WHO 2022 classification of penile and scrotal cancers: updates and evolution.

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as "subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.

Diversity of Vibrio parahaemolyticus in marine fishes of Bangladesh.

AIMS: To determine the occurrence, diversity, antibiotic resistance and biofilm formation of Vibrio parahaemolyticus isolated from marine fishes in Bangladesh. METHODS AND RESULTS: A total of 80 marine fishes were obtained from the local markets and examined for the presence of V. parahaemolyticus. All the isolated V. parahaemolyticus were characterized for the presence of virulence markers, thermostable direct hemolysin (TDH) or thermostable direct hemolysin related hemolysin (TRH). Isolates were serotyped and further characterized by enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) typing to analyse the genetic diversity. Moreover, biofilm formation and antibiotic resistance patterns were also determined. About 63·75% (51/80) of the tested marine fishes were contaminated with V. parahaemolyticus. From the contaminated fishes, 71 representatives V. parahaemolyticus were isolated and none of them harboured tdh and trh virulence genes. Nine different O-groups and seven different K-types were found by serological analysis and the dominant serotype was O5:KUT. In ERIC-PCR analysis, eight clusters (A-H) were found and the most common pattern was A (46·5%). All of the isolates were resistant to ampicillin and 78·9% of isolates were resistant to streptomycin. The highest biofilm formation was found at 37°C compared to 25°C and 4°C. CONCLUSION: Diverse V. parahaemolyticus are present in marine fishes in the local market of Bangladesh with antibiotic-resistant properties and biofilm formation capacity. SIGNIFICANCE AND IMPACT OF THE STUDY: The widespread prevalence of diverse V. parahaemolyticus in marine fishes is an issue of serious concern, and it entails careful monitoring to ascertain the safety of seafood consumers.

Review of renal anastomosing hemangioma with focus on clinical and pathological aspects.

Renal anastomosing hemangiomas (RAH) has been recently proposed as a new entity. In this article, we summarize the clinicopathologic features of this tumor. RAH usually develops on a background of end-stage renal disease. Macroscopically, tumors are well-defined and their cut surface shows mahogany brown spongy tissue with epicenter in the renal medulla. Tumors are usually small, but larger lesions are reported. On microscopic examination, the tumor consists of sinusoid-like vascular channels lined by cuboidal endothelial cells with occasional hobnail-like appearance of endothelial cells closely mimicking splenic sinusoids. Eosinophilic hyaline globules may be present in the cytoplasm of neoplastic endothelial cells. Extramedullary hematopoiesis containing erythroid precursor and megakaryocytes may be present in the vascular lumens. Immunohistochemically, endothelial cells are positive for CD31 and CD34, but negative for D2-40, GLUT-1 and HHV8. The surrounding stroma around endothelial cells demonstrates positivity for  smooth muscle action. To date, there are no studies on molecular genetic aspects of RAH. This tumor is indolent based on site and size of the lesion, partial or nephrectomy is sufficient as a therapeutic modality.

Review of succinate dehydrogenase-deficient renal cell carcinoma with focus on clinical and pathobiological aspects.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) was first identified in 2004 and has been integrated into the 2016 WHO classification of RCC. Succinate dehydrogenase (SDH) is an enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC and SDHD). The tumor which presents this enzyme mutation accounts for 0.05 to 0.2% of all renal carcinomas. Multiple tumors may occur in approximately 30% of affected patients. SDHB-deficient RCC is the most frequent, and the tumor histologically consists of cuboidal cells with eosinophilic cytoplasm, vacuolization, flocculent intracytoplasmic inclusion and indistinct cell borders. Ultrastructurally, the tumor contains abundant mitochondria. Immunohistochemically, tumor cells are positive for SDHA, but negative for SDHB in SDHB-, SDHC- and SDHD-deficient RCCs. However, SDHA-deficient RCC shows negativity for both SDHA and SDHB. In molecular genetic analyses, a germline mutation in the SDHB, SDHC or SDHD gene (in keeping with most patients having germline mutations in an SDH gene) has been identified in patients with or without a family history of renal tumors, paraganglioma/pheochromocytoma or gastrointestinal stromal tumor. While most tumors are low grade, some tumors may behave in an aggressive fashion, particularly if they are high nuclear grade, and have coagulative necrosis or sarcomatoid differentiation.

