American Journal of Surgical Pathology最新文献

p53 cytoplasmic sequestration has been shown to be a mechanism of carcinogenesis. However, until recently, an aberrant p53 cytoplasmic staining pattern by immunohistochemistry (IHC) was under-reported in oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED). Following the identification of a pilot case, the authors studied the clinicopathologic features of 4 OSCCs and 10 OEDs with p53 cytoplasmic staining pattern, 4 of which exhibited co-occurrence of nuclear null/overexpression patterns. Using next-generation sequencing (NGS), we demonstrate that this cytoplasmic staining pattern correlates with TP53 mutations that disrupt or truncate the C-terminal nuclear localization sequence (NLS) or nuclear exclusion sequence (NES). High-impact NLS-altering mutations in the same region are identified in 8.7% to 11.0% of TP53 -mutant samples in the TCGA-HNSC cohort. Our study provides a practical definition for aberrant p53 cytoplasmic staining in HNSCC and OED, a diagnostic pitfall with potential biological implication. This study proposes an updated p53 IHC interpretation algorithm to facilitate further data accrual.

Adult granulosa cell tumors (aGCTs) of the ovary are uniquely characterized by an almost ubiquitous somatic mutation in the FOXL2 gene (p.C134W). We report the first series of 7 aGCTs harboring pathogenic FGFR1 kinase domain mutations, providing a novel alternative oncogenic mechanism in these rare FOXL2 -wildtype tumors. Archival sex cord-stromal tumors that underwent targeted DNA sequencing (MSK-IMPACT, Oncopanel, and Foundation Medicine assays) were reviewed. Histopathologic and immunophenotypic features were reviewed by expert pathologists. Seven cases were identified with FGFR1 hotspot mutations (codons N546, N577, K656, and K687), 6 of which lacked the pathognomonic FOXL2 p.C134W variant. All tumors demonstrated the classic histology of aGCT (microfollicular growth, Call-Exner bodies, "coffee bean" nuclei) with 5/5 showing robust inhibin-α positivity by immunohistochemistry. No distinct morphologic or immunophenotypic differences were found compared with conventional FOXL2 -mutant aGCTs. Clinically, most patients presented at early stage (IA) and underwent surgical management. Four patients experienced recurrent disease involving peritoneal or omental sites, but overall clinical behavior was comparable to typical aGCTs. These findings establish FGFR1 alterations as an alternative oncogenic driver in a subset of FOXL2 -wildtype aGCTs. From a diagnostic standpoint, the absence of FOXL2 p.C134W mutation does not exclude the diagnosis of aGCT when the morphology and immunoprofile are characteristic.

T-cell receptor β chain constant region 1 (TRBC1) is a useful marker for the detection of clonal T-cell populations and has been used in flow cytometry, with limited data on its utility as an immunohistochemical marker. We evaluated TRBC1 by immunohistochemistry (IHC) in 42 CD3-positive, T-cell receptor alpha beta-positive T-cell lymphomas and compared their expression pattern to a control cohort of 35 reactive lymph nodes and tonsils. TRBC1 restriction was evident in 37/42 (88%) lymphomas but indeterminate in 5 cases, most of which were follicular helper T-cell lymphomas, angioimmunoblastic type/nodal T follicular helper cell lymphomas, angioimmunoblastic type (AITL). 34/35 (97%) control cases had ∼50% as much TRBC1 staining as CD3; however, one tonsil, while not TRBC1 restricted, had much less staining than CD3, which was confirmed by TRBC1 flow cytometry. TRBC1 IHC was helpful in demonstrating clonality in most T-cell lymphomas, including all cases lacking flow cytometric studies, and in 2 cases without definite molecular evidence of clonality. In differentiating T-cell lymphoma from reactive lymphoid tissue, it had a sensitivity of 88% and specificity of 97%. Thus, TRBC1 IHC is a useful, rapid, and inexpensive tool in the diagnosis of T-cell lymphomas.

