Squamoid Eccrine Ductal Carcinoma Displays Ultraviolet Mutations and Intermediate Gene Expression Relative to Squamous Cell Carcinoma, Microcystic Adnexal Carcinoma, and Porocarcinoma.

Squamoid eccrine ductal carcinoma is a rare infiltrative tumor with morphologic features intermediate between squamous cell carcinoma (SCC) and sweat gland carcinomas such as microcystic adnexal carcinoma. Although currently classified as a sweat gland carcinoma, it has been debated whether squamoid eccrine ductal carcinoma is better classified as a variant of SCC. Furthermore, therapeutic options for patients with advanced disease are lacking. Here, we describe clinicopathologic features of a cohort of 15 squamoid eccrine ductal carcinomas from 14 unique patients, with next-generation sequencing DNA profiling for 12 cases. UV signature mutations were the dominant signature in the majority of cases. TP53 mutations were the most highly recurrent specific gene alteration, followed by mutations in NOTCH genes. Recurrent mutations in driver oncogenes were not identified. By unsupervised comparison of global transcriptome profiles in squamoid eccrine ductal carcinoma (n = 7) to SCC (n = 10), porocarcinoma (n = 4), and microcystic adnexal carcinoma (n = 4), squamoid eccrine ductal carcinomas displayed an intermediate phenotype between SCC and sweat gland tumors. Squamoid eccrine ductal carcinoma displayed significantly higher expression of 364 genes (including certain eccrine markers) and significantly lower expression of 525 genes compared with other groups. Our findings support the classification of squamoid eccrine ductal carcinoma as a carcinoma with intermediate features between SCC and sweat gland carcinoma.

In Vivo Microstructure Imaging in Oropharyngeal Squamous Cell Carcinoma Using the Random Walk With Barriers Model.

BACKGROUND: Apparent diffusion coefficient is not specifically sensitive to tumor microstructure and therapy-induced cellular changes. PURPOSE: To investigate time-dependent diffusion imaging with the short-time-limit random walk with barriers model (STL-RWBM) for quantifying microstructure parameters and early cancer cellular response to therapy. STUDY TYPE: Prospective. POPULATION: Twenty-seven patients (median age of 58 years and 7.4% of females) with p16+/p16- oropharyngeal/oral cavity squamous cell carcinomas (OPSCC/OCSCC) underwent MRI scans before therapy, of which 16 patients had second scans at 2 weeks of the 7-weeks chemoradiation therapy (CRT). FIELD STRENGTH/SEQUENCE: 3-T, diffusion sequence with oscillating gradient spine echo (OGSE) and pulse gradient spin echo (PGSE). ASSESSMENT: Diffusion weighted images were acquired using OGSE and PGSE. Effective diffusion times were derived for the STL-RWBM to estimate free diffusion coefficient D0 , volume-to-surface area ratio of cellular membranes V/S, and cell membrane permeability κ. Mean values of these parameters were calculated in tumor volumes. STATISTICAL TESTS: Tumor microstructure parameters were compared with clinical stages of p16+ I-II OPSCC, p16+ III OPSCC, and p16- IV OCSCC by Spearman's rank correlation and with digital pathological analysis of a resected tissue sample. Tumor microstructure parameter responses during CRT in the 16 patients were assessed by paired t-tests. A P-value of <0.05 was considered statistically significant. RESULTS: The derived effective diffusion times affected estimated values of V/S and κ by 40%. The tumor V/S values were significantly correlated with clinical stages (r = 0.47) as an increase from low to high clinical stages. The in vivo estimated cell size agreed with one from pathological analysis of a tissue sample. Early tumor cellular responses showed a significant increase in D0 (14%, P = 0.03) and non-significant increases in κ (56%, P = 0.6) and V/S (10%, P = 0.1). DATA CONCLUSION: Effective diffusion time estimation might impact microstructure parameter estimation. The tumor V/S was correlated with OPSCC/OCSCC clinical stages. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Highly Recurrent IDH1 Mutations in Prostate Cancer With Psammomatous Calcification.

