the urinary tract can cause reactive changes in benign urothelial cells and also forcibly exfoliate urothelial tissue fragments as they pass through the ureter into the bladder. The fragments contain cells with increased N/C ratios and dark, hyperchromatic nuclei. The nuclei may be so hyperchromatic that the chromatin pattern cannot be assessed. In addition to increasing one's threshold for an atypical diagnosis in patients with urolithiasis, certain features can be reassuring. The nuclei are usually small and do not vary greatly in size within the fragments. A cytoplasmic collar may be present, and well-preserved single cells concerning for HGUC are absent in the background. (a-b, renal pelvis washing, Cytospin, medium mag.; c, renal pelvis washing, SP, medium mag) Fig. 7.16 True papillary tissue fragments arising from LGUC. (a) This patient had a LGUC in their ureter. The washing procedure forcibly exfoliated this papillary fragment with a fibrovascular stalk and additionally caused the detachment of numerous neoplastic cells (seen in the back- ground). At this magnification, the neoplastic cells appear monotonous, whereas HGUC cells often appear more pleomorphic. Because HGUC may coexist with LGUN and because LGUN lesions may contain foci of HGUC, examination at a higher magnification is warranted to exclude the presence of HGUC. (Renal pelvis washing, SP, low mag.) (b) Note the monotony of the cells attached to this papillary fragment. The cells have round-to-oval nuclei with regular contours. The nuclei are similar in size. Neoplastic cells can also be seen singly in the background and have eccentrically placed nuclei with low N/C ratios (below 0.5). (Renal pelvis washing, SP, medium mag) Fig. 7.17 Cercariform cells derived from LGUN. (a) In washing specimens, urothelial cells derived from papillary neoplasms may exfoliate as single cells. These cells may have cytoplasmic tails, resulting in a "cercariform" appearance. Here, the nuclei are monomorphic and small, sug- gesting that the neoplasm is low-grade. No cytomorphologic features of HGUC can be identified. (Renal pelvis washing, TP, medium mag.) (b) Cells derived from a papillary LGUC appear both epithelioid and spindled (cercariform). The epithelioid cells have eccentrically placed nuclei with a bland chromatin pattern and regular nuclear contours. Some cells possess degenerative features, such as small, pyknotic nuclei. Despite their hyperchromasia, these degenerating cells and their nuclei are notably smaller than those seen in the well-preserved neoplastic cells. (Ureteral wash- ing, SP, high mag) Fig. 7.18 LGUN cells with plasmacytoid morphology. (a and b) These are two representative fields from a renal pelvis washing in a patient with renal LGUC. The neoplastic cells fill the fields with rare benign umbrella cells seen in the background. The cells are monomorphic and have bland chromatin. Their nuclei are mostly eccentrically placed, causing a plasmacytoid appearance. Some cells appear to have irregular nuclear shapes, irregular contours, and nuclear grooves, and many cells have N/C ratios above 0.5. While these findings technically meet the criteria for the AUC category, the specimen could be diagnosed as NHGUC if the overall features are more suggestive of LGUN. (Renal pelvis washing, Cytospin, high mag) Fig. 7.19 Indeterminate cells in a voided urine, derived from an upper tract HGUC. Upper tract HGUC cells naturally exfoliate into the urinary stream but may have degenerated before a voided specimen is collected. These three urothelial cells are quite large compared to the background inflammatory cells. The nuclei have irregular contours and dark chromatin, but the chromatin pat- tern is obliterated, likely due to degeneration. However, these were the only atypical cells seen in the specimen and the N/C ratios are lower that 0.5; a diagnosis of SHGUC rather than HGUC may be appropriate depending on overall quantity and quality. (Voided urine, SP, high mag) Fig. 7.20 Cell block preparation containing HGUC. (a and b) Numerous HGUC cells are found singly as well as in a tissue fragment. Note the anisonucleosis, elevated N/C ratios, and irregular nuclear shapes. Many of these cells have a prominent nucleolus rather than clumped chromatin. (Ureteral washing, TP, intermediate mag.) (c and d) The cell block preparation demonstrates con- cordant morphology. However, the fibrovascular cores of true papillary