American Journal of Surgical Pathology最新文献

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.

We identified 9 cases of primary high-grade serous-like carcinoma (HG-SL-Ca) of the breast that displayed the morphology of high-grade serous carcinoma of Müllerian origin. These cases could represent a new entity of breast carcinoma. This study included 9 cases of HG-SL-Ca of the breast. Extensive clinicopathologic features and outcome data were available and evaluated in 8 cases. We, for the first time, performed whole exome sequencing (WES) on 6 of these cases to identify pathogenic germline and somatic genetic mutations and conducted gene pathway enrichment analyses. Six cases were triple negative; 2 were HER2 positive, and 1 was ER+/PR+/HER2-. Eight of the 9 cases had high nuclear grade and the other 1 had intermediate nuclear grade. Six patients received chemotherapy; the patient with ER+/PR+/HER2-cancer received hormonal therapy only, and 1 patient with dementia did not receive any systemic therapy. Follow-up data showed 2 patients had distant metastasis and 1 had chest wall recurrence. Two patients died of disease, including 1 patient receiving palliative care and 1 with lung and pleural metastasis. Most of the cases were positive for GATA3 immunohistochemistry (IHC) staining and all were negative for PAX8. All except for 1 case (focally positive) were negative for WT1 nuclear stain. Aberrant p53 IHC staining patterns were observed in 6 cases. WES analyses showed 26 genes with pathogenic germline mutations and 28 genes with pathogenic somatic mutations in these cases that were in the ACR GENIE mutated gene list. Pathway analyses showed that these genes with pathogenic germline or somatic mutations were enriched in the PI3K-AKT-mTOR pathway, WNT pathways, and death receptor pathway. TP53 was recurrently mutated, containing somatic variants in 4 cases, and all these 4 cases had aberrant p53 IHC staining patterns. We, for the first time, performed WES analyses on HG-SL-Ca of the breast. The majority of HG-SL-Ca were triple negative or HER2 positive with high nuclear grade. Patients with HG-SL-Ca of the breast had a poor prognosis. Our pathway analyses showed that genes containing pathogenic germline or somatic mutations were enriched in the PI3K-AKT-mTOR pathway, WNT pathways, and death receptor pathway, which could provide potential targeted treatment options. TP53 was recurrently mutated in 4 cases and all these 4 cases had aberrant p53 IHC staining patterns.

Malignancy associated with ileal neobladders or ileal conduits in postradical cystectomy patients is rare. Yet, recurrent urothelial carcinoma or new primary cancers, such as adenocarcinoma, enteric type (EA), are potential complications that pose significant clinical challenges. This study aimed to evaluate the incidence, clinical outcomes, and management strategies for malignancies in patients with ileal neobladders or ileal conduits. A retrospective review was conducted at 3 large academic institutions, identifying 10 cases of malignant tumors arising in ileal neobladders or ileal conduits over a period of 10 years. The study cohort included 9 male and 1 female patient aged 56 to 92 years (mean age = 68.2 y). Data on clinical presentation, management, pathology, and outcomes were collected, with a focus on recurrence and disease-specific survival rates. Seven of 10 patients (all males) were initially diagnosed with invasive high-grade urothelial carcinoma (IHGUC), whereas 3 patients had a history of bladder augmentation with colonic tissue (BA) for benign etiologies. Of patients with IHGUC, 2 patients received neoadjuvant chemotherapy, 1 received a combination of chemotherapy agents, and 3 patients underwent intravesical BCG therapy. All IHGUC exhibited conventional morphology without divergent differentiation. Pathologic staging of the cystectomy for IHGUC ranged from pTa to pT3a, with 4 cases showing lymph node metastasis. IHGUC recurrence was detected in 6 of 7 patients with a latency period range of 7 months to 6.7 years (mean 37 mo) and all tumors again exhibiting conventional morphology without divergent differentiation. IHGUC recurrence demonstrated a pathologic stage ranging from pT2 to pT4, and 5 died (mean = 4.2 mo), whereas 1 patient remains alive and on surveillance. EA occurred in 4 patients, including 3 BA patients and 2 foci in 1 patient with a neobladder for IHGUC. Staging of patients with EA ranged from pTis to pT2 developing 31 to 55 years postsurgery. Three of 5 EA cases were associated with a precursor lesion including 2 tubular adenoma with high-grade dysplasia, and 1 sessile serrated lesion with dysplasia. EA patients had relatively favorable outcomes compared with IHGUC patients, with all surviving patients currently on surveillance though with one case demonstrating nodal metastasis. Although rare, malignancies in ileal neobladders or ileal conduits are a serious complication. Although IHGUC recurrence often leads to poor survival, EA patients-especially those with prior bladder augmentation-seem to be associated with better survival outcomes. The long latency period for IHGUC recurrence and the favorable prognosis for EA underscore the need for vigilant long-term surveillance.

