Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 ...associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis.
Most malignant peripheral nerve sheath tumors (MPNSTs) exhibit combined inactivation of NF1, CDKN2A, and polycomb repressive complex 2 component genes (Embryonic Ectoderm Development EED and ...Suppressor of Zeste 12 SUZ12). Mutations in EED and SUZ12 induce loss of trimethylation at lysine 27 of histone 3 (H3K27me3), with subsequent aberrant transcriptional activation of polycomb repressive complex 2-repressed homeobox master regulators. These findings prompted us to investigate the performance of an anti-H3K27me3 monoclonal antibody clone C36B11 as an immunohistochemical marker for MPNSTs. We assessed the C36B11 reactivity pattern in a pathologically and genetically well-characterized cohort of 68 MPNSTs, spanning various clinical presentations, such as type 1 neurofibromatosis (NF1), radiotherapy, and sporadic MPNSTs. We found that 69% (n=47) of all MPNSTs demonstrated loss of H3K27me3 expression, with 42 (61%) showing complete loss and 5 (7%) showing partial loss, whereas 31% (n=21) retained H3K27me3 expression. Among the NF1-related high-grade MPNSTs, 60% demonstrated loss of expression. In contrast, the majority of both sporadic (95%) and radiotherapy-related (91%) MPNSTs showed loss of H3K27me3 expression. Two of the 3 low-grade MPNSTs and all neurofibromas showed retained expression. Furthermore, all 5 epithelioid MPNSTs retained H3K27me3 labeling. The specificity of H3K27me3 loss as a marker for MPNSTs was studied by testing a large spectrum of lesions included in MPNST differential diagnosis, such as spindle/desmoplastic melanomas, synovial sarcomas, myoepithelial tumors, and other mesenchymal neoplasms, all of which retained expression of H3K27me3. We conclude that immunohistochemical analysis of H3K27me3 has good sensitivity and robust specificity for the diagnosis of MPNST, particularly outside of NF1 clinical history, which represents the most challenging diagnostic setting.
Merkel cell carcinoma (MCC) is a rare neoplasm that arises in the skin of elderly patients on sun‐exposed areas such as the head, neck, and extremities. Involvement of the epidermis by tumor cells is ...a relatively uncommon phenomenon. However, a few cases have been reported of Merkel cell carcinoma in situ (MCCIS) in which tumor cells are confined exclusively to the epidermis without dermal involvement. Herein, we present a peculiar MCCIS lesion in a 66‐year‐old man composed of tumor cells in a nested and lentiginous growth pattern, exhibiting variable quantities of intracytoplasmic dusty brown pigment consistent with melanin, thus closely mimicking melanoma in situ. In addition, the lesion was associated with invasive squamous cell carcinoma, which has not been previously reported in the literature. An extensive search of the PubMed‐indexed, English‐language literature yielded only 17 case reports of MCCIS without documented invasion in which clinical data were available. Out of the cases with available clinical information, individuals with strict MCCIS (n = 13) showed no evidence of recurrence or metastases. The median follow‐up time in the cases with available data (n = 9) was 12 months (mean 12.8 months, range 6–21). Thus, MCCIS without invasion may have a favorable clinical course in contrast to invasive MCC tumors.
Clear cell hidradenoma (CCH) is an uncommon adnexal tumor usually arising from eccrine glands and commonly seen on the face and the upper extremities. CCH occurring in the breast is extremely rare. ...Herein we report a case of MAML2-rearranged CCH of breast with a papillary architecture closely mimicking intraductal papilloma, adenomyoepithelioma and low-grade mucoepidermoid carcinoma, thus representing a source of diagnostic confusion. An overview of salient histologic features and immunophenotypes to distinguish CCH and low-grade mucoepidermoid carcinoma is also integrated into the report.
Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted ...therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported.
We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis.
Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC−/ISH+ and 17 IHC+/ISH−, representing 1.6% and 11.9% of IHC− and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC−/ISH+ and IHC+/ISH− discordances were seen in all antibody clones and ISH methods used. The IHC+/ISH− discordance was significantly higher than IHC−/ISH+ (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC−/ISH+ and IHC+/ISH− were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy.
Accurate detection of human epidermal growth factor 2 (HER2) is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status. We found that IHC−/ISH+ and IHC+/ISH− discordance constituted 2.7% of 1125 cases and 3.2% of those with an unequivocal HER2 IHC status, representing 1.6% and 11.9% of IHC− and IHC+ cases, respectively. Review of the literature revealed a significantly higher IHC+/ISH− discordance than IHC−/ISH+.
Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of ...high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.
GLI1 fusions involving ACTB, MALAT1, and PTCH1 genes have been recently reported in a subset of malignant soft tissue tumors with characteristic monomorphic nested epithelioid morphology and frequent ...S100 positivity. However, we encountered a group of morphologically similar soft tissue tumors lacking the canonical GLI1 gene fusions and sought to investigate their genetic abnormalities. A combined approach including RNA sequencing, targeted exome sequencing and FISH methodologies were used to identify potential novel genetic abnormalities. Ten patients (five females, five males) with an age range of 4-65 years (median 32.5) were identified. Tumors were located in the soft tissues of the limbs, trunk and head and neck, with one each in the tongue and lung. Histologically, tumors revealed ovoid to epithelioid cells arranged in a distinctive nested-trabecular pattern, separated by thin septa and a delicate vascular network. Two cases showed areas of increased nuclear pleomorphism and focal fascicular spindle cell growth. Four tumors showed a high mitotic count (≥15/10 HPFs), with necrosis seen in three of them. Lymphovascular invasion was noted in two cases. No consistent immunoprofile was detected, with positivity for CD56 (six cases), S100 (four cases), SMA (two cases), and pan-CK (one case). FISH showed GLI1 (12q13.3) gene amplification in all 10 cases, with co-amplification of CDK4 (12q14.1) in nine (90%) and MDM2 (12q15) in eight (80%) cases. Targeted exome sequencing performed in three cases confirmed the GLI1, CDK4, and MDM2 co-amplification. Only one case showed the presence of both GLI1 break-apart and amplification, although no gene partner was detected. Our findings suggest that GLI1 amplification, often associated with co-amplifications of CDK4 and MDM2 genes, may represent an alternative genetic mechanism of GLI1 oncogenic activation akin to GLI1 fusions, defining the pathogenesis of an emerging group of malignant soft tissue tumors with a distinctive nested growth pattern and variable immunoprofile.
Anastomosing hemangiomas (AH) are rare benign masses. We report an occurrence of AH in the breast during pregnancy, its pathological analysis, and clinical management. Key in the evaluation of these ...rare vascular lesions is differentiating AH from angiosarcoma. A low proliferative Ki-67 index and small size on imaging and final pathology will confirm AH from angiosarcoma. Clinical management of AH requires surgical resection and standard interval mammography and clinical breast examination.
Myoepithelial tumors arising in soft tissue are uncommon and mostly manifest a benign clinical course, although a malignant form does exist. An EWSR1 gene rearrangement is a common event in these ...tumors. Ossifying fibromyxoid tumor, a rare soft tissue neoplasm of uncertain differentiation, may have overlapping histologic and immunophenotypic features with myoepithelial tumors, but frequently harbors a PHF1 gene rearrangement. Interestingly, a PHF1-TFE3 fusion has been recently reported in both entities. Here we report a case of a malignant soft tissue tumor demonstrating myoepithelial differentiation and harboring a PHF1-TFE3 fusion. Despite being slow-growing and lacking significant cytologic atypia at initial presentation, the patient deteriorated rapidly with local recurrence and distant metastases. A discussion of the potential clinicopathologic implications of a PHF1-TFE3 fusion in these entities is also developed.