Faculty Bibliography

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

Background: Mary Mallon was termed Typhoid Mary for her role in spreading typhoid fever in the early 1900s. Dr. Soper identified her as a super spreader based on her occupation as a cook in many households that were afflicted. She was subsequently sentenced to enforced confinement to reduce the risk of her continuing to spread disease, yet her exact toll is not fully determined. Pre-antibiotic era, typhoid fever resulted in ~10% mortality. While Mallon has been implicated in 53 cases of typhoid fever, she was implicated in only 3 deaths. We examined the autopsy records of a hospital within 1 mile of her home in NYC to identify whether any deaths from typhoid fever could be associated with her geographically. We anticipated the challenges raised by limited availability of records, however derived inspiration from John Snow's use of geolocation data to elucidate the mechanism of cholera spreading events.
Design(s): We investigated all autopsy records of a public hospital located within 1 mile of the home of Mary Mallon from 1905-1907, prior to her confinement. We recorded name, age, and district of the deceased. We then investigated death and voting registry records for information on the deceased and newspapers for any obituaries. We derived home/work addresses, ethnicity and ages of the deceased to identify any clusters, and to geolocate in relation to Mallon's home/work addresses in the 3 weeks prior to death.
Result(s): We found 22 patients that died of typhoid fever as follows: 20 M, 2 F, ages 23-47, 9 of Irish ethnicity. We grouped them into 4-week clusters of dates of death and identified 7 clusters. The ages in these clusters more closely approximated each other as compared to the overall group. Socioeconomic information was available in a minority of the group, however their treatment and subsequent death in a public hospital suggested their employment in low earning jobs, similar to Mallon.
Conclusion(s): The relatively low death count attributed to Mallon remains unexplained. The patients that died during the time that Mallon lived in the neighborhood of the hospital raise possibility for an association. Archived public records have provided further information on some of the deceased and delineation of small clusters, however insufficient evidence has been derived yet to make any association. Further efforts are planned to searchother city and hospital records to identify the estimated 2-3 unaccounted deaths that may be associated with Typhoid Mary

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

Gastric cancer is a rare long-term complication in gastrocystoplasty. We report 2 cases of gastric adenocarcinoma and review the literature for similar cases. A total of 14 cases are identified. The majority of patients are males, presented with hematuria, and developed cancer at a younger age, more than 10 years after gastrocystoplasty. Long-term follow up information was limited, but 5 patients (36%) died within 5 years of diagnosis. Annual surveillance for malignancy may not be effective due to its rarity. However, symptomatic patients, particularly those 10 years after the surgery, warrant detailed evaluation to rule out neoplastic transformation.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

Background: Low risk prostate cancers are amenable to active surveillance which can reduce harmful overtreatment of indolent disease. However there is great variability of criteria in urological practice for determination of active surveillance candidacy. The quantity of Gleason pattern 4 is an important prognostic parameter and may influence treatment decisions. A genomic classifier, the Oncotype DX Genomic Prostate Score has been used to predict both clinical risk and tumor aggressiveness in patients diagnosed on biopsy with low risk prostate cancer (Grade group (GG) 1 and 2). This study investigated whether Genomic Prostate Score (GPS) can predict unfavorable disease and correlates with percentage of Gleason pattern 4 in low grade prostate cancer.
Design(s): We searched our surgical pathology database for prostate biopsies with Oncotype DX Genomic Prostate Score reports (2016- 2019). Oncotype Dx was performed on the single core with worst disease (core with longest tumor and/or maximum percentage of pattern 4). Biopsy results including Gleason Score and length of the tumor and percentage of pattern 4 from the core submitted for Oncotype test were recorded. Follow-up repeat biopsy or prostatectomy, if performed, were also retrieved for review of Gleason Score. Oncotype GPS score and related clinical information were analyzed in the study.
Result(s): 306 prostate biopsy cases with Oncotype DX test report were included in the study. Among these cases, 124 cases were originally diagnosed as GG1 (Gleason Score 3 + 3) and 182 cases were GG2 (3 + 4). The average GPS in GG 2 is significantly higher than GG1 (28.52 +/- 11.80 vs 17.88 +/- 9.35, p < 0.0001). Forty cases in GG1 had follow up repeat biopsy or prostatectomy. Twenty cases were upgraded to GG2. Cases with higher GPS score are more likely to upgrade to GG2 (23.10 +/- 10.13 vs 16.55 +/- 8.22, p < 0.05) in follow up repeat biopsy or prostatectomy. In GG1 group, GPS score correlated with the maximum tumor length and tumor percentage (p < 0.01). In GG2, patients with Gleason pattern 4 greater than 30% received higher GPS score than patients with pattern 4 less than 30% (p < 0.05). GPS significantly correlated with percentage of Gleason pattern 4 but not length of pattern 4, length of tumor, PSA level or PSA density.
Conclusion(s): In GG1, Oncotype Dx GPS can predict the likelihood of unfavorable disease at follow up repeat biopsy or prostatectomy. In GG2, GPS score correlated with percentage of pattern 4, supporting its role as an auxiliary tool for clinical risk classification