Renal cell carcinoma marker reliably discriminates central nervous system haemangioblastoma from brain metastases of renal cell carcinoma.

AIMS: The distinction between central nervous system (CNS) metastases of clear cell renal cell carcinoma (RCC) and CNS haemangioblastoma still poses a challenge to the pathologist. Since both entities occur in von Hippel-Lindau disease, this aggravates the issue. The antibody renal cell carcinoma marker (RCC-ma) has been suggested to identify primary RCCs specifically, but its value for diagnosing metastases of RCC is controversial. The aim was to assess two distinct clones of the RCC-ma for their potential to: (i) identify primary RCCs and (ii) differentiate between CNS metastases of clear cell RCC and CNS haemangioblastomas. METHODS AND RESULTS: Using tissue microarrays, 77% (n = 363; PN-15) and 66% (n = 355; 66.4C2) of clear cell RCCs, and 93% (PN-15) and 74% (66.4C2) of papillary RCCs (n = 46) were immunopositive for RCC-ma, whereas none of the investigated chromophobe RCCs (n = 22) or any of the oncocytomas (n = 15) showed immunoreactivity. Importantly, 50.9% of CNS metastases of clear cell RCCs (n = 55) exhibited RCC-ma expression, whereas all CNS haemangioblastomas (71) were negative. CONCLUSIONS: Both RCC-ma clones, despite some variation in their sensitivity to detect clear cell and papillary RCCs, are of value in differentiating subtypes of primary RCC and are excellent markers for discriminating clear cell lesions in the brain.

Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression.

Ectopical expression of huMUC18, a cell adhesion molecule in the immunoglobulin gene superfamily, causes a non-metastatic human melanoma cell line to become metastatic in a nude mouse system. To determine if MUC18 expression correlates with the development and malignant progression of prostate cancer, we investigated differential expression of human MUC18 (huMUC18) in normal prostate epithelial cells, prostate cancer cell lines, and prostatic normal and cancer tissues. We cloned and characterized the human MUC18 (huMUC18) cDNA gene from three human prostate cancer cell lines and three human melanoma cell lines. The cDNA sequences from the six human cancer cell lines were identical except differences in one to five nucleotides. The deduced amino acid sequences of the longest ORF were 646 amino acids that were identical in these cDNAs except for one to three amino acid residues. The amino acid sequences of all our huMUC18 cDNA genes are similar to that cloned by other group (GenBank access #M28882) except differences in the same seven amino acids. We conclude that huMUC18 cDNA gene reported here represents the gene product from a major allele. The MUC18 mRNA and protein was expressed in three metastatic prostate cancer cell lines (TSU-PR1, DU145, and PC-3), but not in one non-metastatic prostate cancer cell line (LNCaP.FGC). The expression of huMUC18 in these four cell lines is positively related to their extent of in vitro motility and invasiveness and in vivo metastasis in nude mice. HuMUC18 protein was also expressed at high levels in extracts prepared from tissue sample sections containing high grade prostatic intraepithelial neoplasia (PIN), but weakly expressed in extracts prepared from cultured primary normal prostatic epithelial cells and the normal prostate gland. Immunohistochemical analysis showed that huMUC18 was expressed at higher levels in the epithelial cells of high-grade PIN and prostatic carcinomas, and in cells of a perineural invasion, a lymph node, and a lung metastases compared to that in normal or benign hyperplastic epithelium (BPH). We therefore conclude that MUC18 expression is increased during prostate cancer initiation (high grade PIN) and progression to carcinoma, and in metastatic cell lines and metastatic carcinoma. Increased expression of MUC18 is implicated to play an important role in developing and malignant progression of human prostate cancer. Furthermore, the lacking of predominant cytoplasmic membrane expression of MUC18 appeared to correlate with malignant progression of prostate cancer.

Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases.

