Melanocyte colonization and pigmentation of breast carcinoma: A case report.

Pigmented mammary Paget disease is a rare variant of mammary Paget disease that is often clinically misdiagnosed as a melanocytic lesion of the skin or nipple-areolar complex. Careful morphological assessment, along with the performance of adequate immunohistochemical stains, will help in achieving the right diagnosis and avoiding misdiagnosis of the entity as malignant melanoma. We report a rare case of pigmented mammary Paget disease with concomitant colonization of the underlying invasive ductal carcinoma by melanocytes mimicking melanoma.

NONO::TFE3 fusion cutaneous epithelioid and spindle cell tumor: A case series.

The NONO::TFE3 fusion has been described in MiT family translocation renal cell carcinomas as well as extracutaneous perivascular epithelioid cell tumors (PEComas). PEComas are known to express myogenic and melanocytic markers but SOX10 and p63 positivity has never been reported. We report two primary cutaneous tumors that morphologically and molecularly fit PEComas, both harboring the NONO::TFE3 fusion, but with an unusual immunophenotype of SOX10 and p63 positivity. One case was on an 80-year-old male's finger, and the other one was on a 72-year-old female's thigh. Both were well-circumscribed multinodular dermal tumors composed of nests of monotonous epithelioid to spindled cells with pale to vacuolated cytoplasm, some of which were arranged around blood vessels. Both tumors were positive for SOX10, S100, and p63, focally positive for Melan-A, and negative for myogenic markers. There are very little data regarding the molecular findings of primary cutaneous PEComas. While the NONO::TFE3 fusion has been identified in extracutaneous PEComas, it has never been reported in primary cutaneous cases. We believe these cases represent a previously undescribed subtype of cutaneous tumor which shows some immunophenotypic expression of melanocytic markers and we named these cases NONO::TFE3 fusion cutaneous epithelioid and spindle cell tumor. Further, we raise the question of whether this tumor should fall under the rubric of PEComa because of its morphology, partial expression of melanocytic markers, and the presence of the NONO::TFE3 fusion, or whether these tumors represent a separate novel class of tumors since the immunophenotypic expression of SOX10 and p63 is unusual for PEComas.

Sarcoidal Granuloma Annulare-Like Dermatitis and Vasculitis With Granulomatous Features: An Atypical Case of Giant Cell Arteritis.

ABSTRACT: Giant cell arteritis (GCA) is a diagnosis that clinicians should not miss because of the accompanying risk of irreversible vision loss. GCA can present without the classic symptoms of headache and temporal artery tenderness, which may lead to a delay in diagnosis. Cutaneous findings, although rare, have been associated with GCA. Accordingly, it is imperative to be aware of the broad clinical and histological presentations of GCA, including the cutaneous findings, because they may prove to be harbingers of impending disease. We present a unique case of GCA where 2 distinct cutaneous morphologies, sarcoidal granuloma annulare-like dermatitis and leukocytoclastic vasculitis with granulomatous features, presented simultaneously before the classic symptoms of headache and unilateral vision loss.

The role of PRAME and NY-ESO-1 as potential therapeutic and prognostic biomarkers in triple-negative breast carcinomas.

PRAME and NY-ESO-1 are cancer-testis antigens (CTAs) reported to be highly enriched in triple-negative breast cancers (TNBCs), against which vaccines and immunotherapies are currently being developed. This study aims to analyze PRAME and NY-ESO-1 expression in TNBCs and their correlation with clinical outcomes. This is a retrospective cohort study of TNBC patients who have undergone neoadjuvant chemotherapy. PRAME and NY-ESO-1 expression were assessed on pre-therapy biopsies as H-scores (percentage x intensity) with final H scores of 2-3 considered as positive. Association between expression and pathologic complete response (pCR), metastasis, and residual cancer burden (RCB) were assessed via logistic regression. Cox proportional hazards models were used to assess the association with progression-free survival. P-values < 0.05 were considered statistically significant. Sixty-three percent of 76 patients were positive for PRAME. In contrast, only 5 % were positive for NY-ESO-1. PRAME positivity was significantly associated with a lower likelihood of early metastatic disease (OR = 0.24, 95 % CI 0.08-0.62; P = 0.005). However, it was not significantly associated with pCR, RCB category, or progression-free survival. NY-ESO1 score was not significantly associated with early metastatic disease, pCR, RCB category, or progression-free survival. Our results suggest that PRAME positivity may be associated with a lower risk of early metastasis in TNBCs, but not with response to neoadjuvant chemotherapy or progression-free survival. The high expression of PRAME in TNBCs makes it a potential therapeutic target, while NY-ESO1 appears to be a less useful marker. However, further larger studies are needed to ascertain the utility of these markers.