Background: Recent clinical guidelines for management of prostate adenocarcinoma are aimed at expanding active surveillance (AS) to include men with intermediate-risk (Gleason score 3+4=7) disease on needle biopsy (NB). However, studies reported a large portion of men with Gleason 3+4=7 prostate cancer on biopsy, that harbored adverse surgical pathologic findings. It remains unclear which subset of intermediate-risk patients with Gleason score 7 cancers can be safely treated with AS. In this study we investigate whether the percentage of Gleason pattern 4 in NB with Gleason score 7 cancers is an indicator for stratifying risk.
Design(s): We retrospectively reviewed our electronic record database for patients that underwent core NB over a 6-year period. We included NB with Gleason score 3+3=6 (G336), 3+4=7 with <5% Gleason pattern 4 (G4%<5) and 3+4=7 with 6-49% maximum Gleason pattern 4 (G4%6-49); all cases had corresponding radical prostatectomy (RP) within 6 months of the biopsy. We defined adverse pathology (AP) as any RP with Gleason score equal to or greater than 4+3=7 and/or stage T3 or higher. We compare AP outcomes in final follow-up RP of three NB groups: G336, G4%<5 and G4%6-49.
Result(s): A total of 289 NB with corresponding radical prostatectomies were identified. The breakdown of Gleason groups is shown in Table 1. GS336 has an AP rate of 26.6%, while G4<5% an AP rate of 20%. In comparison, the group of patients with G4%6-49 exhibited a 42% rate of AP (Table 1). A Chi-square test performed comparing AP of G4%<5 and G%6-49 is statistically significant p= .0237 (Figure 1). Conversely, there is no statistical difference between the rate of AP in G4<5% and G336, p= 0.46. G336 and G4%<5 were aggregated into a new group G%0-5 with an AP rate of 25.2% compared to G%6-10 AP rate 39.6%, p= 0.0576 (Figure 2). G4%6-10 and G4%11-49 had comparable rates of AP, 39.6% and 43.1%, respectively (p=0.681). (Table presented)
Conclusion(s): Currently there is a paradigm shift amongst pathologist and the significance of minimal percentage pattern 4 on prostate biopsies. Our current data supports the recent literature publications that <5% maximal Gleason pattern 4 on a single core has a similar rate of adverse pathological outcomes as Gleason score 3+3=6 and can be considered for AS. Although we did not detect a statistical difference between the rate of AP between G4%0-5 and G4%6-10, the data is beginning to approach statistical significance and warrants further risk stratification

Parathyromatosis is a rare but recognized cause of recurrent primary hyperparathyroidism. Initially described in 1975 by Palmer et al.(1), about 40 cases have been described in the literature. Most patients are middle-aged females. A small majority of the cases arise in the context of secondary hyperplasia due to end-stage renal disease.(2) The nature of parathyromatosis is unknown. It may be a low-grade carcinoma, seeding of a prior adenoma, or overgrowths of embryologic rests. Several oncogenes of interest have been identified in parathyroid neoplasms (PRAD1, MEN1, HRPT2, CaSR). (3) A biallelic CDC73/HRPT2 inactivating mutation is known to be present in about 75% of sporadic parathyroid carcinomas and absent in most adenomas. (4) Their possible relationship to parathyromatosis has not been studied. As such, differentiating parathyromatosis from other parathyroid neoplasms is challenging.(5-10) This article is protected by copyright. All rights reserved.