American Journal of Surgical Pathology最新文献

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.

Primary Ewing sarcoma (ES) of the kidney is rare. We describe the clinicopathologic features of primary renal ES with emphasis on gene fusion partners. A multi-institutional study was conducted to obtain clinicopathologic data on primary ES of the kidney. All tumors with available tissue underwent NGS to determine fusion partners. Twenty-four patients (8 male, 16 female) were identified. Mean age was 33.2 (±12.3). Mean tumor size was 10.5 cm (±4.2). Clinical presentation was available in 21 patients: flank/abdominal pain (13, 61.9%), hematuria (4, 19%), mass (2, 9.5%), hypertension (1, 4.8%), and incidental (1, 4.8%). For 23 nephrectomies, 2 (8.7%) were ypT0 (post-neoadjuvant therapy), 3 (13%) pT1, 15 (65.2%) pT2, 1 (4.4%) pT3, and 2 (8.7%) pT4. Four (16.7%) had metastatic disease at presentation. Of 18 patients with available follow-up, 9 (50%) were alive with disease, 7 (38.9%) alive with no disease, and 2 (11.1%) died of disease (mean follow-up 34 mo). Metastatic disease was documented in 9/18 patients, including lung (3), adrenal (2), bone (2), retroperitoneum (2), liver (2), lymph node (1), and ureter (1). FISH was performed in 14 tumors and real-time quantitative PCR in 1, confirming EWSR1 rearrangements. NGS was performed in 17 tumors, showing EWSR1::FLI1 in 16 (94.1%) and EWSR1::ETV4 in 1. Primary renal ES is a rare neoplasm occurring in a wide age range. Most tumors invaded adjacent tissues. Although they share similar histologic and molecular features with their counterpart in the bone/soft tissue, we document the first case of a rare EWSR1::ETV4 fusion in the kidney.

Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is a newly categorized disease entity in the 5th WHO Classification of Tumors. Through an analysis of 53 primary adrenal large B-cell lymphoma (PA-LBCL) cases, we unraveled the similarity to IP-LBCL in clinical presentation, pathologic features, and genetic landscape. Our findings reveal a predominant immunophenotype of CD10-/BCL6+/MUM1+ in PA-LBCL, mirroring that observed in IP-LBCL, and a shared mutation spectrum characterized by the notable presence of PIM1, MYD88 L265P, and CD79B mutations. In addition, the results of RNA sequencing showed that there are significant differences in the expression profiles of PA-LBCL and SA-LBCL. The top 5 RNAs with the most significant expression differences were RPL23AP82, IGSF21, CMKLR, PTPRG, and PRKCA. Moreover, PA-LBCL exhibited a more favorable prognosis than DLBCL-NOS with secondary adrenal involvement. The results of this study indicate that PA-LBCL shares similar clinical features, immunophenotypes, and molecular genetic profiles with IP-LBCL, suggesting that it may belong to a subtype of IP-LBCL. This research has improved our understanding of lymphoma, especially those occurring in atypical sites, and reshaped our concept of lymphoma classification and management. We suggest considering incorporating PA-LBCL into IP-LBCL in the future classification of lymphoma.

IDH1 mutant prostatic adenocarcinoma represents a small fraction of prostate cancer with distinct epigenetic changes, characterized by genome-wide DNA hypermethylation. Recently, prostatic adenocarcinoma with intratumoral psammomatous calcifications was found to frequently harbors IDH1 R132 mutations. However, the association with IDH1 hotspot mutations and psammomatous calcifications in prostate cancer remains controversial. Here we report another rare case of IDH1 R132H mutant prostatic adenocarcinoma, showing intratumoral psammomatous calcifications identified in targeted needle biopsies as well as subsequent radical prostatectomy specimen. This case provides independent evidence for identification of IDH1 mutant prostate cancer by combined histologic features, including intratumoral psammomatous calcifications, anterior tumor location, and high Gleason score. In addition, to our knowledge, this is the first case of multifocal prostate cancer reported in the literature, with the co-existence of spatially disparate and genetically distinct tumor foci harboring IDH1 R132H mutation or TMPRSS2 - ERG gene fusion in the same prostate.