Cutaneous metastases of non-cutaneous neuroendocrine neoplasms: A histopathologic review of 15 cases.

BACKGROUND: Cutaneous metastases from non-cutaneous neuroendocrine neoplasms are rare; however, distinction from primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma) guides clinical management. METHODS: We performed a retrospective review from September 1, 2010 to September 30, 2020 of the histopathologic, immunohistochemical, and clinical characteristics of metastatic neuroendocrine neoplasms to the skin from non-cutaneous primaries. RESULTS: Fourteen patients were identified for the study (nine males and five females; mean age of 59.5 years). Fifteen skin specimens from 14 patients were available for review. At the time of skin biopsy, a known non-cutaneous neuroendocrine neoplasm was present in 50% of patients. Primary sites of neuroendocrine carcinoma included lung (n = 5), terminal ileum (n = 2), and one each from prostate, breast, rectum, uterus, esophagus, and sinus, with one unknown (suspected bladder malignancy). Eleven of fourteen patients are dead of disease; one was lost to follow-up. All 15 specimens showed subcutaneous/deep dermal involvement with six involving the papillary dermis and one involving the epidermis. The tumors ranged from well to poorly differentiated. Two of fifteen specimens showed focal CK20 positivity (one metastatic uterine small cell carcinoma and one metastatic ileal carcinoid). TTF-1 was performed in 13 specimens and was positive in six, of which two were of non-pulmonary origin. CONCLUSIONS: While immunohistochemical stains, in particular CK20, CK7, and TTF-1, are integral in the workup of confirming the origin of neuroendocrine tumors found in the skin, results vary and are often non-specific for a single primary site. Therefore, complete radiologic imaging as well as clinical correlation should be recommended to further aid in the identification of a non-cutaneous primary neoplasm.

Molecular analysis of NUT-positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions.

BACKGROUND: Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas. METHODS: Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners. RESULTS: NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. CONCLUSION: While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Epithelioid osteoblastoma with secondary aneurysmal bone cyst and FOS gene rearrangement.

Epithelioid osteoblastoma, sometimes equated with aggressive osteoblastoma, is a variant of osteoblastoma that typically demonstrates more worrisome imaging and pathological features compared to conventional osteoblastoma. These more aggressive features can overlap with those seen in osteosarcoma, creating a diagnostic challenge for radiologists and pathologists. Recent identification of FOS and FOSB gene rearrangements in osteoid osteoma and osteoblastoma has allowed for greater diagnostic confidence following biopsy, but careful radiological-pathological correlation remains a key component for guiding appropriate management. Although the imaging features of conventional osteoblastoma have been previously described, there are limited examples in the literature of the imaging appearance of epithelioid osteoblastoma, and none with secondary aneurysmal bone cyst. In this case report, we detail the clinical, imaging, and histological characteristics of a proximal femoral epithelioid osteoblastoma which was pathologically confirmed by FOS and FOSB genetic testing. The initial imaging impression favored a malignancy, but when the biopsy results were correlated in a multidisciplinary fashion with the imaging, epithelioid osteoblastoma became the leading diagnosis which was subsequently genetically confirmed. This case emphasizes the value of multidisciplinary radiology-pathology correlation in routine practice.

p16 immunostaining in fine-needle aspirations of the head and neck: determining the optimal positivity threshold in HPV-related squamous cell cancer.

INTRODUCTION: There is no consensus for interpretation of p16 immunohistochemistry (IHC) in cytology preparations. Our study aims to assess p16 IHC staining in formalin-fixed cytology cell blocks (CBs) from head and neck squamous cell carcinoma (HNSCC) fine-needle aspiration (FNA) specimens in comparison with surgical pathology p16 staining and to determine the reproducibility of p16 IHC scoring in CBs. METHODS: A total of 40 FNAs from 2014 to 2019 of HNSCC with p16 IHC were obtained. CB p16 staining was scored independently by 5 cytopathologists as interval percentages of tumor cell positivity. Receiver operating characteristic (ROC) curves were examined to determine optimal cutoffs for each pathologist based on sensitivity and specificity values. Gwet's coefficient (AC1) was calculated to assess inter-rater reliability. RESULTS: Greater than 10% was the lowest threshold to reach 100% specificity with high sensitivity (55%-84%) in all 5 raters. Rater performances were similar, with areas under the curve (AUCs) ranging from 0.89 to 0.95. Using the >10% threshold, Gwet's AC1 = 0.72 (95% CI: 0.56-0.89). Diagnostic performance improved further when low-cellularity cases were excluded, with AUC ranging from 0.94 to 0.99 and Gwet's AC1 = 0.79 (95% CI: 0.61-0.98). CONCLUSION: p16 IHC performed on cytology CBs can serve as a surrogate marker for the detection of HPV with high sensitivity and specificity levels. Using a threshold lower than that recommended for surgical pathology for the interpretation of p16 positivity may be appropriate for FNA cytology CB preparations. All cytopathologists in our study displayed reproducible high sensitivity and specificity values at the >10% threshold.