Positive predictive value of ERBB2 copy number gain by tissue or circulating tumor DNA next-generation sequencing across advanced cancers.

BACKGROUND: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood. MATERIALS AND METHODS: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing. RESULTS: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast (n = 67), non-small cell lung (n = 25), colorectal (n = 18), gastroesophageal (n = 17), pancreatic (n = 11), and uterine (n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS (n = 57) and 80% for ctDNA (n = 47). The PPV among breast cancer patients for tissue NGS was 97% (n = 35) and ctDNA was 93% (n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% (n = 22) and by ctDNA to 44% (n = 7). CONCLUSIONS: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer.

Pathologic evaluation of specimens after neoadjuvant chemotherapy in breast cancer: Current recommendations and challenges.

Neoadjuvant chemotherapy is increasingly used to optimize breast conservation surgery and is becoming a standard of care in a subset of breast cancer patients. An accurate pathologic assessment is crucial in guiding clinical decisions and subsequent management and prognosis. This review aims to summarize the most current literature, recommendations, and challenges in the pathologic evaluation of breast cancer after neoadjuvant chemotherapy. Included are the most current definitions of the different types of tumor response, the underlying factors that can affect tumor response, how to assess lymph nodes, margins, and tumor markers post-neoadjuvant chemotherapy, as well as the different classification systems a pathologist can use to assess residual disease. In this era of de-escalation of surgical treatment, studies on imaging techniques to assess residual disease and avoid surgery after neoadjuvant chemotherapy have also been done. However, at least for now, surgical treatment remains the preferred practice. As such, pathologists play an increasingly critical role in standardizing assessment of residual disease post-neoadjuvant chemotherapy, and in optimizing the knowledge gained by this approach to breast cancer therapy.

Primary Biphasic Hepatic Sarcoma in DICER1 Syndrome.

DICER1 tumor predisposition syndrome is a rare genetic disorder that predisposes individuals to multiple benign and malignant neoplasms. The phenotype is vast and includes pleuropulmonary blastoma (PPB), thyroid nodules, cystic nephroma, Wilms tumor, ovarian Sertoli-Leydig cell tumor, and medulloepithelioma, among others. Herein, we describe a patient with a DICER1 germline pathogenic variant presenting with two neoplasms that are not commonly encountered in the context of DICER1 syndrome. The first tumor is a multiloculated cystic hepatic lesion with a biphasic pattern, composed of cysts lined by bland biliary type (CK19-positive) epithelium surrounded by a condensation of sarcomatous spindled cell proliferation in a myxoid stroma. This neoplasm resembled PPB or cystic nephroma with malignant transformation. The second tumor is a chest nodule consistent with low-grade hidradenocarcinoma. Although it is difficult to speculate with just a single case, these unusual neoplasms occurring in particular at a young age raises the possibility that they can be inherent to, and thus, be part of the DICER1 tumor predisposition syndrome phenotype.

Vulvar Elastosis: A Novel Diagnostic Entity.

ABSTRACT: In vulvar biopsies, we have observed histopathologic abnormalities of elastic fibers identical to solar elastosis, with thick, curled, and irregular pale grey fibers in the dermis. In severe cases, changes resemble nodular solar elastosis. We retrospectively evaluated 238 vulvar biopsies with the goal of defining and characterizing changes of vulvar elastosis. Of 238 vulvar biopsies reviewed, 107 (45%) exhibited vulvar elastosis. Patients with vulvar elastosis were older (mean = 65 years old) compared to those without (mean = 44 years old). Sixty-six (62%) were graded as mild, 27 (25%) moderate, and 14 (13%) severe. Vulvar elastosis was significantly more common in women ≥45 years old (P-value < 0.001). There was moderate correlation between age and severity (correlation coefficient = 0.55, P-value < 0.001). Vulvar elastosis was observed in a variety of inflammatory and non-inflammatory pathologies. In 5 cases, the sole pathology was vulvar elastosis presenting clinically as either a pruritic or painful white to white-yellow papule or plaque, or vulvar pain or burning without a clinical lesion. Vulvar elastosis is a novel diagnostic entity occurring in a sun-protected site and its pathogenesis may be a degenerative phenomenon possibly related to advancing age and/or hormonal changes.

