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: 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

Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.

BACKGROUND:As with cases of sporadic gastrointestinal stromal tumor (GIST), familial GIST syndrome arises from mutations in KIT or PDGFRA. Only a few dozen such families have been described in the literature. METHODS:Cases of 2 individuals from 2 different newly described kindreds with familial GIST syndrome were retrospectively reviewed. Pertinent immunohistochemical stains, including CD117, CD34, DOG1, desmin, and S100, were performed. Samples from each case were sent to outside facilities for molecular analysis. A review of the relevant literature was performed and the number of familial GIST syndrome cases reported was updated through July 2014. RESULTS:In case 1, a woman 40 years of age with a family history of GIST presented with abdominal pain and gastrointestinal bleeding. Biopsy of a gastric mass revealed spindle-cell type GIST. Molecular analysis revealed a heterozygous mutation of p.Asp579del in exon 11 of KIT. The patient was placed on imatinib therapy and an initial positive response was demonstrated by imaging. Disease regression was seen on computed tomography, and several GIST tumors were surgically resected. The patient has had stable disease since surgery. In case 2, an asymptomatic woman 29 years of age presented for screening due to a family history of GIST. One small nodule was noted in her stomach and another was noted in the duodenum; both were surgically resected. The patient recovered well following surgery. The GIST in this patient was noted to have similar histological, immunohistochemical, and molecular findings as case 1. CONCLUSIONS:Imatinib has often been shown to be an effective therapy in both the familial and sporadic forms of GIST. There is no standard protocol for addressing the surveillance of patients with spindle-cell type GIST seen in the setting of familial GIST syndrome and with a p.Asp579del mutation of exon 11 on KIT.

BACKGROUND:Myzus persicae, the green peach aphid, is a polyphagous herbivore that feeds from hundreds of species of mostly dicot crop plants. Like other phloem-feeding aphids, M. persicae rely on the endosymbiotic bacterium, Buchnera aphidicola (Buchnera Mp), for biosynthesis of essential amino acids and other nutrients that are not sufficiently abundant in their phloem sap diet. Tobacco-specialized M. persicae are typically red and somewhat distinct from other lineages of this species. To determine whether the endosymbiotic bacteria of M. persicae could play a role in tobacco adaptation, we sequenced the Buchnera Mp genomes from two tobacco-adapted and two non-tobacco M. persicae lineages. RESULTS:With a genome size of 643.5 kb and 579 predicted genes, Buchnera Mp is the largest Buchnera genome sequenced to date. No differences in gene content were found between the four sequenced Buchnera Mp strains. Compared to Buchnera APS from the well-studied pea aphid, Acyrthosiphon pisum, Buchnera Mp has 21 additional genes. These include genes encoding five enzymes required for biosynthesis of the modified nucleoside queosine, the heme pathway enzyme uroporphyrinogen III synthase, and asparaginase. Asparaginase, which is also encoded by the genome of the aphid host, may allow Buchnera Mp to synthesize essential amino acids from asparagine, a relatively abundant phloem amino acid. CONCLUSIONS:Together our results indicate that the obligate intracellular symbiont Buchnera aphidicola does not contribute to the adaptation of Myzus persicae to feeding on tobacco.