Most papillary transitional cell carcinomas (TCC) are characterized architecturally by an exophytic growth of fingerlike papillae, but some exhibit a prominent endophytic growth pattern resulting in considerable difficulty in assessing invasion. We report on 18 cases of TCC (17 urinary bladder, one pelvicalyceal system) in which endophytic growth was evident either as interanastomosing cords and columns of urothelium, often with a striking resemblance to inverted papilloma (inverted papilloma-like pattern), or as broad, pushing bulbous invaginations into the lamina propria (broad-front pattern). The mean age of the patients was 68 years (range, 32-94 years), with a male preponderance (3.5:1). In four cases, the endophytic pattern was exclusively inverted papilloma-like, 10 cases had only the broad-front pattern, and four cases showed both patterns. Exophytic papillary TCC of the usual type was present in all but two cases, varying from focal (five cases) to moderate (five cases) to extensive (six cases). In spite of the extensive incursion into the lamina propria resulting from the inverted growth, only nine cases (50%) had unequivocal destructive invasion (lamina propria invasion, eight cases; muscularis propria invasion, one case). Follow-up data, available in 14 cases (1-48 months; mean, 15.5 months), revealed one patient alive with disease, 11 patients with no evidence of disease, and two patients dead of other causes. The limited follow-up does not permit evaluation of the impact of the endophytic patterns on outcome. Because the phenomenon of endophytic growth in TCC has received little attention, we present detailed morphologic descriptions of our cases and review the problems associated with assessment of invasion and the different patterns of invasion by TCC.

Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component.

We report five angiomyolipomas with a prominent component of epithelioid smooth muscle cells that occurred in patients from 20 to 48 (mean, 36) years of age. The tumors often posed problems in diagnosis, particularly with regard to distinction from renal cell carcinoma. Two patients had tuberous sclerosis. Two patients with more than 5 years' follow-up are alive and well. The epithelioid smooth muscle cells typically formed sheets that in two tumors were traversed by hyaline cords. The epithelioid cells ranged from medium sized and polygonal with slightly pleomorphic nuclei and eosinophilic cytoplasm to giant cells with prominent nucleoli. Hemorrhage, necrosis, and clusters of foamy macrophages were present in three tumors. Mitotic figures were easy to find in two of the tumors, but they were absent in the others. Obvious elements of typical angiomyolipoma were present in two tumors. The others contained only scattered, thick-walled blood vessels or a few fat cells suggestive of typical angiomyolipoma. None of the tumors was positive for low- or high-molecular-weight cytokeratins or epithelial membrane antigen. Actin was detected in the epithelioid areas in four tumors. Melanoma-associated antigens related to the gp100-cl gene product, HMB-45 and HMB-50, were present in all the tumors. Another melanoma-associated antigen, CD63 (NKI/C3), also was present in all the tumors, a finding suggesting that angiomyolipoma has features in common with melanoma beyond premelanosomal structures.

Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining.

Positive staining with Hale's colloidal iron stain, or modifications thereof, is considered a diagnostic feature for chromophobe renal cell carcinoma and has been used as a discriminatory feature to differentiate it from other renal tumors. We studied colloidal iron staining in 62 cases encompassing a wide histologic spectrum of renal neoplasms (14 chromophobe renal cell carcinomas, 19 renal oncocytomas, 11 each of granular variants and conventional clear cell renal cell carcinomas, and 7 eosinophilic variants of papillary renal cell carcinoma) to investigate the specificity of the stain for chromophobe renal cell carcinoma. In cases of chromophobe renal cell carcinoma, sections from two different areas were stained to ascertain whether there was any spatial variation in staining. Influence of staining techniques on the results also was investigated by staining each case of chromophobe renal cell carcinoma using two different methods: the traditional Hale's and a modified Mowry's technique, which treats sections with 3% acetic acid before adding the colloidal iron. Our results show that positive staining with colloidal iron stain is not limited to chromophobe renal cell carcinoma, however, a diffuse and strong, reticular staining pattern was observed only in cases of chromophobe renal cell carcinoma (14 of 14). The staining patterns were less consistent in all other renal neoplasms and differed from the reaction observed in chromophobe renal cell carcinoma. Most renal oncocytomas (16 of 19) had focal and weak, fine dustlike positivity, and all clear cell carcinomas showed focal, coarse, dropletlike positive staining (22 of 22), in addition to a focal, coarse, bubbly pattern in 5 of 11 clear cell subtypes. Although all seven cases of the eosinophilic variant of papillary renal cell carcinoma showed strong, coarse, dropletlike staining, most of the positivity was coincident with the Perl's (prussian blue) reaction, indicating that the staining was due to hemosiderin, which is frequently present in this histologic subtype of renal cell carcinoma. Staining intensity did not vary considerably among different areas of chromophobe renal cell carcinoma, but the modified Mowry's method yielded brighter and sharper reticular staining, as compared with the Hale's method. Our results show that in the appropriate morphologic context diffuse and strong reticular positivity using the modified Mowry's colloidal iron stain method is highly characteristic for chromophobe renal cell carcinoma. Treatment of sections with 3% acetic acid before adding the colloidal iron gives technically superior staining results.

Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens.

Distinction of urothelial carcinoma in situ (CIS) from reactive atypia on the basis of morphology alone may be difficult in some cases. Because this distinction is therapeutically and prognostically critical, we attempted to determine if an immunohistochemical panel would help in this differential diagnosis. The immunoprofile of 21 cases of CIS and 25 non-neoplastic urothelia (15 urothelial biopsies with reactive atypia from patients without a history of bladder cancer and 10 normal ureter sections from nephrectomies performed for renal cell carcinoma) was determined using antibodies against cytokeratin 20 (CK20), p53, and CD44 (standard isoform). In the normal urothelium CK20 showed patchy cytoplasmic immunoreactivity in only the superficial umbrella cell layer and CD44 stained only the basal cells. Nuclear immunoreactivity to p53 varied from negative to weak and patchy. Reactive urothelium also showed CK20 immunoreactivity in only the umbrella cell layer in all 15 cases, and p53 nuclear staining was predominantly negative with occasional weak positivity in the basal and parabasal intermediate cells. CD44 was overexpressed in the entire reactive urothelium in 9 cases (60%) or focally positive in intermediate cells in 6 cases (40%). In contrast, CIS showed intense CK20 and p53 positivity (81% and 57%, respectively) in the majority (>50%) of malignant cells. CD44 staining revealed residual basal cells with membranous reactivity in 44% of the cases of CIS; however, the neoplastic cells were immunonegative in all cases. At least one positive immunomarker (CK20 or p53) was abnormally expressed in all cases of CIS. Abnormal expression of CK20 (increased), p53 (increased), and CD44 (decreased) in urothelial CIS, and increased expression of CD44 in reactive atypia allows more confident distinction of urothelial CIS from non-neoplastic urothelial atypias. From a differential diagnosis perspective, use of a panel of all three antibodies with morphologic correlation would be essential.

Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens.

Postatrophic hyperplasia is a histologic pattern showing atrophic and hyperplastic glands, sometimes with a small acinar configuration. Because distinction from small acinar carcinoma may be challenging, particularly in needle biopsy specimens, we studied 56 needle biopsy specimens containing 68 foci to ascertain the morphologic spectrum of postatrophic hyperplasia. All foci showed a distinct lobular small acinar proliferation with varying proportions of atrophic and hyperplastic glands. Gland size was typically variable, predominantly of small caliber but occasionally of intermediate to larger caliber. Round, oval, elongated, slitlike and stellate glands were seen. The nuclei were generally regular without hyperchromasia, with rare small nucleoli seen in 10 (15%) foci. The cytoplasm was variable, ranging from scant in atrophic glands to moderate or abundant and clear or occasionally eosinophilic in hyperplastic glands. An irregular internal gland contour was noted in glands with features of both atrophy and hyperplasia. Basal cells were apparent by light microscopy in most foci, although their distribution within foci and between foci varied. This finding was confirmed in all 26 cases studied with the high molecular weight cytokeratin immunohistochemical stain (34betaE12). Associated pathology included adenocarcinoma (12%), high-grade prostatic intraepithelial neoplasia (3%), atrophy distinct from foci of postatrophic hyperplasia (55%), and atypical adenomatous hyperplasia (2%). Adjunctive features of cancer were not seen in any of the foci of postatrophic hyperplasia. Familiarity with the histologic features of postatrophic hyperplasia will allow its confident separation from cancer, especially in limited biopsy material.

Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases.