Serous borderline tumors of the testis and paratestis are rare, and experience with these neoplasms is limited. We report a series of 19 tumors, emphasizing their morphologic spectrum and clinical behavior. Eighteen tumors (95%) had conventional serous borderline tumor morphology identical to ovarian serous borderline tumors, and 1 case (5%) had a pattern resembling the epithelial subtype of noninvasive implants of serous borderline tumor. A component of micropapillary serous borderline tumor was present in 6 tumors (31%), including 1 that was exclusively micropapillary. Five tumors (26%) had associated autoimplants. Microinvasion was identified in 4 tumors (21%). One tumor had associated low-grade serous carcinoma, and 1 tumor had associated high-grade serous carcinoma. Immunohistochemical stains demonstrated diffuse expression of PAX8 in 12 of 12 (100%) cases. Estrogen receptor was diffusely positive in 11 of 12 (92%) cases and progesterone receptor was positive in 8 of 9 (89%) cases. D2-40 was negative in 7 of 9 (78%) cases and calretinin was negative in 11 of 11 cases (100%). Clinical follow-up data were available in 9 patients (47%) with pure serous borderline tumors, of which 4 had micropapillary features (44%), 3 had microinvasion (33%), and 2 had autoimplants (22%). None of these 9 patients experienced adverse outcomes related to serous borderline tumor over the follow-up period (mean: 94 mo, median: 85 mo, range: 17 to 204 mo). Serous borderline tumors of the testis and paratestis are identical morphologically to their ovarian counterparts and can be associated with similar histologic phenomena (microinvasion, autoimplants, and micropapillary features). Although they can develop associated serous carcinoma, we conclude that serous borderline tumors of the testis and paratestis (when pure) appear to show indolent behavior.

Massive/mass-forming ductular reaction of the liver (MDR) is occasionally in the differential diagnosis with true bile duct tumors. Our diagnostic histomorphological and immunohistochemical study of 14 cases from a consultant collective of 2970 cases follows the appearance of MDR with regard to various underlying liver diseases and the conditions of pathologic perfusion. We describe MDR measuring up to 7 cm in localized form or affecting up to 70% of the parenchyma in subacute liver necrosis. MDR developed in the context of severe inflammatory liver diseases and liver cirrhosis, as well as in colocalization with true malignant neoplasms such as hepatocellular carcinoma, epithelioid hemangioendothelioma, and hepatic angiosarcoma. In all cases, MDR was associated with intra- or directly perilesional thrombotic or tumorous obliteration of intrahepatic portal or hepatic veins or liver sinusoids. In end-stage liver cirrhosis, it was additionally associated with fibrotic occlusion of the portoseptal vascular bed. Further key diagnostic features of this hypoperfused, extensive parenchymal transformation included a monolayered network of small cytokeratin 7-, cytokeratin 19-, and CD56-positive ductules with fingertip-like endings, low proliferative activity (<3% Ki-67-positive cells), and embedded in a loose stroma. The pre-existing lobular architecture, including portal tracts or cirrhotic remodeling, was preserved. In conclusion, MDR of the liver is a rare, confluent pluriacinar and sometimes pseudo-tumorous transformation of the liver parenchyma that is associated with altered liver perfusion. Clinically and histomorphologically, it can mimic a true biliary neoplasm.

