High-risk human papilloma virus status & outcomes for penile squamous cell carcinoma: A single institution experience.

OBJECTIVES: There is a paucity of data on North American cohorts of patients with penile squamous cell carcinoma (pSCC). Herein, we aimed to assess the sensitivity of various modalities to identify human papillomavirus (HPV) status, determine the prevalence of high-risk HPV-positivity, and evaluate the prognostic impact of relevant clinicopathologic variables. METHODS: Patients with pSCC (n = 121) consecutively treated with partial/total penectomy (2000-2022) at a single institution were included. HPV status (based on immunohistochemistry [IHC], in situ hybridization [ISH], and panviral metagenomic sequencing [PMS]), histologic features, and outcomes were reviewed. Outcome events included death due to disease and progression. RESULTS: The majority of patients were white (105/121, 86.8%). Thirty-seven (30.6%) were high-risk HPV-positive, and morphologic evaluation had a sensitivity of 97.3% (95% confidence interval [CI], 86.2-99.5) for predicting high-risk HPV status compared to IHC/ISH/PMS. Disease progression was more common among high-risk HPV-negative compared to high-risk HPV-positive patients (HR 2.74, CI 1.12-8.23, P = 0.03). Moreover, among high-risk HPV-negative patients, those with moderate-poorly differentiated tumors had increased disease-specific mortality (32.6%, CI 17.1-48.1) compared to those with well-differentiated tumors (0%). Among high-risk HPV-positive patients, those with basaloid morphology had lower disease-specific mortality (0% vs 14.4%, CI 0.0-33.1). CONCLUSIONS: We demonstrate high-risk HPV-positivity in approximately one-third of patients with pSCC. Morphologic evaluation alone had a high sensitivity in correctly determining HPV status. Our results suggest that high-risk HPV status and morphologic features (differentiation in high-risk HPV-negative, and basaloid subtype in high-risk HPV-positive pSCC) may have prognostic value.

Comparison of a modified staging system with 8th edition AJCC criteria in a North American cohort of pT2/pT3 HPV-negative penile squamous cell carcinoma.

The staging for pT2/pT3 penile squamous cell carcinoma (pSCC) has undergone major changes. Some authors proposed criteria wherein the distinction between pT2/pT3 was made using the same histopathological variables that are currently utilized to differentiate pT1a/pT1b. In this single-institution, North American study, we focused on (HPV-negative) pT2/3 pSCCs (i.e., tumors invading corpus spongiosum/corpus cavernosum), and compared the prognostic ability of the following systems: (i) AJCC (8th edition) criteria; (ii) modified staging criteria proposed by Sali et al. (Am J Surg Pathol. 2020; 44:1112-7). In the proposed system, pT2 tumors were defined as those devoid of lymphovascular invasion (LVI) or perineural invasion (PNI), and were not poorly differentiated; whereas pT3 showed one or more of the following: LVI, PNI, and/or grade 3. 48 pT2/pT3 cases were included (AJCC, pT2: 27 and pT3: 21; Proposed, pT2: 22 and pT3: 26). The disease-free survival (DFS) and progression-free survival (PFS) did not differ between pT2 and pT3, following the current AJCC definitions (p = 0.19 and p = 0.10, respectively). When the pT2/3 stages were reconstructed using the modified criteria, however, a statistically significant difference was present in both DFS and PFS between pT2 and pT3 (p = 0.004 and p = 0.003, respectively). The proposed staging system has the potential to improve the prognostication of pT2/pT3 tumors in pSCC. Each of these histopathologic variables has been shown to have a significant association with outcomes in pSCC, which is an advantage. Further studies are needed to demonstrate the utility of this modified staging system in patient populations from other geographic regions.

Single nucleotide polymorphism (SNP) chromosomal microarray as a diagnostic tool for mucinous tubular and spindle cell carcinoma: A validation study.

Mucinous tubular and spindle cell carcinoma (MTSCC) shows significant overlap with papillary renal cell carcinoma (PRCC), and harbor recurrent copy-number alterations (CNA). We evaluated 16 RCC with features suggestive of MTSCC using chromosomal microarrays. The cohort was comprised of 8 females and males, each, with an age range of 33-79 years (median, 59), and a tumor size range of 3.4-15.5 cm (median, 5.0). Half the tumors were high-grade (8/16, 50%) with features such as necrosis, marked cytologic atypia, and sarcomatoid differentiation, and 5/16 (31%) were high stage (≥pT3a). Three (of 16, 19%) cases had a predominant (>95%) spindle cell component, whereas 5/16 (31%) were composed of a predominant (>95%) epithelial component. Most cases (12/16, 75%) exhibited a myxoid background and/or extravasated mucin, at least focally. Twelve (of 16, 75%) cases demonstrated CNA diagnostic of MTSCC (losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22). In addition, 2 high-grade tumors showed loss of CDKN2A/B, and gain of 1q, respectively, both of which are associated with aggressive behavior. Three (of 16, 19%) cases, demonstrated nonspecific CNA, and did not meet diagnostic criteria for established RCC subtypes. One (of 16, 6%) low-grade epithelial predominant tumor (biopsy) demonstrated characteristic gains of 7, 17, and loss of Y, diagnostic of PRCC. MTSCC can be a morphologically heterogenous tumor. Our study validates the detection of characteristic chromosomal CNA for diagnostic use that may be useful in challenging cases with unusual spindle cell or epithelial predominant features, as well as in high-grade tumors.

Genomic attributes of prostate cancer across primary and metastatic noncastrate and castrate resistant disease states: a next generation sequencing study of 183 patients.

Primary prostatic adenocarcinoma (pPC) undergoes genomic evolution secondary to therapy-related selection pressures as it transitions to metastatic noncastrate (mNC-PC) and castrate resistant (mCR-PC) disease. Next generation sequencing results were evaluated for pPC (n = 97), locally advanced disease (involving urinary bladder/rectum, n = 12), mNC-PC (n = 21), and mCR-PC (n = 54). We identified enrichment of TP53 alterations in high-grade pPC, TP53/RB1 alterations in HGNE disease, and AR alterations in metastatic and castrate resistant disease. Actionable alterations (MSI-H phenotype and HRR genes) were identified in approximately a fifth of all cases. These results help elucidate the landscape of genomic alterations across the clinical spectrum of prostate cancer.

Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.