Renal oncocytoma has several features that overlap with other renal neoplasms with a preponderance of granular cytoplasm, such as chromophobe, granular, and papillary renal cell carcinomas. Lack of knowledge of this entire spectrum of eosinophilic renal cell neoplasms has led to several misconceptions in the literature regarding renal oncocytoma. These include the "grading of oncocytomas," "metastatic oncocytomas," and the impression that renal oncocytoma is usually low grade and lacks prominent nucleoli. In order to further characterize the histologic features and embelLish diagnostic criteria, we evaluated 93 tumors from 80 patients. Four tumors were bilateral and two were multifocal. The mean age was 67.2 years (32-89 years), men were more commonly affected (3.1:1), and 82.7% tumors were incidental findings. Grossly, the tumors were mahogany brown, lacked necrosis, and averaged 4.4 cm in size (range 0.6-15 cm). Histologically, renal oncocytoma was composed of an exclusive or predominant component of acidophilic cells with three architectural patterns of disposition: (a) The "classic" pattern (57.5%), composed of a characteristic nested or organoid arrangement of cells, each surrounded by a distinct reticulin framework; (b) a "tubulocystic pattern" (6.3%) with numerous closely packed cystically dilated tubular structures; and (c) "mixed pattern" (36.2%), which had both the organoid and tubulocystic patterns. A gross or microscopic scar was noted in 53.8% cases, and histologically a distinctive myxoid and/or hyalinized stroma separated nests of cells. Generally, the nuclei of renal oncocytoma were round with uniform nuclear contours. Nearly half of the tumors had prominent nucleoli (42.5% had prominent nucleoli equivalent to Fuhrman's grade III or IV). Pleomorphism was absent in 50% of cases but was conspicuous in 12.5% of cases including foci of bizarre cells. Other atypical features included perinephric fat involvement (11.3%), renal parenchymal invasion not associated with desmoplasia (10%), and hemorrhage (31.3%). Renal oncocytoma by definition lacks areas of clear cell carcinoma, significant lesional necrosis, or conspicuous papillary formations. Ancillary features noted included normal-appearing renal tubules within the lesion (15%), intranuclear holes (20%), psammoma bodies (7.5%), and foam cells (7.5%). 15% of tumors were locally excised, and 85% resulted in radical nephrectomy. Mean follow-up of 7.6 years (range 15-200 months) showed no evidence of recurrence, metastasis, or death due to tumor. In conclusion, renal oncocytoma, herein described, is a benign neoplasm and therefore does not merit a nuclear grading scheme. It has unique histologic features including an organoid and tubulocystic architecture, myxoid or hyalinized stroma, and occasionally some atypical findings including nuclear pleomorphism, prominent nucleoli, and adjacent renal parenchymal and perinephric fat involvement.

Antimitochondrial antibody (113-1) in the differential diagnosis of granular renal cell tumors.

Abundant granular eosinophilic cytoplasm is a common feature of renal oncocytoma, chromophobe renal cell carcinoma, eosinophilic variant of papillary renal cell carcinoma, and the granular variant of clear cell renal cell carcinoma (RCC). Each of these entities has a unique architectural pattern and a distinctive molecular or cytogenetic profile. The chief reason for their distinction from one another is the difference in their biologic behavior. Careful and thorough light microscopic examination distinguishes most cases based on individual characteristic architectural and cytomorphologic features. However, precise characterization may be difficult in some cases because of overlapping morphologic features. We evaluated the antimitochondrial antibody 113-1 in an attempt to ascertain differences in immunostaining patterns in 57 cases of granular renal tumors, including 20 renal oncocytomas, 15 chromophobe RCCs, 13 granular variants of clear cell RCC, and nine eosinophilic variants of papillary RCC. Distinctive, and nearly exclusive, staining patterns were observed among the groups, with chromophobe RCC showing peripheral accentuation of coarse cytoplasmic granules (15 of 15), renal oncocytoma with diffuse and fine granularity (20 of 20), and granular variant of clear cell RCC with irregular cytoplasmic distribution of coarse granules (11 of 13). Staining was most intense in the eosinophilic variant of papillary RCC and was generally coarsely granular and diffuse. Staining patterns also differed in clear cell areas within chromophobe RCC and the granular variant of clear cell RCC. Although clear cells in the former group showed granular staining with peripheral accentuation, most of the clear cells in the latter lacked any staining. We conclude that, in addition to distinct cytoarchitectural features, immunostaining patterns with antimitochondrial antibody 113-1 appear to be a useful discriminatory adjunct in the complex differential diagnosis of granular renal cell tumors.

