Tumour necrosis is a valuable histopathological prognostic parameter in melanomas of the vulva and vagina.

Vulvar and vaginal melanomas (VVMs) are rare and aggressive malignancies with limited prognostic models available and there is no standard reporting protocol. VVMs were selected from six tertiary Canadian hospitals from 2000-2021, resected from patients aged ≥18 years, with 6 months or longer follow-up data, and confirmation of melanocytic differentiation by at least two immunohistochemical markers. Cases were reviewed by pathologists to identify histological biomarkers. Survival outcomes were tested with Kaplan-Meier log-rank, univariate Cox, and multivariate Cox regression. There were 79 VVMs with median follow-up at 26 months. Univariate analysis revealed that tumour necrosis, tumour ulceration, positive lymph nodes, and metastasis at diagnosis were significantly associated with disease-specific mortality, progression, and metastasis. Multivariate analysis identified tumour necrosis as an independent prognostic factor for disease-specific mortality (HR 4.803, 95% CI 1.954-11.803, p<0.001), progression (HR 2.676, 95% CI 1.403-5.102, p=0.003), and time-to-metastasis for non-metastatic patients at diagnosis (HR 3.761, 95%CI 1.678-8.431, p=0.001). Kaplan-Meier survival analyses demonstrated that tumour necrosis was a poor prognostic factor for disease-specific, progression-free, and metastasis-free survival (p<0.001 for all comparisons). Vaginal melanomas displayed decreased survival compared to vulvar or clitoral melanomas. This study identifies tumour necrosis as an independent prognostic factor for VVMs. Vaginal melanomas specifically showed worse survival outcomes compared to vulvar or clitoral melanomas, consistent with previously reported findings in the literature, emphasising the importance of differentiating between these primary tumour epicentres for prognostication and treatment planning in the care of genital melanoma patients.

Using Artificial Intelligence as a Melanoma Screening Tool in Self-Referred Patients.

INTRODUCTION: Early detection of melanoma requires timely access to medical care. In this study, we examined the feasibility of using artificial intelligence (AI) to flag possible melanomas in self-referred patients concerned that a skin lesion might be cancerous. METHODS: Patients were recruited for the study through advertisements in 2 hospitals in Halifax, Nova Scotia, Canada. Lesions of concern were initially examined by a trained medical student and if the study criteria were met, the lesions were then scanned using the FotoFinder System®. The images were analyzed using their proprietary computer software. Macroscopic and dermoscopic images were evaluated by 3 experienced dermatologists and a senior dermatology resident, all blinded to the AI results. Suspicious lesions identified by the AI or any of the 3 dermatologists were then excised. RESULTS: Seventeen confirmed malignancies were found, including 10 melanomas. Six melanomas were not flagged by the AI. These lesions showed ambiguous atypical melanocytic proliferations, and all were diagnostically challenging to the dermatologists and to the dermatopathologists. Eight malignancies were seen in patients with a family history of melanoma. The AI's ability to diagnose malignancy is not inferior to the dermatologists examining dermoscopic images. CONCLUSION: AI, used in this study, may serve as a practical skin cancer screening aid. While it does have technical and diagnostic limitations, its inclusion in a melanoma screening program, directed at those with a concern about a particular lesion would be valuable in providing timely access to the diagnosis of skin cancer.

Merkel cell carcinoma: an update.

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine carcinoma associated with an adverse prognosis. In recent years, our understanding of MCC biology has markedly progressed. Since the discovery of the Merkel cell polyomavirus, it has become clear that MCC represents an ontogenetically dichotomous group of neoplasms with overlapping histopathology. Specifically, most MCCs arise secondary to viral oncogenesis, while a smaller subset is the direct result of UV-associated mutations. The distinction of these groups bears relevance in their immunohistochemical and molecular characterization, as well as in disease prognosis. Further recent developments relate to the landmark utilization of immunotherapeutics in MCC, providing optimistic options for the management of this aggressive disease. In this review, we discuss both fundamental and emerging concepts in MCC, with a particular focus on topics of practical relevance to the surgical or dermatopathologist.

