Aims
Extramammary Paget disease (EMPD) is an epithelial neoplasm that can occur at many sites, including the vulva and scrotum. EMPD is characterised by the presence of neoplastic cells, in single ...cells and clusters, that infiltrate all layers of non‐neoplastic squamous epithelium. The differential diagnosis for EMPD includes melanoma in situ and secondary involvement of tumours from other sites, such as urothelial or cervical; pagetoid spread of tumor cells can also been seen at other sites, such as anorectal mucosa. The most frequently utilised biomarkers for confirming the diagnosis of EMPD include CK7 and GATA3; however, these biomarkers lack specificity. The purpose of this study was to evaluate TRPS1, a newly described breast biomarker, in pagetoid neoplasms of the vulva, scrotum and anorectum.
Methods and results
Fifteen cases of primary EMPD of the vulva (two with associated invasive carcinoma) and four primary EMPD of the scrotum showed strong nuclear immunoreactivity for TRPS1. In contrast, five cases of vulvar melanoma in situ, one case of urothelial carcinoma with secondary pagetoid spread into the vulva and two anorectal adenocarcinomas with pagetoid spread into anal skin (one with associated invasive carcinoma) were negative for TRPS1. Additionally, weak nuclear TRPS1 staining was observed in non‐neoplastic tissues (e.g. keratinocytes), but always with less intensity when compared to tumour cells.
Conclusions
These results demonstrate that TRPS1 is a sensitive and specific biomarker for EMPD, and may be especially useful for excluding secondary involvement of the vulva by urothelial and anorectal carcinomas.
TRPS1 expression is sensitive and specific for extramammary Paget disease of the vulva and scrotum. Melanoma in situ and secondary tumours with pagetoid spread, including urothelial carcinoma, are negative for TRPS1.
Summary Renal oncocytoma and chromophobe renal cell carcinoma (RCC) have been long recognized as distinct tumors; however, it remains unknown if uniform diagnostic criteria are used to distinguish ...these tumor types in practice. A survey was distributed to urologic pathologists regarding oncocytic tumors. Responses were received from 17/26 invitees. Histologically, >1 mitotic figure was regarded as most worrisome (n = 10) or incompatible (n = 6) with oncocytoma diagnosis. Interpretation of focal nuclear wrinkling, focal perinuclear clearing, and multinucleation depended on extent and did not necessarily exclude oncocytoma if minor. Staining techniques most commonly used included: CK7 (94%), KIT (71%), vimentin (65%), colloidal iron (59%), CD10 (53%), and AMACR (41%). Rare CK7-positive cells (≤5%) was regarded as most supportive of oncocytoma, although an extent excluding oncocytoma was not universal. Multiple chromosomal losses were most strongly supportive for chromophobe RCC diagnosis (65%). Less certainty was reported for chromosomal gain or a single loss. For tumors with mixed or inconclusive features, many participants use an intermediate diagnostic category (82%) that does not label the tumor as unequivocally benign or malignant, typically “oncocytic neoplasm” or “tumor” with comment. The term “hybrid tumor” was used variably in several scenarios. A slight majority (65%) report outright diagnosis of oncocytoma in needle biopsies. The morphologic, immunohistochemical, and genetic characteristics that define oncocytic renal tumors remain incompletely understood. Further studies correlating genetics, behavior, and histology are needed to define which tumors truly warrant classification as carcinomas for patient counseling and follow-up strategies.