fragments can be identified in the cell block preparation (c). (Renal pelvis washing, H&E, low mag. [c] and high mag. [d]) Fig. 7.21 Cell block preparation containing LGUC. (a) Given the bland cytomorphology seen in their cellular constituents, these benign-appearing tissue fragments could represent either frag- ments of benign urothelial lining or fragments derived from an LGUN. No features of HGUC can be identified. (Renal pelvis washing, TP, medium mag.) (b) The cell block preparation shows a cross section of a papillary fragment containing a fibrovascular stalk. The cells have monomorphic nuclei, corresponding to LGUN (and, in this case, LGUC). (Renal pelvis washing, H&E, medium mag) ■■■【8】Non Urothelial Malgnancies Fig. 8.1 Primary pure squamous cell carcinoma (SqCC) of the urinary bladder. (a) Resection specimen shows a muscle invasive carcinoma composed entirely of squamous components. (b) Another case of SqCC (upper part of photo) is associated with calcified Schistosoma haematobium eggs deposited in the stroma (lower part of photo). (H&E, medium mag.) Fig. 8.2 SqCC of the urinary bladder. (a) Cellular specimen displays tightly cohesive clusters of atypical keratinized squamous cells. (Voided urine, TP, medium mag.) (b) Loosely cohesive clus- ters consist of highly atypical keratinized and non-keratinized squamous cells. (Instrumented urine, TP, medium mag.) Fig. 8.3 SqCC of the urinary bladder. (a) Predominately single highly atypical keratinized squa- mous cells are large, polygonal with high N/C ratio, sharp cytoplasmic borders, and hyperchro- matic nuclei. (Voided urine, TP, high mag.) (b) Elongated keratinized "fiber" and "tadpole cells" may also be present, as well as inflammatory cells and some debris in the background. (Bladder washing, TP, high mag.) Fig. 8.4 Primary SqCC of the urinary bladder. Tightly cohesive three-dimensional clusters of non-keratinized squamous cells. The tumor cells show nuclear enlargement, high N/C ratio, marked overlapping, and severe hyperchromasia. Occasional nucleoli are observed. In the absence of a keratinizing component, it is difficult to distinguish this morphology from HGUC or AdCa. (Bladder washing, CS, high mag.) Fig. 8.5 SqCC of the urinary bladder. Non-keratinized atypical squamous cells may be arranged in loose clusters (a) and as single cells (b). The tumor cells have a metaplastic appearance with rigid basophilic cytoplasm and nuclear elongation with marked hyperchromasia. In the absence of keratinization, it is difficult to distinguish HGUC from non-keratinizing SqCC of the bladder. (Instrumented urine, TP, high mag.) Fig. 8.6 SqCC of urinary bladder. A background of necrotic debris and inflammatory cells surrounds rare atypical keratinizing and non- keratinizing squamous cells. (Bladder washing,TP, low mag.) Fig. 8.7 HGUC with squamous differentiation. Only highly atypical keratinized squamous cells are present in this urine. Histologic follow-up (not shown) revealed divergent squamous differentiation associated with invasive HGUC. (Voided urine, TP, high mag.) Fig. 8.8 Atypical squamous cells (ASC). This specimen obtained from a 57-year-old female con- tains rare clusters of keratinized squamous cells with significant atypia. A diagnosis of "ASC, suspicious for squamous carcinoma" was rendered. Follow-up transurethral resection (TUR) revealed Schistosoma-associated SqCC of the bladder. (Instrumented urine, TP, high mag.) Fig. 8.9 Atypical squamous cells (ASC), suspicious for squamous cell carcinoma (SqCC). This patient was recently diagnosed with SqCC of the penile meatal opening. The specimen shows singly scattered atypical non-keratinized squamous cells with high N/C ratio and marked hyper- chromasia. Absent the history, it would be impossible to distinguish these atypical non-keratinized squamous cells from HGUC. (Voided urine, TP, high mag.) Fig. 8.10 Atypical squamous cells (ASC). (a) Atypical keratinized and non-keratinized cells have moderate atypia, and increased N/C ratios. The nuclei are enlarged and hyperchromatic, but have a smudgy, degenerated appearance. (Bladder washing, TP, medium mag.) (b) Follow-up resection revealed a noninvasive papillary HGUC with squamous differentiation. Inset shows surface kera- tinized squamous cells, identical to those observed in the cytology specimen. (H&E, low mag.; inset, high mag) Fig. 8.11 Atypical squamous cells (ASC). (a) Rare keratinized ASC with mild to