The diagnostic utility of PRAME and p16 in distinguishing nodal nevi from nodal metastatic melanoma.

The status of the sentinel lymph node is the strongest predictor of recurrence in patients with malignant melanoma, making accurate distinction between nodal metastases and nodal nevi of paramount importance. We explored the utility of p16 and PRAME in differentiating nodal nevi from metastatic melanoma by immunohistochemistry. We searched our institutional database for cases of nodal nevi and nodal metastatic melanoma. p16 and PRAME expression were assessed with immunolabeling quantified by extent of nuclear positivity (0-25 %, >25 %-50 %, >50 %-75 % and >75 %). Sensitivities and specificities were calculated, and discrimination assessed using the area under the receiver operating characteristic curve (AUC). Forty-nine cases out of 51 nevi and 56/56 melanoma cases had lesional tissue present for p16, while 44/51 nevi and 54/56 melanoma cases had lesional tissue present for PRAME. 43 nodal nevi (88 %) had >50 % nuclear staining for p16, while none had >50 % staining for PRAME. More than half (55 %) of melanoma cases had complete loss of nuclear staining for p16, while majority (94 %) had >50 % nuclear staining for PRAME. Using a cut-off value of 50 %, higher PRAME expression had a sensitivity and specificity of 94 % and 100 %, respectively, while lower p16 expression had a sensitivity and specificity of 66 % and 88 %, respectively, for detecting metastatic melanoma. PRAME showed significantly better discrimination (AUC = 0.97, 95 % CI 0.94-1.00) than p16 (AUC = 0.77, 95 % CI 0.68-0.86) for differentiating nodal nevi from nodal melanoma (P < 0.001). Our findings suggest that PRAME is more accurate than p16 in discriminating between the two entities, with excellent sensitivity and specificity.

Ovarian Carcinosarcoma and Concurrent Serous Tubal Intraepithelial Carcinoma With Next-Generation Sequencing Suggesting an Origin From the Fallopian Tube.

Background. Ovarian carcinosarcomas are rare aggressive biphasic tumors. Evidence suggests that these tumors are monoclonal and that the sarcoma component is derived from a stem cell undergoing divergent differentiation. Currently, there remains a paucity of data regarding its origin, with few reports suggesting an association with serous tubal intraepithelial carcinoma (STIC) by immunohistochemistry and genetics. Objective. We sought to determine the relationship of carcinosarcoma to high-grade serous carcinoma and STIC by investigating for similar mutation signatures through next-generation sequencing. Methodology. A case of carcinosarcoma with associated high-grade serous carcinoma and STIC was macrodissected, and next-generation sequencing was performed on each component separately. Results. The STIC, high-grade serous carcinoma component, and chondrosarcoma component were all diffusely positive for p53 and p16 by immunohistochemistry. Next-generation sequencing demonstrated an identical TP53 gene c.376-1G>A 5' splice site pathogenic mutation in all 3 components. Conclusions. Our findings suggest that carcinosarcomas may also originate from the fallopian tube.

Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis.

BACKGROUND: Acantholysis can be seen in multiple skin diseases. Adnexal acantholysis has been regarded as a feature distinguishing pemphigus vulgaris (PV) from acantholytic conditions. METHODS: A retrospective review of the histopathologic features of diseases with acantholysis including PV, pemphigus foliaceus (PF), Hailey-Hailey disease (HHD), Darier disease (DD), Grover disease, and pityriasis rubra pilaris (PRP) was performed. RESULTS: Biopsies of PV (n = 49), HHD (n = 27), DD (n = 25), Grover disease (n = 65), and PRP (n = 33) showed suprabasilar acantholysis. Acantholysis was limited to the lower epidermis in PV and PRP, and involved all epidermal layers in HHD, DD, and Grover disease. Acantholysis in PF (n = 38) mainly involved the upper epidermis. Follicular acantholysis occurred more frequently in PV and PF (P < 0.0001). Eccrine acantholysis was found in PV (42%), HHD (18%), PF (13%), and DD (4%). Grover disease, DD, and HHD had greater dyskeratosis (P < 0.0001). Neutrophils were more common in PV, PF, and HHD, while eosinophils were more common in Grover disease and DD. A pattern termed acantholytic hypergranulosis occurred predominantly in PF. CONCLUSION: Adnexal acantholysis does not reliably distinguish PV from PF. The level of acantholysis, degree of dyskeratosis, and acantholytic hypergranulosis are distinguishing features between the two types of pemphigus and other acantholytic disorders.