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee.

This WHO/ISUP system is an attempt to develop as broad a consensus as possible in the classification of urothelial neoplasms, building upon earlier works and classification systems. It is meant to serve as a springboard for future studies that will help refine this classification, thus enabling us to provide better correlation of these lesions with their biologic behavior using uniform terminology.

Morphologic expressions of urothelial carcinoma in situ: a detailed evaluation of its histologic patterns with emphasis on carcinoma in situ with microinvasion.

The recently proposed World Health Organization/International Society of Urological Pathology (WHO/ISUP) consensus classification of flat urothelial lesions expands the definition traditionally used for urothelial (transitional cell) carcinoma in situ (CIS), basing its diagnosis predominantly on the severity of cytologic changes. Lesions now encompassed within the diagnosis of CIS exhibit an array of cytologic and architectural features, which have not been documented in detail. In this study, cases were examined with respect to histologic patterns and microinvasion (invasion into the lamina propria to a depth of less than 2 mm). Five major patterns of CIS, often occurring in the same specimen (160 patterns in 77 cases), were noted. Common to each pattern was the presence of high-grade cytologic atypia, the definitional feature. The patterns found include 1) large cell CIS with pleomorphism (57%), in which the cells had abundant cytoplasm and nuclear pleomorphism; 2) large cell CIS without nuclear pleomorphism (48%); 3) small cell CIS (14%), in which the cytoplasm was relatively scant and pleomorphism was usually minimal; 4) clinging CIS (40%), in which the urothelium was denuded with a patchy, usually single layer of atypical cells; and 5) cancerization of urothelium (16%) with either pagetoid spread (clusters or isolated single cells) or undermining or overriding of the normal urothelium. Carcinoma in situ with microinvasion into the lamina propria (13 cases: 3 of 77 CIS cases studied above and 10 additional cases) was evident as invasive cells with retraction artifact mimicking vascular invasion (77%, 10 cases); nests, irregular cords, and strands, or isolated single cells with desmoplasia (8%, 1 case); or absent stromal response (15%, 2 cases). Although the diagnostic terminology for all of these patterns, for the purposes of the surgical pathology report, should be simply urothelial CIS with no specific mention of the morphologic pattern, awareness of the histologic diversity of CIS will facilitate the diagnosis of this therapeutically and biologically critical flat lesion of the urothelium. These lesions may be associated with microinvasion, which may be clinically unsuspected and histologically subtle.

Histologic variations in the epididymis: findings in 167 orchiectomy specimens.

Nonpathologic morphologic variations in the epididymal histology in 167 orchiectomy specimens were analyzed to assess and document the nature, frequency, and possible relation to patient age and underlying testicular pathology. Variations in histology included intranuclear eosinophilic inclusions, lipofuscin pigment, cribriform hyperplasia, Paneth cell-like metaplasia, and nuclear atypia. Intranuclear eosinophilic inclusions were observed in 72.5% of patients, and they appeared to occur at an older age than cribriform hyperplasia and Paneth cell-like metaplasia. Lipofuscin pigment was found in 32.9% of patients; this change was observed predominantly in ductuli efferentes and was more commonly associated with obstructive changes. Cribriform hyperplasia was seen in 41.9% of patients, and it occurred in 1 normal testis and in 33 testes with diverse pathologic alterations. Paneth cell-like metaplasia characterized by bright eosinophilic intracytoplasmic hyaline-like granules and globules, was present in 8.3% of patients and was accompanied by changes of obstruction in almost all instances. The globules were strongly periodic acid-Schiff positive, both before and after diastase digestion, and were negative for chromogranin A, KP-1, and MAC387 immunostains. Nuclear atypia, similar to that seen in seminal vesicles, was focally present in 13.8% of patients and tended to occur at an older age. The authors conclude that variations in epididymal morphology are fairly common and, therefore, surgical pathologists should be aware of these changes. Although exuberant in some patients, in no cases did these variations cause serious diagnostic problems.