moderate atypia is present in this specimen from a 50-year-old female. (Voided urine, TP, high mag.). (b) Follow-up Pap test reveals low-grade squamous intraepithelial lesion and positivity for high-risk HPV. (Pap test, TP, medium mag.). ASC in this urine specimen represented contamination from the genital tract Fig. 8.12 Primary enteric adenocarcinoma (AdCa) of the urinary bladder. (a) Cytology demon- strates a cluster of cells with enlarged elongated palisading nuclei, hyperchromasia, irregular nuclear membranes, and prominent nucleoli. (Voided urine, TP, high mag.). (b) Resected bladder shows AdCa exhibiting similar morphology to its colorectal counterpart. (H&E, medium mag.) Fig. 8.13 Primary enteric AdCa of the urinary bladder. In this case, the malignant cells have more voluminous cytoplasm with prominent vacuolization, but characteristic palisading morphology is not demonstrated. (a) There is elongation of the nuclei with significant pleomorphism. (b) Some of the cells display signet ring appearance, created by a large cytoplasmic vacuole pushing the crescent-shaped hyperchromatic nucleus to the periphery of the cell. (a, b: Catheterized urine, CS, high mag.). Although histologic resection demonstrated enteric AdCa, cytologic features in this urinary cytology do not allow for determination of subtype of AdCa Fig. 8.14 Clear cell AdCa of the urethra. (a) Specimens are usually of high cellularity with cohe- sive clusters of malignant cells. The tumor cells have abundant vacuolated and/or eosinophilic cytoplasm, centrally placed nuclei, and prominent nucleoli. (Bladder washing, TP, high mag.). (b) Resection revealed clear cell AdCa of the urethra invading the bladder. The tumor had a tubulo- papillary architecture, lined by highly pleomorphic cells with abundant eosinophilic or clear cytoplasm, and frequent hobnailing. (H&E, high mag.) Fig. 8.15 Primary AdCa, not otherwise specified (AdCa-NOS) displays a cluster of cells with eccentrically placed irregular nuclei, prominent nucleoli, and finely vacuolated cytoplasm. Although the cytology of the malignant cells is consistent with AdCa, HGUC with glandular differentiation and secondary AdCa should also be considered in the differential diagnosis. (Voided urine, TP, high mag.) Fig. 8.16 Atypical glandular cells (AGC). (a) This urine specimen from a 69-year-old male con- tains rare clusters of glandular cells with mild atypia, including slightly enlarged palisaded nuclei, and nuclear hyperchromasia. Inflammatory cells are present in the background. A diagnosis of AGC was rendered in this case, with a comment/note stating that the differential diagnosis included benign nonneoplastic conditions versus low-grade AdCa. Follow-up (not shown) revealed florid cystitis glandularis. (Instrumented urine, CS, high mag.). (b) This specimen, from a 73-year-old female, contains a single cluster of highly atypical glandular cells. No history was available at the time of evaluation of the cytology specimen. A diagnosis of "AGC, suspicious for AdCa" was rendered, with appropriate differential diagnosis listed. Follow-up revealed that the patient had stage 4 ovarian serous carcinoma; therefore, this most likely represented secondary involvement of the urinary tract. (Voided urine, TP, high mag.) Fig. 8.17 AdCa-NOS. (a) This urine from a 67-year-old female contains single and loosely cohe- sive atypical cells with enlarged hyperchromatic nuclei, high N/C ratio, and marked pleomor- phism. The case was signed out as "HGUC." (Voided urine, CS, high mag.). (b) Follow-up cystectomy revealed primary AdCa of the urinary bladder, enteric type. (H&E, medium mag.). In some instances, the AdCa cells tend to round up in cytologic specimens, and it may be extremely difficult to distinguish them from HGUC. Therefore, rendering HGUC diagnosis was not unreasonable in this case, since it resulted in further workup of the patient Fig. 8.18 Primary small-cell carcinoma (SmCC) of the urinary bladder. (a) Urine cytology speci- men is highly cellular and shows tightly cohesive clusters of small, individual cells. The tumor cells have minimal amount of cytoplasm, round to oval nuclei, and salt and pepper chromatin pat- tern. Nucleoli are absent or inconspicuous. Individual cell necrosis and apoptosis are also noticed. Background is bloody with necrotic debris. (Voided urine, CS, medium mag.). (b) Resection specimen revealed SmCC with histologic appearance similar