The proper categorization of mature T-cell neoplasms with coexpression of CD30/CD15 is unresolved. Prior studies suggested an overlap with ALK-negative anaplastic large cell lymphoma (ALCL). We evaluated the morphologic, immunophenotypic, and molecular features of 28 T-cell lymphomas coexpressing CD30/CD15, and performed a comparison with 8 ALK/CD15-negative ALCL and published data. Clinical information was retrieved from the submitting physician. Immunohistochemistry, TRG and IG gene rearrangement, DNA and RNA targeted next-generation sequencing, and fluorescence in situ hybridization for DUSP22 rearrangement were performed. Cases were classified as conforming to 3 histologic variants: ALCL-like, Hodgkin-like, and PTCL-NOS-like. Median age was 62 years (range: 33 to 87). Male:female ratio was 3:1. Twenty-four cases presented with lymphadenopathy (24/28, 85.7%). Six cases had skin involvement (6/28, 21.4%), including 4 primary cutaneous cases (4/28, 14.3%). Ten cases were designated as ALCL-like, 12 as Hodgkin-like, and 2 as PTCL-NOS-like. There was frequent loss of T-cell markers, with expression of CD3 in 7/27 cases (25.9%), CD2 in 15/23 (65.2%), and expression of at least one cytotoxic marker in 13/24 (54.2%). DUSP22 was rearranged in 4 cases (4/16, 25%). The JAK-STAT pathway was frequently altered due to mutations in JAK1 (6/28, 21.4%), STAT3 (5/28, 17.8%), and JAK2 fusions (2/28, 7.1%). PI3K-AKT-mTOR pathway alterations due to PIK3R1 mutations (5/28, 17.8%) were also frequent and mutually exclusive with JAK-STAT pathway activation. In summary, most T-cell neoplasms with CD30/CD15 coexpression share clinical, morphologic, immunophenotypic, and molecular features with ALK -negative ALCL but do not segregate as a homogeneous entity as defined by histologic or genetic features.

Succinate dehydrogenase (SDH), a critical enzyme in the citric acid cycle and respiratory electron transport chain, consists of 4 subunits: SDHA, SDHB, SDHC, and SDHD. Deficiency of a single subunit leads to the loss of SDH activity which is implicated in the development of a subset of gastrointestinal stromal tumors (GISTs): SDH-deficient GISTs. These GISTs arise almost exclusively in the stomach, have a female predilection, and primarily affect children and young adults. Their characteristic morphologic features include multinodular architecture, lymphovascular invasion, and lymph node metastasis. At the molecular level, these tumors lack KIT , PDGFRA, BRAF , or NF1 mutations, which are alternative oncogenic drivers typically observed in GIST. Recently, a sarcoma DNA methylation classifier was developed and was shown to be a valuable diagnostic tool. This study evaluated the DNA methylation classifier results for 30 SDH-deficient GISTs and discovered that methylation profiles clustered in a unique region separate from GISTs and leiomyosarcomas. Moreover, MGMT promoter methylation, a predictive biomarker of tumor cell sensitivity to alkylating agent chemotherapy, was identified in 6 primary and 5 metastatic tumors. In addition, 3 primary and 4 metastatic tumors showed gain/low-level amplification of MDM4 , which pathologically activates MDM4-p53 axis, a target of inhibitors. In summary, these findings expand the sarcoma DNA methylation classifier to include SDH-deficient GIST as a new sarcoma DNA methylation entity and identified 2 predictive biomarkers for targeted therapy: methylation of MGMT promoter and gain/low-level amplification of MDM4 .

More than half of patients with plasma cell myeloma (PCM) relapse after treatment and require novel therapies. Venetoclax, a highly specific and effective oral BCL2 inhibitor, has a favorable risk-benefit ratio for PCM patients with t(11;14)/IGH:: CCND1 . Standard of care for new or relapsed cases of PCM incorporates fluorescence in situ hybridization (FISH) analysis for the detection of IGH ::CCND1. However, FISH requires a high-quality bone marrow (BM) aspirate sample and plasma cell (PC) purification. Immunohistochemical (IHC) staining to detect overexpressed cyclin D1 protein resulting from IGH ::CCND1 is lower cost, more widely available, and has a faster turnaround time than FISH. However, a predictive cyclin D1 IHC cutoff has yet to be established for correlation with IGH ::CCND1 . We evaluated a testing cohort of 85 BM biopsy cases diagnosed as PCM with adequate core biopsies and corresponding myeloma FISH results (43 fusion positive and 42 fusion negative) to develop a multitiered classification system for cyclin D1 IHC expression in plasma cell myeloma that can predict IGH ::CCND1 fusion status with high confidence in the majority of cases. Using H-score to predict fusion status yielded positive and negative predictive values of 97% and 100%, respectively. A validation cohort consisting of 50 additional cases (24 fusion negative and 26 fusion positive) had 93% positive and 100% negative predictive values for fusion status. We find that cyclin D1 IHC has high concordance with FISH for IGH ::CCND1 fusion status and is a valuable alternative when FISH is suboptimal or unavailable.