Germ cell tumors (GCTs) are the most common nonhematopoietic malignancies in young men and typically present as primary testicular masses. However, in ∼12% of cases, GCTs manifest as metastatic disease without a known testicular primary, leading to significant diagnostic challenges. We retrospectively reviewed 55 cases of GCTs presenting as metastases, focusing on the morphologic and immunohistochemical pitfalls encountered in core biopsy specimens. Among a total of 55 cases, seminoma was the most common histologic subtype (61%), followed by embryonal carcinoma (14%) and mixed GCTs (13%), with a median age of 44 years (range: 21 to 87 y). The most frequently biopsied metastatic sites were the retroperitoneum (55%) and left neck (22%). Notably, only 7% of cases had an identified testicular mass at diagnosis. Only a third (32%) of cases were submitted with an initial diagnosis of GCT, while 10% were misclassified as non-GCT malignancies. Histologic features such as crush artifact (83%) and necrosis (54%) frequently obscured morphology, leading to extensive IHC panels. Cytokeratin expression (particularly CAM 5.2 and AE1/3) was identified in 51% of cases, often confounding the diagnosis. A greater number of IHC stains were performed at outside institutions compared with intramurally (9 vs. 4, P =0.0001). The use of OCT3/4 and CD30 proved crucial in diagnosing seminomas and embryonal carcinomas, respectively. In rare cases (n=4) with atypical histology, fluorescence in situ hybridization (FISH) for isochromosome 12p provided additional diagnostic support. Diagnosing metastatic germ cell tumors in needle biopsies remains a significant challenge, often compounded by lack of a known testicular mass, cytokeratin expression, and confounding histologic features such as crush artifact and necrosis that could be used as clues rather than impediments to diagnosis. Awareness of these findings, along with careful integration of clinical context, histology, and immunohistochemistry, is critical to avoid misdiagnosis, particularly in light of the exquisite chemosensitivity of GCTs. The use of reliable markers like OCT3/4 and CD30, coupled with a high index of suspicion in men with retroperitoneal or left neck masses, can aid in improving diagnostic accuracy.

Undifferentiated melanoma poses a unique diagnostic challenge as, by definition, it lacks expression of the melanocytic markers S100 protein, Sox10, Mart1, and HMB45. Despite this aberrant phenotype, undifferentiated melanoma is characterized by known melanoma driver alterations, including BRAF and NRAS mutations. Due to variable morphologic features and a lack of melanocytic differentiation, molecular diagnostics are often required for the identification of melanoma-compatible driver alterations to support the diagnosis. Here, we describe a cohort of 27 undifferentiated melanomas and employ gene expression profiling to compare undifferentiated melanoma to conventional melanoma in both matched cases arising in the same patients and unmatched cases. The histologic spectrum of undifferentiated melanoma was variable and included tumors composed of epithelioid, spindled, pleomorphic, rhabdoid and balloon cells, often with necrosis. Notably, a subset of undifferentiated melanomas demonstrated a prominent stroma, including myxoid and vascular components. We demonstrate that the histologic category is the main determinant of differential gene expression between conventional and undifferentiated melanoma. In addition, undifferentiated melanomas show several significantly upregulated gene expression pathways, including those associated with epithelial-mesenchymal transition. These data provide novel insights into the transcriptomic expression profile of undifferentiated melanoma and offer potential explanations for the unusual phenotype. Notably, HMGA2 was found to be the most significantly up-regulated gene in the undifferentiated melanoma cohort, with immunohistochemical studies demonstrating that HMGA2 is a sensitive and specific marker for the diagnosis of undifferentiated melanoma and for its distinction from mimics which show overlapping morphologic features and lack melanocytic differentiation.

This manuscript summarizes the first part of the proceedings of the 2023 Dublin ISUP Consensus Conference encompassing the best practice recommendations on the pathology of neoplasms of urachal origin. The rationale for convening this consensus conference was the lack of structured and consented histopathologic recommendations in these rare tumors. Consensus among the meeting participants (n=80) was reached on the following statements: (1) combination of gross, histologic, clinical and imaging findings with exclusion of secondary tumor metastasis are to be used in the diagnosis of urachal carcinoma; (2) the 2022 World Health Organization (WHO) separate criteria for the diagnosis of urachal adenocarcinoma and for nonglandular carcinoma should be applied; (3) specific elements are to be evaluated and recorded in the gross examination of resection specimens containing urachal tumors; (4) sampling considerations for resection specimens containing urachal tumors are advised; (5) participants are against using 5% or 10% cutoff for the extent of intraepithelial carcinoma in urachal mucinous cystic tumor of low malignant potential; (6) use of immunohistochemical markers for the differential diagnosis of urachal adenocarcinomas in transurethral resection (TUR) specimen is considered optional; (7) similar tumor classificatory (nosology) rules for carcinomas arising from bladder mucosa (eg, urothelial carcinoma, squamous cell carcinoma, and neuroendocrine carcinoma) should be applied for nonglandular urachal carcinomas; (8) a new staging approach other than the previously proposed systems should be designed for urachal carcinoma; (9) a system modifying the current Tumor-Node-Metastasis (TNM)/American Joint Committee on Cancer (AJCC) staging system for urinary bladder cancer is considered appropriate for a study in urachal carcinoma; and (10) several histologic elements are to be reported when diagnosing urachal carcinoma in TUR and resection specimens. This report from the Dublin ISUP consensus conference will serve as a practice recommendation for pathologists and as a guide for future standardized reporting protocols and research regarding urachal tumors. In addition, an international database for urachal cancers under the guidance of ISUP is being planned to be established to address pertinent issues in the pathology of urachal cancers.