to its pulmonary counterpart. The tumor cells were positive for neuroendocrine markers (not shown) and had no associated divergent histologies. (H&E, high mag.) Fig. 8.19 SmCC of the bladder. (a) Cytology displays cells arranged in a loosely cohesive cluster. Tumor cells are small, show high N/C ratio, round to oval hyperchromatic nuclei with evenly dis- tributed fine to coarse chromatin, and absent or inconspicuous nucleoli. Nuclear overlapping and spindling are more pronounced than molding, and the background is clean, compared to Cytospin preparations (see Fig. 8.18a). (Voided urine, TP, high mag.). (b) In this sample, the cytologic fea- tures are similar to “a," but nuclear molding and linear arrangement of the malignant cells are more pronounced. (Bladder washing, SurePath, high mag.) Fig. 8.20 Primary SmCC. (a) Urine cytology from a 76-year-old man shows a predominantly discohesive cell pattern. The tumor cells are small (approximately two to three times the size of RBCs or neutrophils) and have scant cytoplasm. The nuclei are round and have finely to coarsely granular chromatin. Single-cell necrosis is present. No nuclear molding or spindling is appreci- ated. This morphology also raises the differential diagnosis of lymphoma, melanoma, and HGUC. (Voided urine, TP, high mag.). (b) Immunohistochemistry performed on TP slides demon- strates positive staining with synaptophysin and chromogranin. (Synaptophysin, high mag.) Fig. 8.21 Non-keratinizing SqCC. Voided urine from a 48-year-old man with locally advanced anal squamous cell carcinoma. The cytology consists of tightly cohesive clusters of basaloid tumor cells with overlapping round to oval, hyperchromatic and irregular nuclei, and ill-defined cytoplasm. This cytologic appearance can be confused with SmCC, especially in the absence of clinical history or previous pathology for comparison. Features favoring SqCC over SmCC are the open chromatin pattern of nuclei and presence of conspicuous nucleoli. (Voided urine, CS, high mag.) Fig. 8.22 Colorectal AdCa. (a) Clusters of pleomorphic columnar cells display elongated irregu- lar nuclei and coarse chromatin. The cytoplasm is vacuolated, with occasional signet ring cells. The background shows necrosis and inflammatory cells. Follow-up revealed rectal AdCa directly invading the bladder. (Bladder washing, SurePath, medium mag.). (b) This patient had metastatic colon AdCa to the bladder diagnosed via bladder biopsy, collected at the same time with urine cytology. The malignant cells are columnar with elongated hyperchromatic nuclei and vacuolated cytoplasm. Notice that the background in TP tends to be cleaner than that of SurePath or Cytospins. (Bladder wash, TP, high mag.). Cytologic features of colorectal AdCa overlap with those of pri- mary bladder AdCa, enteric type Fig. 8.23 Prostate AdCa. (a) Characteristic cytologic features of prostatic AdCa are best appreci- ated in lower Gleason score carcinomas. The tumor cells are large, arranged in cohesive groups, and have a uniform appearance. The cells have abundant delicate cytoplasm, round to oval nuclei, fine chromatin, and prominent nucleoli. (Instrumented urine, TP, high mag.). (b) In higher Gleason score AdCa, the tumor cells tend to have less voluminous cytoplasm but retain the uniform appearance and prominence of nucleoli. There is a suggestion of acinar formation at the periphery of the cluster. Follow-up biopsy (not shown) revealed prostatic AdCa, Gleason score 8. (Bladder washing, Sure Path, high mag.) Fig. 8.24 Prostate AdCa. This specimen is from an 80-year-old male, who presented with urinary retention and elevated serum PSA levels. (a) Urine cytology is hypercellular and contains a disco- hesive population of intermediate sized cells with minimal dense cytoplasm. The nuclei are round with conspicuous nucleoli and relative uniformity. (Voided urine, TP, high mag.). (b) The cell block reveals similar cytologic features, including hyperchromatic nuclei and occasional prominent nucleoli. Differential diagnosis includes HGUC, prostatic AdCa, poorly differentiated carcinoma- NOS, and melanoma. (Cell block of voided urine, H&E, high mag.). (c) There is strong positive staining of the tumor cells with NKX3.1 and PSA and negative staining with P63 and GATA3. (NKX3.1 immunohistochemistry, high mag.). (d) Follow-up prostate biopsies confirm AdCa, Gleason score 10-grade group 5. (H&E, high mag.) Fig. 8.25 Cervical