Digital image analysis supports a nuclear-to-cytoplasmic ratio cutoff value below 0.7 for positive for high-grade urothelial carcinoma and suspicious for high-grade urothelial carcinoma in urine cytology specimens.

BACKGROUND: Urinary cytology is sensitive and specific for diagnosing and screening high-grade urothelial carcinomas (HGUC). The Paris System (TPS) for urinary cytology was introduced in 2016 to standardize reporting. According to TPS diagnostic categories of HGUC and suspicious for HGUC (SHGUC), the average nuclear-to-cytoplasm (N:C) ratio of atypical cells should be ≥0.7. The objective of the current study was to measure the N:C ratio of urine cytology specimens with HGUC and SHGUC diagnoses and biopsy-proven HGUC follow-up. METHODS: A cohort of 64 cases (HGUC, 49 cases; SHGUC, 15 cases) from 57 patients was constructed. Urine cytology slides were scanned into whole-slide digital images. The nuclear and cytoplasmic areas were enumerated by digital image analysis (DIA), and the N:C ratios were measured. RESULTS: In total, 640 cells were analyzed by DIA (HGUC, 490 cells; SHGUC, 150 cells). For HGUC and SHGUC, the average N:C ratios were 0.57 and 0.53, respectively. The maximum average N:C ratio was 0.73 for HGUC and 0.68 for SHGUC. HGUC had higher average N:C ratio (P < .001), higher average nuclear area (P < .001), higher average maximum N:C ratio (P = .005), and higher average maximum nuclear area (P = .006) compared with SHGUC. CONCLUSIONS: The N:C ratios for the HGUC (0.57) and SHGUC (0.53) categories are lower than those previously suggested in TPS. The authors advocate reducing the N:C ratio below the current threshold of 0.7.

Improved correlation of urinary cytology specimens using The Paris System in biopsy-proven upper tract urothelial carcinomas.

BACKGROUND: Urine cytology specimens are essential for screening and monitoring high-grade urothelial carcinomas. However, inconsistent reporting and equivocal diagnostic categories have remained a challenge. The Paris System for Reporting Urinary Cytology (TPS) was developed to provide clear cytomorphologic criteria for urine cytology specimens. Significant correlation between the surgical biopsy diagnosis (SD) and TPS diagnosis (PD) has been established in lower urothelial tract carcinomas, but to the authors' knowledge limited information is available regarding upper urinary tract carcinomas. METHODS: A total of 56 cytology specimens from 35 patients within 90 days of an SD of upper urinary tract carcinoma were included. Cytology was re-reviewed and assigned a PD. The original diagnosis (OD) and PD were compared with the corresponding SD to determine which correlated best. RESULTS: The PD corresponded to the SD in 35 of 56 cases (63%), which was greater than that for the OD and SD, which were concordant in 19 of 56 cases (34%). Both the OD and PD were concordant in 18 of 56 cases (32%), and neither corresponded in 20 of 56 cases (36%). A total of 27 of 33 cases of high-grade urothelial carcinoma/carcinoma in situ on SD (82%) were identified using the PD whereas only 15 cases (45%) were identified with the OD. The number of "atypical" diagnoses in the OD was reduced from 16 of 56 cases (29%) to 7 of 56 cases (13%) using the PD. Of the 14 of 56 "negative" OD (25%), only 4 remained after implementation of the PD. A diagnosis of low-grade urothelial neoplasm was established in 6 of 20 cases (30%) with the PD compared with 3 of 20 cases with the OD (15%). CONCLUSIONS: The authors found that reclassification with TPS improved correlation with the SD compared with previous methodologies. Specifically, TPS increased the number of high-grade urothelial carcinoma diagnoses and decreased the number of equivocal or "atypical" diagnoses. Cancer Cytopathol 2018. © 2018 American Cancer Society.