Proposed origins of pelvic serous carcinoma include the ovary, fallopian tube, and peritoneum. Prophylactic salpingo-oophorectomies in BRCA+ women have recently identified the fimbria as a site of ...origin for early serous carcinoma (tubal intraepithelial carcinoma or TIC). We explored the relationship of TIC to pelvic serous carcinomas in consecutive cases with complete adnexal exam (SEE-FIM protocol). Cases positive (group A) or negative (group B) for endosalpinx (including fimbria) involvement, were subclassified as tubal, ovarian, or primary peritoneal in origin. Coexisting TIC was recorded in group A when present and p53 mutation status was determined in 5 cases. Of 55 evaluable cases, 41 (75%) were in group A; including tubal (n = 5), peritoneal (n = 6), and ovarian (n = 30) carcinomas. Foci of TIC were identified in 5 of 5, 4 of 6, and 20 of 30, respectively. Ninety-three percent of TICs involved the fimbriae. Five of 5 TICs and concurrent ovarian carcinomas contained identical p53 mutations. Thirteen of 14 cases in group B were classified as primary ovarian carcinomas, 10 with features supporting an origin in the ovary. Overall, 71% and 48% of "ovarian" serous carcinomas had endosalpinx involvement or TIC. TIC coexists with all forms of pelvic serous carcinoma and is a plausible origin for many of these tumors. Further studies are needed to elucidate the etiologic significance of TIC in pelvic serous carcinoma, reevaluate the criteria for tubal, peritoneal, and ovarian serous carcinoma, and define the role of the distal tube in pelvic serous carcinogenesis.
Aims
Renal epithelial neoplasms (RENs) can be difficult to subclassify, owing to overlapping morphological features. Carbonic anhydrase 9 (CA9) is a common biomarker for clear cell renal cell ...carcinoma (CCRCC); however, the sensitivity and specificity across REN subtypes are less clear. The aim of this study was to investigate CA9 expression in RENs, especially those in the differential diagnosis with CCRCC and less common entities, to determine its reliability as a diagnostic biomarker.
Methods and results
CA9 immunostaining was performed on 262 RENs, including 119 CCRCCs and 143 non‐CCRCC. Immunostaining was evaluated as negative (0%), rare (1+, 1–10%), focal (2+, 11–50%), or diffuse (3+, >50%). CCRCCs were 3+ CA9‐positive in 93% of cases; 4% were CA9‐negative. Sixty‐seven percent of papillary renal cell carcinomas (RCCs) were 1+/2+ CA9‐positive, whereas 33% were CA9‐negative. Chromophobe RCCs were nearly always CA9‐negative (93%), with 7% showing rare cell reactivity. Clear cell tubulopapillary RCCs (CCTPRCCs) were consistently 3+ CA9‐positive, but with a cup‐like staining pattern. Fifty‐three percent of Xp11.2 RCCs were CA9‐negative; however, 6% were 3+ CA9‐positive and 12% were 2+ CA9‐positive. Two of eight fumarate hydratase‐deficient RCCs were 3+ CA9‐positive. A small subset of the remaining RCCs showed rare to focal CA9 expression. All oncocytomas and eosinophilic solid and cystic RCCs were CA9‐negative.
Conclusions
Overall, diffuse CA9 expression was identified in nearly all CCRCCs and in all CCTPRCCs (high sensitivity); however, CA9 was not entirely specific. At least focal CA9 expression can been seen in a subset of many RCCs, and such findings should be taken into consideration with other morphological, immunophenotypic and clinical findings.
In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% ...sarcomatoid differentiation.
Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory.
Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9)
19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy.
In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.
Ovarian-type (ie, Mullerian) epithelial tumors occurring in the testicular and paratesticular regions are exceptionally rare, with only a handful reported worldwide. Serous tumors are the most ...frequently encountered subtype among these rare tumors. The pathogenesis of these tumors within the testicular and paratesticular regions remains a subject of intrigue and debate, with various hypotheses attempting to explain their presence in the paratestis region, where most tumors occur. However, our understanding of the pathogenesis of intratesticular tumors is limited. To date, 11 known examples of intratesticular serous Mullerian tumors have been reported globally. In this report, we present an extraordinary tumor, an intratesticular Mullerian serous borderline tumor with foci of microinvasion, in a 38-year-old male patient. This tumor exhibits histological features similar to their ovarian counterparts and is confirmed through an immunohistochemical panel. Our report underscores the extreme rarity of these tumors, emphasizes the importance of heightened awareness among clinicians and pathologists, and provides valuable insights into their complex development and histogenesis. This contribution aims to enhance diagnostic precision and optimize therapeutic strategies for similar tumors.
