American Journal of Surgical Pathology最新文献

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

Astroblastoma, MN1-altered, is a newly recognized entity in the 5th edition of the WHO Classification of CNS Tumors. Its genetic definition is the presence of an alteration, most commonly gene fusions, in the MN1 gene, with BEND2 being the most frequent fusion partner. However, some astroblastomas and astroblastoma-like tumors with fusion of non-MN1 to BEND2 have been reported recently. These tumors exhibit epigenetic profiles similar to those of astroblastomas with MN1::BEND2, suggesting that BEND2 may play a more important role than MN1 in tumorigenesis. Therefore, investigation of BEND2 fusion will be essential to make an accurate diagnosis of astroblastomas in the near future. In this study, we aimed to explore the diagnostic utility of BEND2 immunohistochemistry using a commercially available rabbit polyclonal antibody. As a result, nuclear expression of BEND2 was observed in all 15 cases of astroblastomas with BEND2 fusion (9 with MN1::BEND2, 4 with EWSR1::BEND2, 1 with MAMLD1::BEND2, and 1 with TCF3::BEND2), whereas it was not found in 147 cases of other CNS tumors from 48 different entities. In contrast, negative nuclear staining for BEND2 was observed in a previously reported case of spindle cell sarcoma with MN1::BEND2, whose fusion junction differed from those of the astroblastomas analyzed in this study. In conclusion, we demonstrated that BEND2 immunohistochemistry has extremely high sensitivity and specificity, suggesting its utility as a reliable marker for the diagnosis of astroblastoma with BEND2 fusion.

A comprehensive understanding of newly described tumors is often an evolutionary process. In this study, we describe the extended spectrum of morphologic patterns in a cohort of 144 ALK fusion Spitz neoplasms and provide the largest data set of ALK fusion Spitz with clinical follow-up. In addition to the most classic morphologic pattern of a nodular silhouette with wavy fascicles of spindle cells, these tumors may also form a desmoplastic pattern, a combined nevus of Reed-Spitz pattern, a predominantly epithelioid pattern, and a nevoid pattern. There are genomic correlates to some of these morphologic patterns, with Reed-Spitz cases frequently having TPM4 as the fusion partner (P=0.001), epithelioid cases frequently having EHBP1 as the fusion partner (P=0.0002), and nevoid cases frequently having KIF5B as the fusion partner. Two fusion partners, ZEB2 and EML4, were only seen in Spitz melanoma (SM) cases. TERT promoter mutations and c-MYC amplification were only seen in SM. A meta-analysis of the literature suggests that adverse events tend to be associated with c-MYC amplification, CDKN2A homozygous deletion, and higher mitotic count (5.5 mitoses/mm2 in metastatic cases vs. 2.2 mitoses/mm2 in nonmetastatic cases). Our study expands the morphologic spectrum and the associated genomic correlates of ALK-rearranged Spitz neoplasms and identifies parameters associated with malignant behavior.

Leiomyomas (LMs) represent the most frequent mesenchymal tumors of the urinary bladder. Despite their relative frequency, large clinicopathological studies are scarce, and their pathogenesis remains poorly understood. In this study, we performed a clinicopathological analysis of 35 bladder LMs and explored whether they share pathogenic mechanisms previously documented in uterine LMs. The tumors occurred in 18 women and 17 men, with a median age of 55 years (range: 20 to 78 y). Clinical data were available for 30 cases (85%). Most tumors were incidentally discovered (16/30, 53%), while the remaining patients presented predominantly with lower urinary tract symptoms. Ten patients had a prior history of cancer, and 3 women had a history of uterine LM. Tumor size, available in 12 cases, ranged from 6 to 66 mm (mean, 31 mm). Histologically, most tumors showed a uniform morphology, consisting of well-circumscribed nodules composed of bland smooth muscle cells without mitotic activity. Rare findings included extensive necrosis (3/35, 8%) and a pseudohyperplastic appearance (1/20, 5%). On immunohistochemistry, a subset of tumors, predominantly in females, expressed estrogen receptors (7/28, 25%), progesterone receptors (5/24, 21%), and androgen receptors (10/23, 43%). HMGA2 expression was observed in one case (1/27, 4%). Fumarate hydratase (FH) expression was retained in all tested tumors (n=31); 2SC expression was detected in 4 tumors (4/32; 12%), all with preserved FH and lacking distinctive histomorphological features of FH-deficient LMs. DNA sequencing of 2SC-positive tumors identified a pathogenic FH variant in one of the 4 analyzed cases at a low variant allele frequency. No other known pathogenic variants, including MED12 commonly seen in uterine LMs, were detected. Altogether, this study characterizes the clinicopathological features of large cohort of bladder LMs, highlighting unrecognized morphologic features, including cases with massive necrosis. Our findings suggest that bladder LMs differ pathogenetically from their uterine counterparts, with a more limited role for hormone receptor signaling and distinct genetic alterations.

