Faculty Bibliography

Introduction: The Paris System classifies polyoma virus cytopathic effect (P-CPE) as "negative for high grade urothelial carcinoma (HGUC)". However, P-CPE may raise false suspicion for HGUC. Conversely, HGUC cells may display considerable degenerative nuclear changes mimicking P-CPE. Thus, P-CPE remains a known source of "atypia" in urine cytology. The aim of our study was to determine the frequency of P-CPE cases reported as atypical urothelial cells (AUC) in our laboratory, and to assess the diagnostic utility of SV40 immunostaining (IHC) in this setting.
Material(s) and Method(s): Urine cytology cases, all processed as single Thin prep (TP) slides, were searched for P-CPE diagnosis from 2018 to 2020. An additional slide was prepared for a subset of 40 randomly selected cases (19 P-CPEs, 21 negative controls) for SV40 IHC validation on TP slides.
Result(s): There were 111 urines with P-CPE. 51% were included in this study (Figure 1). Of these, 25% were diagnosed as negative for HGUC, 72% as AUC, and 3% as suspicious for HGUC. Follow-up histology showed HGUC in 3 (5%) cases (2 with AUC and 1 with suspicious for HGUC presurgical cytology). SV40 IHC was positive in 61.5% of cases in the P-CPE group and negative in 38.5% including one with confirmed HGUC on biopsy (Figure 2). In the control group, SV40 IHC was negative in 88% and equivocal in 12% (Figure 3). The difference in SV40 IHC between the P-CPE and control group was statistically significant (p<0.001).
Conclusion(s): Majority of urine samples with P-CPE were reported as AUC with a very low incidence of confirmed HGUC. SV40 IHC aided in the confirmation of viral infection. Our study shows that once the source of atypia is confirmed as polyoma virus with SV40 IHC, downgrading atypia to negative can safely be accomplished without the concern for missing a high-grade lesion. [Formula presented] [Formula presented] [Formula presented]
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Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a "glomeruloid-like" pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a "glomeruloid-like" pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.

CONTEXT.—:Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential diagnosis for each specific type of lesion involving the GU organs. The following summary of the contents presented at the 6th Annual Chinese American Pathologists Association (CAPA) Diagnostic Course (October 10-11, 2020), supplemented with relevant literature review, exemplifies the common diagnostic challenges and pitfalls for mass lesions of the GU system of adults, including adrenal gland, with emphasis on immunohistochemical and molecular updates when relevant. OBJECTIVE.—:To describe the common mass lesions in the GU system of adults, including adrenal gland, with emphasis on the diagnostic challenges and pitfalls that may arise in the pathologic assessment, and to highlight immunohistochemical workups and emerging molecular findings when relevant. DATA SOURCES.—:The contents presented at the course and literature search comprise our data sources. CONCLUSIONS.—:The diagnostic challenges and pitfalls that arise in the pathologic assessment of the mass lesions in the GU system of adults, including adrenal gland, are common. We summarize the contents presented at the course, supplemented with relevant literature review, and hope to provide a diagnostic framework to evaluate these lesions in routine clinical practice.

Inflammatory myofibroblastic tumors (IMT) are rare, mesenchymal tumors that can occur in any anatomic location. IMTs have a variable clinical course but usually require wide surgical excision to prevent local recurrence. There have been limited case reports of IMT occurring in solid organ transplant recipients. Herein we report on a case of IMT presenting in a failed renal allograft. A 53-year-old male awaiting re-transplant presented with pain and a palpable mass in his allograft. Imaging demonstrated an infiltrative soft tissue mass encasing the renal hilum. Percutaneous biopsy demonstrated a myofibroblastic proliferation with myxoid background and no high-grade features. The tumor cells were diffusely positive for anaplastic lymphoma kinase-1 (ALK-1) and had a Ki-67 proliferation index of 10%. These findings were consistent with a diagnosis of IMT. A transplant nephrectomy was performed with wide margins to achieve an R0 resection. Pathology on the resection specimen confirmed an IMT that measured 6.5 cm x 6.3 cm. The patient has no evidence of local recurrence at 6-months follow-up and has been relisted for a second kidney transplant.

This morphological and immunohistochemical study demonstrates that tumors currently known as "middle ear adenomas" are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.