Among soft tissue tumors, MUC4 is expressed in low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, and is regarded as a specific and sensitive marker for these malignant entities. These tumors are driven by oncogenic fusions involving FUS or EWSR1 as a 5' partner and CREB3L1 or CREB3L2 as a 3' partner. In this study, we describe the clinicopathologic and molecular features of a distinctive fibroblastic soft tissue neoplasm characterized by consistent co-expression of MUC4 and beta-catenin, and frequent underlying APC inactivation without evidence of EWSR1 or FUS rearrangements. Fifteen hyalinized spindle cell neoplasms with MUC4 and aberrant nuclear beta-catenin co-expression were identified from our institutional archives. The cohort comprised 15 adult patients (6 female, 9 male) with a median age of 40 years (range: 20 to 61). Tumors arose in the extremities (n=9), trunk (n=5), and retroperitoneum (n=1), with a median size of 8.5 cm (range: 2.8 to 18.0 cm). The tumors consisted of a hypocellular proliferation of spindled-to-stellate fibroblastic cells in a variably hyalinized collagenous stroma. No atypia, fascicular growth, or myxoid stroma was present. Targeted DNA sequencing was successfully performed on 8 tumors. In addition, 8 tumors underwent FISH testing to assess for FUS and/or EWSR1 rearrangement. In the majority of tumors, DNA sequencing demonstrated APC inactivation (7/8; 88%). In 6 of these cases, 2 concurrent deleterious APC alterations were present, indicative of biallelic inactivation. No rearrangements involving FUS or EWSR1 were identified by NGS and/or FISH. Clinical follow-up data were available for 4 patients, with no local recurrences or metastases reported, including 1 patient followed for 8 years. No patients had a known history of familial adenomatous polyposis. We describe a novel fibroblastic soft tissue neoplasm characterized by co-expression of MUC4 and beta-catenin and frequent underlying APC inactivation, for which we propose the name "MUC4-positive fibroblastoma."

FLCN -associated eosinophilic renal tumors mainly refer to hybrid oncocytic/chromophobe tumors (HOCT) and other oncocytic tumors related to Birt-Hogg-Dubé (BHD) syndrome, which can sometimes occur sporadically. Accurate diagnosis of FLCN -associated tumors is challenging due to their morphologic heterogeneity and the lack of reliable biomarkers. We evaluated the clinicopathologic and IHC profiles of 18 eosinophilic renal tumors with targeted DNA sequencing-confirmed FLCN mutations, including 10 typical HOCT and 8 unclassified tumors. Fourteen of these, plus 45 cases from the control group, were profiled transcriptionally by RNA-seq. Ten typical HOCT displayed consistent mosaic morphology and immunohistochemical patterns. Eight unclassified FLCN -mutated tumors exhibited diverse morphologies, including chromophobe renal cell carcinoma (ChRCC)-like, succinate dehydrogenase-deficient renal cell carcinoma (SDH-RCC)-like, and histiocyte-rich patterns, lacking obvious hybrid cellular components and typical immunohistochemical features. Despite this heterogeneity, glycoprotein non-metastatic melanoma protein B (GPNMB) was identified as a highly sensitive biomarker for FLCN -mutated tumors, showing strong and diffuse positivity in both typical HOCT, unclassified FLCN -mutated tumors, and in the oncocytosis surrounding the tumors. RNA sequencing revealed that typical HOCT formed a unique gene expression cluster, distinct from recognized renal tumor types. Some unclassified FLCN -mutated tumors were grouped with HOCT, while others remained unclassified among known kidney tumors, existing independently. This study expanded the morphologic spectrum of FLCN -mutated renal tumors and highlighted GPNMB as a valuable diagnostic marker for both typical and unclassified FLCN -mutated tumors. GPNMB should be utilized to screen eosinophilic renal tumors that cannot be classified, aiding in the precise diagnosis and management of BHD or sporadic FLCN mutation-related patients.