RB1-deficient squamous cell carcinoma: the proposed source of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine (NE) carcinoma arising from integration of Merkel cell polyomavirus (MCPyV) DNA into a host cell or from ultraviolet light-induced genetic damage (proportions vary geographically). Tumors in the latter group include those with "pure" NE phenotype and those "combined" with other elements, most often squamous cell carcinoma (SCC). We performed comprehensive genomic profiling (CGP) of MCPyV+ and MCPyV- (pure and combined) tumors, to better understand their mutational profiles and shed light on their pathogenesis. Supplemental immunohistochemistry for Rb expression was also undertaken. After eliminating low quality samples, 37 tumors were successfully analyzed (14 MCPyV+, 8 pure MCPyV- and 15 combined MCPyV-). The SCC and NE components were sequenced separately in 5 combined tumors. Tumor mutational burden was lower in MCPyV+ tumors (mean 1.66 vs. 29.9/Mb, P < 0.0001). MCPyV- tumors featured frequent mutations in TP53 (95.6%), RB1 (87%), and NOTCH family genes (95.6%). No recurrently mutated genes were identified in MCPyV+ tumors. Mutational overlap in the NE and SCC components of combined tumors was substantial ('similarity index' >24% in 4/5 cases). Loss of Rb expression correlated with RB1 mutational (P < 0.0001) and MCPyV- status (P < 0.0001) in MCCs and it was observed more frequently in the SCC component of combined MCC than in a control group of conventional cutaneous SCC (P = 0.0002). Our results (i) support existing evidence that MCPyV+ and MCPyV- MCCs are pathogenetically distinct entities (ii) concur with earlier studies linking the NE and SCC components of combined MCCs via shared genetic profiles and (iii) lend credence to the proposal that an Rb-deficient subset of SCC's is the source of phenotypically divergent combined MCCs.

Morphological patterns of metastases from combined Merkel cell carcinomas: study of an eastern Canadian cohort of cases.

Combined Merkel cell carcinomas are hybrid tumors composed of neuroendocrine and other phenotypic (usually squamous) elements. They form a minority of Merkel cell carcinomas (MCCs) as a whole, are usually Merkel cell polyomavirus-negative, and have rarely been segregated for specific study. Sporadic reports have indicated that metastases from these tumors can show a combined phenotype. We retrospectively studied 38 cases (24 men [63%], 14 women [37%], mean age 78 years [range, 46-99 years]) of combined MCC. Metastases occurred in 20 patients (53%) (at presentation and/or in follow-up [mean 38 months (range, 0.6-185 months)]). Those from 17 individuals (45%) were examined microscopically. These were mainly nodal in distribution. In 12 patients (71%), the secondary deposits were of pure neuroendocrine type, whereas in 5 (29%), combined deposits were identified. Squamous elements were the most common divergent component, in the primary and secondary tumors. The combined metastases varied from obvious squamous nests in a neuroendocrine background to scattered bizarre tumor giant cells expressing CK5/6 on immunohistochemistry. In one case, individual nodes within a single basin displayed purely squamous or purely neuroendocrine deposits. The mean overall survival in the cohort was 48 months (range, 30-67 months) and the mortality was 82%. Our work sheds light on the frequency and patterns of metastases in combined MCCs. In concert with the poor outcome data documented by others, it also raises a question as to the potential prognostic significance of a combined phenotype per se, independent of a virus-negative status and other variables. This issue deserves further study.

PAXgene Fixation for Pancreatic Cancer: Implications for Molecular and Surgical Pathology.

Genomic profiling of pancreatic cancer using small core biopsies has taken an increasingly prominent role in precision medicine. However, if not appropriately preserved, nucleic acids (NA) from pancreatic tissues are known to be susceptible to degradation due to high intrinsic levels of nucleases. PAXgene fixation (PreAnalytix, Switzerland) represents a novel formalin-free tissue preservation method. We sought to compare the NA and histomorphological preservation of pancreatic cancer tissues preserved with PAXgene-fixed paraffin-embedding (PFPE) and formalin-fixed paraffin-embedding (FFPE). Tissues from 19 patients were obtained prospectively from pancreaticoduodenectomy specimens and evaluated by four gastrointestinal pathologists. The extracted NA were quantified by Nanodrop and Qubit and assessed for quality by qPCR, targeted next-generation sequencing (NGS) assay, and RNA-sequencing. Our results demonstrated that, when assessed blindly for morphological quality, the four pathologists deemed the PFPE slides adequate for diagnostic purposes. PFPE tissues enable greater yields of less fragmented and more amplifiable DNA. PFPE tissues demonstrated significantly improved quality control (QC) metrics in a targeted NGS assay including Median Absolute Pair-wise Difference (MAPD) scores. Our results support the use of PAXgene fixative for the processing of specimens from pancreatic cancers with the potential benefits of improved yields for more amplifiable DNA in low-yield biopsy specimens and its ideal use for amplicon-based NGS assays.

Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus-mediated (MCPyV+) and/or ultraviolet radiation-associated (MCPyV-) pathways. Advanced clinical stage and an MCPyV- status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV- status. p63 is a member of the p53 family of proteins among which complex interactions occur. It has two main isoforms (proapoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+ and 14 MCPyV-) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semiquantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed "wild-type" expression in 69%, with "aberrant" staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases) and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV- subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53 and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (ie, proapoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.

Independent primary cutaneous and mammary apocrine carcinomas with neuroendocrine differentiation: Report of a case and literature review.

Cutaneous apocrine carcinomas share common features with their counterparts in the breast; hence, metastatic mammary carcinoma must be excluded before such lesions can be designated primary cutaneous neoplasms. Primary tumors from either source rarely exhibit neuroendocrine differentiation. We report a case of a 72-year-old female with a painless 1.2-cm scalp nodule. An incisional biopsy revealed dermal involvement by an invasive apocrine carcinoma juxtaposed to a benign apocrine cystic lesion. Immunohistochemically, the carcinoma expressed neuroendocrine proteins including synaptophysin, chromogranin, and CD56. A primary cutaneous apocrine carcinoma with neuroendocrine differentiation was favored, but additional investigations to exclude breast origin were recommended. These revealed a 1.1-cm nodule in the right breast, which proved to be an invasive ductal carcinoma, morphologically and immunophenotypically similar to the scalp lesion. This confounded the case, yet factors militating against metastatic breast carcinoma to skin included (a) the small size of the mammary tumor, (b) absence of other metastatic disease, and (c) juxtaposition of the scalp carcinoma to a putative benign precursor. Molecular studies were undertaken to resolve the diagnostic quandary. Single nucleotide polymorphism microarray analysis revealed distinct patterns of chromosomal copy number alterations in the two tumors, supporting the concept of synchronous and unusual primary neoplasms.

Metastasis of cutaneous squamous cell carcinoma to the stomach: a rare entity.

Metastatic spread of cutaneous squamous cell carcinoma (cSCC) to the gastrointestinal tract is a rare entity. A 63-year-old woman with a history of poorly controlled HIV and a recurrent cSCC on the right temple presented with functional decline, ascites and shortness of breath. A CT scan showed widespread metastatic malignancy involving lung, pleura, heart, stomach, liver, retroperitoneum and soft-tissue. In the case presented here, an upper endoscopy revealed a submucosal lesion in the stomach. Biopsies described the lesion as a poorly differentiated SCC. Comprehensive genomic profiling yielded striking molecular similarities between the gastric tumour and the patient's prior cSCC. It confirmed the origin of the disease and excluded spread from an occult primary. This case adds to the limited literature on gastrointestinal metastases of cSCC and serves as a reminder that non-AIDS-defining cancers are on the rise in the HIV-population.

Comparing Pathology Report Quality Indicators in 2 Distinct Whipple Resection Specimen Protocols.

OBJECTIVES: Pancreaticoduodenectomy specimens are complex, with varying gross examination techniques. In 2012, our institution began using axial sectioning. We sought to determine if this resulted in more complete pathology reporting. METHODS: Quality indicators were analyzed for pathology reports from 2 cohorts: 2001 to 2009 grossed traditionally and 2012 to 2017 using an axial technique (n = 81 and 51). Continuous and categorical data were compared using 2-tailed t test and Fisher exact test, respectively. RESULTS: The later cohort exhibited increased reporting of stage, lymphovascular invasion, margins/surfaces, mean number of lymph nodes, and mean number of slides (P < 0.01). No differences were seen in reporting of size, grade, or perineural invasion. In the later cohort, superior mesenteric vein/portal vein surface was positive in 17 cases (33%), showing strong correlation with superior mesenteric artery/uncinate margin involvement (13/17 cases; P = 0.0001). There was a higher rate of lymph node positivity (86% vs 65%, P < 0.01) in the later cohort. CONCLUSIONS: There is a trend toward higher-quality pathology reports in 2012 to 2017. A possible drawback of the axial approach is increased histopathology slides. Potential additional contributors include College of American Pathologists protocols, increasing subspecialty practice, and updates to the American Joint Committee on Cancer staging criteria.

Isolated Tumor Cells in Sentinel Lymph Nodes of Primary Invasive Breast Carcinoma: A Cohort Analysis.