Primary signet-ring cell carcinoma of lung: immunohistochemical study and comparison with non-pulmonary signet-ring cell carcinomas.

Signet-ring cell carcinoma (SRCC) of lung is a rare variant of pulmonary adenocarcinoma. In view of this rarity, the question of whether an SRCC is primary pulmonary or metastatic arises frequently because the majority of SRCCs seen in lung are metastatic tumors having arisen in stomach, colon, or breast. On routine histologic examination it is difficult to distinguish between pulmonary SRCC from SRCC metastasizing from other organs. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is almost exclusively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has been demonstrated in various neoplasms of lung; however, the expression of TTF-1 in SRCCs has not been investigated so far. In the present study, using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1, cytokeratin 7, cytokeratin 20, and villin (a specific marker expressed in tumors of the digestive tract, renal proximal tubules, and hepatic bile ducts) in 32 SRCCs from various organs (17 lung, 5 breast, 5 stomach, and 5 colon). Fourteen (82.4%) of 17 pulmonary SRCCs exhibited TTF-1 positivity, whereas none of the SRCCs of other organs were positive for TTF-1. A cytokeratin profile (CK7+/CK20-) was identified in 94.1% of pulmonary SRCC, and although it differed from the profile exhibited in colonic SRCCs (CK7-/CK20+), a similar profile was seen in breast SRCCs and some SRCCs arising in the stomach. Villin was identified in 29.4% of pulmonary SRCCs and 20% (one case) arising in the breast. Although the pattern of villin immunostaining exhibited by nondigestive tract SRCCs (cytoplasmic) differed from those of digestive tract SRCCs (membranous), distinguishing between the two groups based on their pattern of immunostaining alone would be difficult. The results of this study indicate that TTF-1 is expressed in a high percentage of pulmonary SRCCs and is very specific and that TTF-1 would be extremely valuable in distinguishing pulmonary SRCCs from those arising in other organs.

Lymphoepithelioma-like carcinoma of the urinary bladder.

We report the cases of 11 patients who were treated for undifferentiated carcinoma of the urinary bladder with a prominent lymphoid stroma (lymphoepithelioma-like carcinoma [LELC]). The chief complaint of all 11 patients was hematuria. Their ages ranged from 52 to 79 years (mean of 67). All tumors except one invaded the muscle wall and showed the typical syncytial growth pattern of undifferentiated cells with ill-defined cytoplasmic borders, prominent nucleoli, and numerous mitoses. A significant lymphocytic reaction was an essential component of all these tumors. There were three pure LELC tumors without concurrent invasive transitional-cell carcinoma (TCC) or TCC in situ; these cases morphologically simulated large-cell lymphoma. The remainder were mixed TCC and LELC (five predominant and three focal LELC). The tumor cells were immunoreactive for keratin and showed negative results for leukocyte common antigen. The lymphoid population was an admixture of T cells and B cells with a predominance of T cells. Seven patients (four with predominant and three with focal LELC) were treated with various therapeutic methods. Four patients (three with pure and one with predominantly LELC) received only chemotherapy after transurethral resection of the tumor, and follow-up found no evidence of disease for 9-72 months (mean of 38 months). Awareness of an LELC component in a urinary bladder tumor is also important in order to avoid misinterpreting these tumors as malignant lymphoma or severe chronic cystitis. Our data suggest that the pure LELC tumor appears to be morphologically and clinically different from TCC and that it merits recognition as a separate clinicopathologic entity. In addition, there is strong suggestive evidence that it responds to chemotherapy and therefore there is the potential of salvaging bladder function.

Papillary (chromophil) renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 62 cases.

