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HER2 (ERBB2) overexpression and/or HER2 gene amplification has been well established in several tumors types and when present HER2 directed therapy may be to be efficacious. While recent findings suggests that HER2 overexpression and HER2 amplification are a relatively common in serous endometrial carcinoma, similar data regarding clear cell endometrial carcinoma (CCC) is difficult to interpret due to issues such as diagnostic criteria, sample type and HER2 interpretation criteria. Our goals were to study HER2 expression and HER2 copy number status in hysterectomy specimens from a large series of patients with pure CCC to determine the frequency of HER2 overexpression and HER2 amplification and evaluate applicability of current HER2 interpretation criteria. Pure CCC specimens derived from hysterectomy specimens from 26 patients were identified. All diagnoses were confirmed by two gynecologic pathologists. Immunohistochemistry for HER2 protein and fluorescence in situ hybridization (FISH) studies for HER2 were performed on whole-slide sections from all cases. Results were interpreted according to the 2018 ASO/CAP HER2 guidelines for breast cancer and International Society of Gynecologic Pathologists (ISGyP) HER2 guidelines for serous endometrial carcinoma. Additional testing was performed when indicated by the guidelines. HER2 expression by immunohistochemistry was 3+ in 4% and 0% of cases, and 2+ in 46% and 52% of cases, by 2018 ASCO/CAP and ISGyP criteria, respectively, while the remaining cases were negative. HER2 testing by FISH showed a positive result in 27% of tumors with 2018 ASCO/CAP guidelines, while 23% were positive with the ISGyP criteria. Our findings indicate that HER2 overexpression and HER2 amplification occur in a subset of CCC. Therefore, additional study into the potential benefit of HER2 targeted therapy in patients with CCC is warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Adamantinoma of the long bones is a rare, typically low-grade malignant tumor that frequently involves the tibia. Radiographically, adamantinoma is characteristically a lytic, intracortical, and expansile lesion with variable margins. Histologically, adamantinoma is a bimorphic neoplasm, composed of epithelial and osteofibrous elements. Herein, we describe a 72-year-old man with a long-standing tibial mass that, on imaging, rapidly developed cortical destruction with soft tissue extension. Imaging revealed no evidence of a distant site of origin. Needle core biopsy demonstrated high-grade squamous cell carcinoma, and metastasis was initially favored. However, the combined clinicoradiologic and pathologic features were most compatible with a high-grade squamous cell carcinoma arising in adamantinoma. The diagnosis was confirmed in the resection specimen. Both the age at presentation and histologic features make this case unusual and highlight a potential for misdiagnosis in the evaluation of squamous cell carcinoma-containing lesions of the tibia, reinforcing the importance of clinicoradiologic correlation in bone pathology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Germline BRCA mutations account for a significant proportion of genetic/familial risk of breast and ovarian cancer (GBOC) susceptibility, but a broader spectrum of GBOC susceptibility genes has emerged in recent years. Genotype-to-phenotype correlations are known for some established forms of GBOC; however, whether such correlations exist for less common GBOC variants is unclear. We reviewed our institution's experience with non-BRCA GBOC, looking specifically for trends in pathologic and clinical features. Eighteen women with deleterious germline mutations in RAD51C (5 patients), BARD1 (1 patient), BRIP1 (2 patients), PALB2 (3 patients), MUTYH (2 patients), or CHEK2 (5 patients) were identified between January 2011 and December 2016. Thirteen (72%) of 18 patients developed carcinoma of the breast, fallopian tube, or ovary, with 1 patient developing 2 separate primary neoplasms. Twelve (86%) of 14 tumors occurred in the breast. One (7%) arose in the fallopian tube and another (7%) arose in the ovary. Evidence of genotype-phenotype correlation was not identified. However, some data suggest that the type of alteration in select genes may influence tumor behavior and patient outcome. In our PALB2 mutation cohort, 2 patients with frameshift mutations led to early onset and rapid progression to stage IV breast cancer in contrast to stage IA breast cancer in 1 patient with a nonsense mutation. Despite no apparent genotype-phenotype trends, our data indicate that some loss-of-function variants in PALB2 may lead to differences in tumor behavior and patient outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The use of prosthetic implants for breast augmentation has become commonplace. Although implants do not increase the risk of conventional mammary carcinoma, they are rarely associated with anaplastic large cell lymphoma. We report 2 cases of breast implant capsule-associated squamous cell carcinoma with poor