BACKGROUND: The practice of performing routine cytokeratin immunohistochemistry (CK-IHC) on sentinel lymph nodes in early stage invasive breast cancer leads to frequent identification of isolated tumor cells (ITCs), the clinical significance of which remains unclear. After emergence of guidelines that suggested limited clinical utility of ITC detection, routine CK-IHC (rCK-IHC) staining was discontinued at our institution. We studied the rate and clinical utility of ITC detection before and after the discontinuation of rCK-IHC. PATIENTS AND METHODS: We retrospectively reviewed 2 cohorts of 250 consecutive early stage invasive breast cancer (IBC) patients with sentinel lymph node biopsies (SLNBs) in 2010 to 2011 (rCK-IHC) and 2015 to 2016 (selective CK-IHC [sCK-IHC]). Variables abstracted included: tumor histology, tumor size, grade, lymphatic-vascular invasion, hormone receptor expression, HER2 status, and nodal status including ITCs. All cases from the 2015 to 2016 cohort for which sCK-IHC was performed underwent pathology review. A clinical review of treatment decision effect and cost analysis was undertaken. Data were analyzed using descriptive statistics and Fisher exact test. RESULTS: In the rCK-IHC cohort, all 250 cases underwent CK-IHC staining versus 57 cases in the sCK-IHC cohort. There were 23 ITC cases observed in the rCK-IHC cohort compared with 11 in the sCK-IHC cohort (P = .049). Excluding lobular carcinomas, 19 ITC cases were observed with rCK-IHC versus 7 with sCK-IHC (P = .02). ITC detection did not affect adjuvant treatment decision-making and resulted in savings of at least Can$8000. CONCLUSION: Selective rather than routine use of CK-IHC staining for SLNB evaluation in early-stage IBC results in decreased ITC detection without affecting treatment decisions and leads to cost savings.

Bowen disease with invasive mucin-secreting sweat gland differentiation: Report of a case and review of the literature.

Bowen disease (BD) with divergent adnexal differentiation is a rare composite cutaneous tumor featuring different phenotypic elements. Sebaceous, poroid and trichilemmal invasive components have been described in this setting and very infrequent reports of mucinous glandular differentiation are extant. Clinically, these tumors are not sufficiently distinctive to enable recognition without histopathological evaluation. From a microscopic perspective, care must be taken to exclude a collision tumor as well as other combined cutaneous neoplasms featuring squamous and glandular differentiation. Direct continuity between the two epithelial phenotypes helps to establish the correct diagnosis and generates interesting speculation about the pathogenesis of these and other epithelial skin tumors. We describe a case of BD in continuity with an invasive adenocarcinoma exhibiting mucinous sweat gland differentiation on the face of an elderly man. Details of the case are outlined with the objective of adding to a scant literature on this topic.

Signet Ring Stromal Cell Tumor: A Legitimate (Benign) Mimic of Krukenberg Tumor.

Signet ring stromal cell tumor is a rare, benign ovarian neoplasm thought to arise from ovarian stromal cells. The pathophysiology of these tumors is poorly understood. They present in women in a wide age range, often with nonspecific symptoms including lower abdominal or pelvic pain. Their morphologic appearance raises a critical differential diagnosis of Krukenberg tumor, an aggressive malignancy with significant implications for patient management. For this reason, it is important for the pathologist to be aware of signet ring stromal cell tumor and its differentiating features, including useful histochemical and immunohistochemical ancillary tests. These tumors are curable with surgical excision, and there have been no recurrences or metastases among reported cases.

Paratesticular fibrous pseudotumour: Intraoperative frozen section analysis can help prevent unnecessary orchiectomy.

Paratesticular fibrous pseudotumours are rare intrascrotal lesions, most frequently affecting the testicular tunics. They are benign in nature; however, their pathogenesis is not completely understood. Presenting features are similar to testicular malignancy, which may result in unnecessary radical surgery. It has been suggested that additional diagnostic imaging combined with frozen section analysis may help prevent orchiectomy in these patients. We describe a case of paratesticular fibrous pseudotumour in a 40-year-old male treated with testicle-sparing surgery aided by intraoperative frozen section analysis.

Acute renal infarct without apparent cause: A case report and review of the literature.

Acute renal infarction is a rare clinical entity most commonly occurring as a result of a thromboembolic event in patients with predisposing risk factors. Its non-specific presentation can lead to delayed or missed diagnosis. However, modern imaging technology has allowed for the diagnosis of renal infarction to be made earlier in its clinical course. Due to its rare nature, treatment guidelines do not exist. We report a case of acute renal infarction identified on computed tomography scan in a patient with no known predisposing factors to thromboembolism that was treated through suction thrombectomy.