Background: Entrapped cells or tubules within the fibrous stroma/central scar (fibrous epithelial cellular component = FECC) of oncocytoma have been previously reported although not to date studied in detail. While benign, the varied features of these cells may at times pose a diagnostic challenge. Although these have been attributed as entrapped tubules of oncocytoma, the underlying nature and differentiation of the fibrous epithelial cellular component (FECC) remains unexplored.
Design(s): We evaluated cases of renal oncocytoma for cellular components in the fibrous stroma ('entrapped tubules') and describe their morphologic variation and immunohistochemical features in comparison to the surrounding oncocytoma.
Result(s): We examined twelve oncocytoma cases with fibrous stroma ('central scar') containing FECC which were evaluated further by immunohistochemical studies, including CD117 and CK7. In select cases, additional immunohistochemical stains were performed depending on the renal tumor differential diagnosis. These included carbonic anhydrase IX (CA-9), 34Be12 and AE1/AE3 in select cases. The fibrous stroma of the oncocytoma ('central scar') was noted to represent from 10% to 50% of the tumor area and while predominantly central also extended peripherally as short septa. FECC was predominantly in the stroma immediately subjacent to the usual oncocytoma component. The architecture varied as tubular, trabecular, to diminutive acini with adjacent single cells and showed mixed pattern in majority. Cytologically the FECC had cleared cytoplasm, and slightly larger and vesicular nuclei than oncocytoma cells. Some cases demonstrated an area of transition between oncocytoma and the fibrous cellular component with trabecular bands containing scattered oncocytic intermingled with clear cells. Immunohistochemical studies showed FECC positive for CK7 and CA-9 and negative for CD117 (CK7 +/ CA- 9 +/CD117 -), whereas oncocytoma cells showed the reverse pattern (CK7 -/ CA-9 -/CD117 +). Immunostains for 34betaE12 and AE1/AE3 performed in a subset of cases showed positive staining of in contrast to the nonreactivity in the oncocytoma. (Figure Presnted)
Conclusion(s): FECC or 'entrapped tubules' likely represents a fibrous stromal component of oncocytoma with different microscopic appearance and immunohistochemical profile. It is important to be aware of the variant histological pattern and immunohistochemical profile of oncocytoma as may pose diagnostic difficulty in limited sampling by core needle biopsy. The clear appearance and narrowed trabecular/ tubular pattern is suggestive of an atrophic/ entrapped tumor component, however its varied immunoprofile also raises question as to whether this represents a different differentiation of tumor in an altered microenvironment

Background: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes encoding polycystin 1 and polycystin 2 (PKD1 and PKD2, respectively), leading to florid cystic change of the renal parenchyma. The incidence of carcinoma associated with ADPKD remains unclear although there are studies to suggest that the incidence may be higher.
Design(s): We queried our department pathology database for surgical specimens with ADPKD from 1990 to 2020. We evaluated these cases for the presence of associated malignant or benign neoplasia, as well as pathological and clinical parameters.
Result(s): The majority of the surgical specimens are kidney explants with a clinical diagnosis of ADPKD and the status of end stage kidney diseases. All specimens showed radiological, gross and microscopic features of ADPKD. Eight of 33 ADPKD patients with kidney resection specimens examined contained a malignant neoplasm, including 2 patients with bilateral malignancy. The types of renal cell carcinoma (RCC) associated with the following types: four cases of clear cell RCC, two cases of papillary RCC, type 2, two cases of unclassified high grade RCC, one case of unclassified low grade, as well as one case of TFE3 translocated RCC. Associated carcinomas ranged in size from less than 1 cm to 12 cm. One case with a concurrent oncocytoma and several cases with associated papillary adenoma were also reported.
Conclusion(s): In this cohort, a wide distribution of renal cell carcinoma subtypes were observed, with clear cell RCC being the most common type. The incidence of associated malignancy (24%) is higher than previously reported by Jilg et al. 2013 (5%), possibly due to differences in patient management or patient populations between the institutions. This case series highlights the high occurrence of carcinoma in APKD nephrectomies suggesting a clinical risk of malignancy in patients with ADPKD. Additionally this case series reports the first case of a TFE3 translocated renal cell carcinoma arising synchronously with a contralateral clear cell renal cell carcinoma in a patient with ADPKD. The heterogeneity of renal carcinoma subtypes within the group (and within contralateral kidneys in one patient with bilateral involvement) suggests that stimuli for tumorigenesis arise at the kidney microenvironment level rather than on the basis of gene mutation alone. Accrual of an expanded cohort of patients is planned to enable confirmation of differences between carcinomas arising in the setting of ADPKD versus those arising in end stage renal disease due to other causes, and in the sporadic setting. Furthermore a role for molecular studies is suggested to evaluate if any of the ADPKD causing mutations (PKD1, PKD2, or other) is associated with the development of carcinoma