Prostate cancer is a heterogeneous disease with several well-recognized morphologic subtypes and histologic variants-subsets of which are enriched for or associated with specific genomic alterations. Herein, we report a cohort of 4 unique prostate cancers characterized by intratumoral psammomatous calcification-which we have termed prostate cancer with psammomatous calcification (PCWPC). Clinicopathologic review demonstrates that PCWPCs are high-grade (grade group ≥3) tumors that involve the anterior prostate, and integrative targeted next-generation sequencing reveals recurrent hotspot IDH1 mutations. This morphology-molecular correlation is independently confirmed in The Cancer Genome Atlas prostatic adenocarcinoma cohort, with 3 of the 5 IDH1-mutant prostate cancers showing psammomatous calcification (rφ = 0.67; Fisher exact test, P < .0001). Overall, these findings suggest that PCWPC represents a novel subtype of prostate cancer enriched for an anterior location and the presence of hotspot IDH1 mutations. Recognition of these unique morphologic features could help identify IDH1-mutant prostate cancer cases retrospectively and prospectively-facilitating future large research studies and enabling clinical trial enrollment and precision medicine approaches for patients with advanced and/or aggressive disease.

Endometrial, Ovarian, and Peritoneal Involvement by Endometrioid Carcinoma, Yolk Sac Tumor, and Endometriosis: Molecular Evidence for a Shared Precursor.

Recent studies have provided molecular confirmation that a subset of yolk sac tumors is somatically derived. Somatically derived yolk sac tumors are typically diagnosed in older women and are often seen adjacent to epithelial proliferations (such as endometriosis or endometrioid carcinoma) with which they share mutations. Here, we present a case of a postmenopausal woman with a yolk sac tumor and endometriosis in the right ovary, endometriosis with glandular crowding and reactive changes in the left ovary, endometrial endometrioid carcinoma, and yolk sac tumor involving the serosa of the colon. Targeted next-generation sequencing of these five tumor components demonstrated identical mutations in PTEN (p.R130G), PIK3CA (p.G1049S), FGFR2 (p.S252W), and FBXW7 (p.R689Q), suggesting that all components arose from a common precursor. The endometrial endometrioid carcinoma harbored additional exclusive mutations involving PIK3CA (p.H1048R) and CTNNB1 (p.S37F).

Unusual Ovarian Tumors With Endometrioid Proliferations Co-Expressing Estrogen Receptor and CDX-2 Arising in Cystadenofibromatous Background: Report of 3 Cases.

This report describes 3 cases of ovarian tumors with unusual glandular proliferations co-expressing estrogen receptor and CDX-2 by immunohistochemistry set in cystadenofibromatous background. Targeted next-generation sequencing was performed on the cyst lining epithelium and glandular proliferations for all cases; CTNNB1 mutations were detected in the glandular proliferations of all neoplasms. The cyst lining of case 1 demonstrated a different CTNNB1 mutation from the matched glandular proliferation. No mutations were detected in the cyst lining from case 2. The cyst lining and glandular proliferation for case 3 harbored identical ATM and PIK3CA mutations with an additional CTNNB1 mutation in the glandular proliferation. To our knowledge, this is the first reported series of endometrioid proliferations with co-expression of estrogen receptor and CDX-2 in cystadenofibromatous background.

Malignant Neoplasms of the Penis with Radiologic and Pathologic Correlation.