clinical outcomes. Both patients (56-year-old woman and 81-year-old woman) had long-standing implants (>25 years) and presented with acute unilateral breast enlargement. In both cases, squamous cell carcinoma arose in (focally dysplastic) squamous epithelium-lined breast implant capsules and widely invaded surrounding breast parenchyma or chest wall. Neither patient had evidence of a primary mammary carcinoma or squamous cell carcinoma at any other anatomic site. Within 1 year, one patient developed extensive, treatment-refractory, locoregional soft tissue metastasis, and the second patient developed hepatic and soft tissue metastases and died of disease. There are 2 prior reported cases of implant-associated squamous cell carcinoma in the plastic surgery literature; one provides no pathologic staging or outcome information, and the second case was a capsule-confined squamous cell carcinoma. Together, all 4 cases share notable commonalities: the patients had long-standing breast implants and presented with acute unilateral breast pain and enlargement secondary to tumors arising on the posterior aspect of squamous epithelialized implant capsules. Because of both its rarity and its unusual clinical presentation, implant capsule-associated squamous cell carcinoma may be underrecognized. The aggressive behavior of the tumors in this series underscores the importance of excluding malignancy in patients with long-standing breast implants who present with acute unilateral breast pain and enlargement., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma that most often involves the distal extremities of adults. Some MIFSs have been reported to show TGFBR3 and MGEA5 rearrangements. TGFBR3 and MGEA5 rearrangements have also been reported in hemosiderotic fibrolipomatous tumor (HFLT), in pleomorphic hyalinizing angiectatic tumor (PHAT), and in rare tumors allegedly showing features of both HFLT and MIFS (hybrid HFLT-MIFS). These findings have led to speculation that HFLT, MIFS, PHAT, and hybrid HFLT-MIFS are closely related; however, areas resembling HFLTs are only very rarely encountered in previous series of MIFSs. We studied classic examples of these tumors with the goal of clarifying the relationship between MIFS and HFLT-MIFS. Cases of MIFS (n=31), hybrid HFLT-MIFS (n=8), PHAT (n=2), HFLT (n=1), and undifferentiated pleomorphic sarcoma (n=4) were retrieved from our archives, and the diagnoses were verified by 5 soft tissue pathologists. Using previously validated break-apart fluorescence in situ hybridization probes, we analyzed for TGFBR3 and MGEA5 rearrangements. Only 2 of 31 MIFSs harbored MGEA5 rearrangements; all lacked TGFBR3 rearrangements. Six of 8 hybrid HFLT-MIFSs harbored rearrangements of TGFBR3 and/or MGEA5. Both PHATs were positive for rearrangements of TGFBR3 and/or MGEA5. The HFLT was positive for rearrangements of both TGFBR3 and MGEA5. All undifferentiated pleomorphic sarcomas with focal myxoid change were negative. We conclude that (1) TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFSs than in classic MIFSs, (2) HFLTs and MIFSs may be unrelated lesions, and (3) hybrid HFLT-MIFSs most likely represent HFLTs with sarcomatous progression, rather than tumors strictly related to classic MIFSs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Solitary (juvenile) xanthogranuloma (SXG) is an uncommon, benign lesion that usually occurs in children. The cell of origin of SXG has been the subject of debate, with hypotheses including endothelium, dermal dendrocytes, dermal indeterminate cells, and the plasmacytoid monocyte, among others. We further characterized the immunophenotype of SXG with an extended immunohistochemical panel, paying special attention to recently described or novel markers of histiocytic lineage. Forty-one SXG and 23 benign fibrous histiocytomas (BFHs) were immunostained for factor XIIIa, CD4, CD11c, CD163, CD31, CD45, lysozyme, and S-100. The mononuclear cells of SXG and the spindled cells of BFH were scored as "negative," "1+" (<10% positive), "2+" (10%-50% positive), and "3+" (>50% positive). SXG immunohistochemistry showed the following: factor XIIIa, 35/40 (88%); CD4, 34/36 (94%); CD11c, 36/37 (97%); CD163, 36/36 (100%); CD31, 14/31 (45%); CD45, 14/32 (44%); lysozyme, 23/30 (77%); and S-100, 0/32 (0%). The 5 factor XIIIa-negative cases all showed 2+-3+ CD4, CD11c, and CD163 expression. In contrast, only 8 (35%) of 23 BFH cases were factor XIIIa positive. All other stains were universally negative in the lesional cells of BFH, although these tumors frequently contained interspersed cells expressing various histiocytic markers. Our results strongly support histiocytic lineage for the mononuclear cells of SXG. CD11c expression has not been previously described in SXG. CD163 expression appears to be characteristic of SXG, as it was not expressed by the lesional cells of BFH, in contrast to previous reports. CD31 expression in SXG represents a potential diagnostic pitfall, as many (dermato)pathologists are unaware of CD31 expression in histiocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)