SqCC. This 51-year-old female presented with malignant squamous cells in the urine cytology. There is focal suggestion of keratinization. It is not possible to distinguish between primary and secondary SqCC or HGUC with squamous differentiation, based on cytologic exam alone.Clinical correlation is needed in such instances. Clinical follow-up revealed locally advanced SqCC of the cervix. (Instrumented urine, TP, high mag.) Fig. 8.26 Endometrial serous AdCa. This urine cytology is from a 61-year-old female. (a) There are many tightly cohesive clusters of large pleomorphic cells, with marked nuclear irregularity and high N/C ratio. A papillary configuration is suggested. (Voided urine, TP, high mag). (b) An endometrial biopsy, performed 1 week prior, demonstrated serous papillary AdCa, FIGO grade 3. (H&E, high mag.) Therefore, the cytologic features are consistent with metastatic high-grade serous carcinoma Fig. 8.27 Breast lobular carcinoma. This patient is a 48-year-old woman with a remote history of lobular carcinoma of the breast. (a) Urine cytology reveals discohesive small to intermediate sized cells, with high N/C ratios, hyperchromatic nuclei, and small nucleoli. Some cells have eccentri- cally placed nuclei with a plasmacytoid appearance. Immunohistochemistry performed on the cell block (not shown) revealed positive staining of the tumor cells for gross cystic disease fluid protein-15 (GCDFP-15). (Voided urine, TP, high mag.). (b) Follow-up transurethral resection revealed metastatic lobular carcinoma diffusely invading the urinary bladder and undermining and penetrating the surface urothelium. (H&E, medium mag.) Fig. 8.28 Metastatic breast ductal AdCa. Both of these patients had a previous history of invasive breast ducal carcinoma. (a) In this first patient, the tumor cells are forming a cellular sphere ("morula"), which is commonly seen in metastatic breast ductal carcinomas involving exfoliative fluid cytologies. The cluster has a sharp community border, and tumor cells are relatively uniform. (Voided urine, TP, high mag.). (b) In this second case, the tumor cells are more loosely cohesive with suggestion of acinar formation but are not forming spheres. The neoplastic cells have a moderate amount of cytoplasm, round to oval nuclei, and prominent nucleoli. (Voided urine, CS, high mag.) Fig. 8.29 Metastatic gastric signet ring cell AdCa from a 78-year-old male with advanced stage disease, including peritoneal dissemination. The tumor cells are small- to medium-sized, are discohesive, and have cytoplasmic vacuoles that indent and displace the nuclei to the periphery. (Catheterized urine, TP, high mag.) Fig. 8.30 Lung AdCa. This specimen is from a 91-year-old man with stage 4 lung AdCa. (a) Urine cytology reveals a few clusters of large pleomorphic malignant cells with abundant delicate cyto- plasm. The nuclei are round to oval shaped, have open chromatin, and have prominent nucleoli. Based on cytologic evaluation alone, it is not possible to determine the primary origin of AdCa. (Voided urine, TP, high mag.). (b) TTF1 IHC, performed on cell block, shows positive staining of the malignant cells, consistent with clinical history of lung AdCa. (TTF1, high mag.) Fig. 8.31 Renal cell carcinoma (RCC). This urine specimen is from a patient with an established history of advanced RCC. (a) On lower power exam, there are cohesive clusters of large tumor cells with abundant cytoplasm that has a hypervacuolated and/or granular appearance. (b) High power illustrates the cytoplasmic quality and enlarged round nuclei with large prominent nucleoli. (a, b: Catheterized urines, CS, medium and high mag.) Fig. 8.32 Atypical cells suspicious for RCC. The specimen is from a 79-year-old man without clinical history at the time of evaluation of urine cytology. (a) Rare discohesive large cells with abundant granular cytoplasm are seen. The nuclei have small, distinct nucleoli, but no significant pleomorphism. The background is bloody. This case was initially reported out as reactive/repara- tive changes. (Voided urine, CS, high mag.). (b) Subsequently provided clinical history and review of surgical resection revealed an advanced RCC that eroded into the renal pelvis. (H&E, high mag.). In retrospect, these atypical cells most likely represented RCC Fig. 8.33 Leiomyosarcoma of the urinary bladder. (a) Urinary cytology shows fragments of atypi- cal spindle cells amid stroma containing