Sarcomatoid transformation occurs in ∼8% of chromophobe renal cell carcinoma (chRCC) and is associated with aggressive clinical behavior. In recent years, several studies have identified genomic, ...transcriptomic, and epigenomic correlates of aggressive behavior in chRCC; however, the molecular mechanisms associated with sarcomatoid transformation remain incompletely understood. In this study, we analyzed paired conventional and sarcomatoid histologic components of individual chRCC to elucidate the genomic alterations that underlie sarcomatoid transformation in this tumor type. Massively parallel sequencing was performed on paired (conventional and sarcomatoid) components from 8 chRCCs. All cases harbored TP53 variants (87.5% showing TP53 variants in both components and 12.5% only in the sarcomatoid component). Intratumor comparisons revealed that TP53 variants were concordant in 71% and discordant in 29% of cases. Additional recurrent single-nucleotide variants were found in RB1 (37.5% of cases) and PTEN (25% of cases), with the remaining single-nucleotide variants detected in these tumors (PBRM1, NF1, and ASXL1) being nonrecurrent. Copy number variant analysis showed the characteristic pattern of chromosomal losses associated with chRCC (1, 2, 6, 10, 13, 17, and 21) in the conventional histologic components only. Interestingly, the sarcomatoid components of these tumors demonstrated widespread loss of heterozygosity but lacked the above chromosomal losses, likely as a consequence of whole-genome duplication/imbalanced chromosomal duplication events. Overall, the findings suggest that TP53 variants followed by whole-genome duplication/imbalanced chromosomal duplication events underlie sarcomatoid transformation in chRCC.
Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm ...12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.
A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring
(
). Here, we show that PRKCI is also expressed in early fallopian tube lesions, ...called serous tubal intraepithelial carcinoma. Transgenic mouse studies establish
as an ovarian cancer-specific oncogene. Mechanistically, we show that the oncogenic activity of PRKCI relates in part to the up-regulation of TNFα to promote an immune-suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T-cell infiltration. Furthermore, system-level and functional analyses identify YAP1 as a downstream effector in tumor progression. In human ovarian cancers, high PRKCI expression also correlates with high expression of TNFα and YAP1 and low infiltration of cytotoxic T cells. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer.
Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, ...SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next-generation sequencing was performed on DNA extracted from paraffin-embedded tissue. Eleven tumors were identified from 10 patients, 22–72 years of age (median 40). Two patients had paragangliomas, 1 bilateral SDH-deficient RCC, and 1 contralateral oncocytoma. Grossly, tumors were tan or red–brown, 2–20 cm in diameter (median 4.25 cm). Fuhrman grade was 2 (n=10) or 3 (n=1). Stage was pT1a–pT2b. One patient developed widespread metastases 16 years after nephrectomy and died of disease 6 years later. All tumors were composed of uniform eosinophilic cells containing vacuoles or flocculent cytoplasmic inclusions. Architecture was primarily solid; entrapped renal tubules and intratumoral mast cells were common. By immunohistochemistry, tumor cells were negative for SDHB (11/11) and rarely SDHA (1/11). Labeling was uniformly positive for PAX8 and kidney-specific cadherin and absent for KIT, RCC, and carbonic anhydrase IX. Staining for broad-spectrum epithelial markers was often negative or focal (positive staining for AE1/AE3 in 4/10, CAM5.2 3/7, CK7 1/11, EMA 10/10). By sequencing, SDHB mutation and loss of the second allele were present in 5/6 tumors; the SDHA-deficient tumor showed no SDHB abnormality. SDH-deficient RCC is a unique neoplasm that is capable of progression, often harboring SDHB mutation. A monomorphic oncocytic renal tumor with solid architecture, cytoplasmic inclusions of flocculent material, and intratumoral mast cells should prompt evaluation of SDH status, as it may have implications for screening the patient and relatives. Negative immunohistochemistry for KIT and heterogeneous labeling for epithelial antigens are other supportive features.
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