For more than two decades, papillary renal cell carcinoma has been recognized as a possible distinct clinicopathologic subtype of renal cell carcinoma (RCC). However, the histologic criteria for its diagnosis and the clinical outcome are still debated. In an attempt to clarify the diagnostic criteria and resolve issues pertaining to biologic potential, we have evaluated the histologic spectrum of 62 papillary RCCs and assessed significance of conventional pathologic prognostic parameters (Fuhrrman's nuclear grade [NG], pathologic stage [Robson and TNM], tumor size, multifocality, necrosis, and foam cells) and correlated these with outcome. The mean age of patients was 61.8 years (range 22-83), and males were more commonly affected (1.8:1). Grossly, most tumors were well circumscribed, averaged 6.7 cm in size (range 1.8-18), and were predominantly localized to the renal poles (polar vs. mid-renal, 3:1). Multifocality was a prominent feature (24 cases), and in three cases tumors were bilateral. Microscopically, papillary RCCs were predominantly papillary or tubulopapillary, often with a thick fibrous capsule, foam cells, necrosis, hemorrhage, and multifocality. Thirty-five percent of these tumors were low grade (NG I and II) and 65% high grade (NG III and IV). Sixteen of these tumors presented in a higher stage (stages III and IV), and the overall stage correlated with NG (chi 2, p = 0.009). Tumors were further distinguished by cytoplasmic features: eosinophilic (42%), basophilic (34%) and mixed (24%). Eosinophilic tumors were predominantly high grade, and basophilic tumors low grade (chi 2, p = 0.000). A mean follow-up of 57 months showed progression (metastasis, recurrence, or death due to disease) in 21%, whereas 63% were free of disease. Eleven percent died of unrelated causes, and 5% were lost to follow-up. Kaplan-Meier survival analysis showed that both high NG and stage were strongly associated with decreased survival (p = 0.0000 each), as were decreased foam cell (p = 0.0025) and vascular invasion (p = 0.0002). Comparison of 196 reported cases of papillary RCC, including the current series, with reported large series of conventional RCC indicates that papillary RCC usually presents at an early stage, and stage I (Robson) papillary RCC has better 5 year survival rates (87%-100%) than does RCC of the same stage (65-75%). The overall 5 years survival rate for papillary carcinoma (82-90%) was also higher than that of conventional RCC (44-54%). In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable (p = 0.0000, hazard ratio 10.1) in predicting outcome among papillary RCC. Based on this experience, we conclude that (a) papillary RCC is a malignant tumor, with a tendency to present at a lower stage, but with a distinct potential for progression and aggressive behavior; (b) stratification of these tumors according to cell type, amount of foam cells, presence or absence of vascular invasion, nuclear grade, and pathologic stage provides useful prognostic information; (c) the better 5-year survival rate of papillary RCC (overall and for stage I tumors) compared with that of conventional RCC suggests that it is a tumor with lower malignant potential. Thus, histologic subcategorization of a renal carcinoma as papillary RCC appears to have prognostic implications.

Primary malignant melanoma of the urethra: a clinicopathologic analysis of 15 cases.

The clinical and pathologic features of 15 primary urethral melanomas occurring in patients (nine women and six men) age 44 to 96 years (mean age, 73 yrs) are described. In the men the tumor involved the distal urethra. In eight women it involved the distal urethra, usually the meatus; both the distal and proximal urethra were involved in one woman. The tumors were typically polypoid and ranged from 0.8 to 6 cm (mean, 2.6 cm) in maximum dimension. A vertical growth phase was present in all tumors, with a prominent nodular component in seven of them. A radial growth phase was seen in nine tumors. The depth of invasion ranged from 2 to 17 mm. The tumors had diffuse, nested, storiform, or mixed growth patterns. The neoplastic cells typically had abundant eosinophilic cytoplasm, large nuclei with prominent nucleoli, and brisk mitotic activity. Melanin pigment was seen in 12 tumors but was conspicuous in only six. At the time of diagnosis, 13 tumors were confined to the urethra and two patients had lymph node metastasis. Nine patients died of disease 13 to 56 months after initial diagnosis and treatment, and one patient had a local recurrence at 4 years and subsequently died of sepsis 1 year later. Three patients were alive and well at 11 months, 23 months, and 7 years. One patient died at the time of the initial operation, and one died of a ruptured aortic aneurysm at 3 years without evidence of melanoma at autopsy. Primary malignant melanomas of the urethra, one fifth of which are amelanotic, must be included in the differential diagnosis of a number of primary neoplasms that involve the urethra, including transitional cell carcinoma, sarcomatoid carcinoma, and sarcomas. Conventional prognostic factors, such as depth of invasion or tumor stage, do not seem to play as important a role in predicting survival as the mucosal location and the nodular growth present frequently in these tumors.