inflammatory cells. The cells contain large elongated ("cigar"-shaped) mildly hyperchromatic nuclei with a moderate amount of ill-defined cytoplasm. (Bladder washing, CS, medium mag.). (b) Histology of the resected leiomyosarcoma demonstrates bundles of spindle-shaped cells in profile and cross section with elongated and pleomorphic nuclei. (Biopsy, H&E, medium mag.) Fig. 8.34 Pleomorphic rhabdomyosarcoma of the bladder. (a) Cytology demonstrates numerous highly pleomorphic and bizarre malignant cells with spindle and epithelioid features. Individual cell necrosis is evident in the background. Differential diagnosis based on this morphology includes any pleomorphic malignancy, including sarcoma, sarcomatoid carcinoma, and melanoma. (Bladder washing, SP, medium mag.). (b) Histology shows pleomorphic rhabdomyosarcoma. (H&E, high mag.) Fig. 8.35 Sarcomatoid HGUC. This 63-year-old male presented with gross hematuria. Urine cytology contains atypical spindle cells and individual cell necrosis. This case was reported as "high grade spindle cell malignancy, can't exclude HGUC." (Voided urine, TP, high mag.). Follow-up cystoscopy and TURP showed a muscle invasive sarcomatoid HGUC Fig. 8.36 Malignant melanoma. (a) Metastatic cutaneous melanoma displays scattered large atyp- ical cells with round to oval nuclei and variable amount of cytoplasm. The cytoplasm contains dark dusty brown melanin pigment. The nuclei are enlarged and have prominent nucleoli. (Voided urine, TP, high mag). (b) In this primary urethral melanoma, the malignant cells are huge and show extremely pleomorphic nuclei that are eccentrically placed and have macronucleoli. In contrast to specimen "a," the cytoplasm is dense and amelanotic. (Urethrovaginal fluid, TP, high mag.) Fig. 8.37 Diffuse large B-cell lymphoma (DLBCL). (a) This 59-year-old woman presented with gross hematuria, urinary frequency and lower abdominal pain. Urine cytology demonstrates a dispersed bi-morphic population of small and large lymphoid cells. The larger cells predominate and show clumped chromatin, prominent single or multiple nucleoli, and variably stripped cytoplasm. Follow-up biopsy (not shown) revealed a primary DLBCL in the bladder dome. (Voided urine, CS, medium mag.). (b) This is a case of secondary DLBCL involving the bladder, showing a monomorphic population of large cells with round to oval nuclei, vesicular chromatin, and prominent nucleoli. Some of the cells have a plasmacytoid appearance. Differential diagnosis includes high-grade carcinoma and melanoma. (Voided urine, TP, high mag.) Fig. 8.38 Marginal zone (MALT) lymphoma from a 78-year-old woman with a history of chronic cystitis Urine contains monomorphic small- to medium-sized atypical centrocyte-like lymphocytes. Follow-up biopsy (not shown) revealed MALT lymphoma, confirmed by IHC and flow cytometry. (Voided urine, Cytospins, high mag.) Fig. 8.39 Paraganglioma. (a) Urine cytology shows a loose cluster of large epithelioid cells with abundant delicate cytoplasm, anisonucleosis, round to oval nuclei with fine chromatin, and inconspicuous nucleoli. (Bladder washing, SurePath, high mag.). (b) Bladder tumor resection displays cells arranged in a nested (zellballen)/trabecular pattern, separated by delicate vasculature. The cells are large and have acidophilic cytoplasm, round to oval nuclei, and prominent nucleoli. (H&E, high mag.) Fig. 8.40 Nephrogenic adenoma (NA), from a 64-year-old man. (a) Histology shows characteris- tic tubulocystic and papillary architecture of NA, which involves the urothelial surface and lamina propria. The tubules are closely packed and associated with background inflammation. A small uninvolved portion of the urothelium is present at left top corner of photo (*). (H&E, low mag.). (b) NA shows PAX8 positivity but spares the portion of uninvolved urothelium (*). (c) Urine cytol- ogy demonstrates rare groups of large cells with abundant dense cytoplasm, round nuclei, and small nucleoli. There is no significant atypia. (Instrumented urine, TP, high mag.). (d) Lesional cells of NA have abundant eosinophilic dense cytoplasm with round nuclei and small nucleoli (right part of photo); these cells have similar cytologic appearance to those observed in corre- sponding urine cytology. However, it would be very difficult, in isolation, to distinguish between the lesional cells and adjacent uninvolved urothelial cells (left part of photo). (H&E, high mag.)