Penile malignancy is the third most common male-specific genitourinary malignancy, with squamous cell carcinoma representing the most common histologic type. Squamous cell carcinoma is an epithelial malignancy, frequently developing from the mucosal surfaces of the foreskin, glans, and coronal sulcus and manifesting as a distal infiltrative or ulcerated mass. This typically occurs in men from the 6th to 8th decades of life, and risk factors include human papillomavirus, phimosis, presence of foreskin and poor hygiene, chronic inflammatory conditions such as lichen sclerosus, trauma, and smoking. Primary urethral malignancies including urothelial carcinoma and adenocarcinoma can occur but may lack this distal predilection. Sarcoma, melanoma, leukemia or lymphoma, and metastatic disease are less common sources of penile malignancy. Because of the sensitive nature of penile malignancies, there may be delays in seeking care and in subsequent diagnosis. Recently, the staging guidelines for penile cancer have been updated concurrently with a shift toward more penile-preserving therapies, which have led to a larger role of imaging in diagnosis, staging, and treatment planning for penile malignancies. A variety of imaging modalities may play a role in the identification and staging of penile malignancy, including an increased use of MRI for local staging of tumors, CT and PET/CT for identification of nodal and distant disease, and US for image-guided biopsy. The authors discuss an imaging approach to a spectrum of penile malignancies, with an emphasis on radiologic and pathologic correlation and how knowledge of normal tissue types and anatomic structures can aid in the diagnosis and staging of these tumors. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

p53 null phenotype is a "positive result" in urothelial carcinoma in situ.

The concept of a "p53 null phenotype" (complete loss of staining) is well-recognized in the gynecologic pathology literature, implicitly reflecting that this staining pattern represents a TP53 mutation. However, in the genitourinary pathology literature, a p53 null phenotype has only been addressed regarding the prognosis of invasive urothelial carcinoma, and not as a diagnostic biomarker for urothelial carcinoma in situ (CIS). Herein, 25 cases of urothelial carcinoma in situ [diagnoses made on hematoxylin and eosin (H&E) stained sections] showing null pattern p53 staining were retrieved from 22 different patients (16 males and 6 females, age range 52-85 years; average 69.6 years), most commonly showing large cell pleomorphic pattern morphology. One representative tissue block per case was selected for next-generation DNA sequencing (NGS). All 21 cases (100%) passing quality control for NGS showed at least 1 TP53 mutation (majority nonsense or frameshift mutations), including 3 cases with 2 mutations and 3 cases with 3 mutations. Three patients with multiple available samples harbored 1 or more shared TP53 mutations at 2 different time points, indicating clonality of the temporally distinct lesions. Additionally, 2 patients had an additional unique TP53 mutation at a later time point, suggesting intratumoral heterogeneity and/or temporal clonal evolution. While urothelial CIS remains an H&E diagnosis in most cases, a p53 immunostain may be useful in a subset of challenging cases. This study demonstrates that a p53 null phenotype represents an aberrant result in urothelial CIS with supportive molecular analysis showing a previously unknown level of complexity for TP53 mutations among these noninvasive lesions. Adequate recognition of the p53 null phenotype as a "biologically supportive result", similar to strong and diffuse staining with p53, is important and may warrant a formal consensus statement for recommended p53 reporting (i.e., "wild type" versus "aberrant or mutant").

Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma.

OBJECTIVES: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis. METHODS: BPRN mice were treated with TAM to induce tumors at defined ages and parity status. RESULTS: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRNfl/+), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01). CONCLUSIONS: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.

Uterine PEComatosis With TSC1 Mutation in a Patient With Tuberous Sclerosis: Case Report and Literature Review.

Uterine PEComatosis is a rare phenomenon characterized by the presence of multiple perivascular epithelioid cell tumors (PEComas) and/or microscopic proliferations of perivascular epithelioid cells. Herein, we report a case of PEComatosis arising in a 49-yr-old woman with a known history of tuberous sclerosis. Targeted next-generation sequencing revealed a TSC1 stopgain mutation (p.Q732X) in all tested nodules, with single-copy TSC1 loss or copy-neutral TSC1 loss of heterozygosity. To our knowledge, this is the second report of TSC1 inactivation in uterine PEComa and the first report of confirmed TSC1 abnormalities in PEComatosis.