Sex cord-like morphology is now a well-known feature of occasional examples of endometrioid carcinoma of the ovary or fallopian tube. Recently, we have observed that these tumors are frequently negative for PAX8, prompting us to review their morphologic, immunohistochemical, and genomic spectrum. Twenty tumors (17 ovarian, 3 fallopian tube) with available tissue were identified in patients ranging from 32 to 78 (median 60) years. Sex cord-like patterns included cords/trabeculae (n=17), small tubular glands (n=16), and "granulosa-like" nests (n=12). In addition, 1 had ependymoma-like features with perivascular pseudorosettes and 3 had focal spindled cells. Conventional endometrioid glands were often sparse. All had conspicuous fibromatous stroma and 11 tumors had background endometrioid adenofibromas. Six tumors had associated endometriosis. PAX8 was positive in only 2/20 (diffuse in both), while SOX17 was positive in all (focal in 1, diffuse in 19). Beta-catenin showed aberrant nuclear staining in 17/20. Of the 10 sequenced tumors, 9 showed activating pathogenic variants in CTNNB1; each of these also showed nuclear beta-catenin staining. All lacked alterations in mismatch repair genes, TP53, and POLE. In summary, adnexal endometrioid carcinomas with sex cord-like features are frequently PAX8-negative, which may result in diagnostic difficulty. However, SOX17 is typically positive and thus useful to establish the diagnosis. Most of these tumors are classified in the "no specific molecular profile" subgroup and have high rates of nuclear beta-catenin/CTNNB1 alterations. Awareness of these morphologic and immunohistochemical associations may help avoid misclassification as sex cord-stromal or other neoplasms.

Since its description by Hull and colleagues in 1981, several case series have described the clinicopathological features of glycogen-rich breast carcinoma (GRC); however, no detailed genetic study has been performed. We identified 10 patients with GRC; all were female (ages: 32 to 74 y; median: 51). Tumor size ranged from 0.7 to 3.8 cm (median: 1.45). All except one GRC showed relatively well-defined borders, and all were composed predominantly of nests containing clear cells with glycogen accumulation in cytoplasm confirmed by Periodic Acid-Schiff/Periodic Acid-Schiff- Diastase (PAS/PAS-D)staining. Using Nottingham grading, four were grade 2 and six were grade 3. Seven showed associated ductal carcinoma in situ (DCIS) with glycogen-rich features. Lymph node macrometastasis was seen in 2=two. Six were hormone receptor (HR) +/ human epidermal growth factor receptor 2 (HER2)-, 2 HR low +/ HER2- and 2 triple-negative. Follow-up (available for 9/10) ranged from 9 to 186 months (median: 38). All patients were alive; two patients had distant metastasis, one patient had local recurrence and six had no evidence of disease. DNA sequencing suggested two molecular subgroups: GATA3-mutant GRCs (5/10) with frequent RPKSB1 copy number gain (4/5) and TP53-mutant GRCs (4/10). GATA3-mutant GRCs were mixed grade 2/3, all were HR+ without distant metastasis while TP53-mutant GRCs were all grade 3, showed low +/- HR, and 3/4 patients showed distant metastasis/local recurrence. p53 immunohistochemistry showed mutant-pattern staining in three TP53-mutant GRCs tested as opposed to wild-type pattern in five GATA3-mutant GRCs. Molecular studies or p53 immunohistochemistry as a surrogate could be helpful to identify the TP53-mutant subgroup for closer follow-up and/or more aggressive treatment.

Occult breast carcinoma (OBC) refers to the clinical presentation of breast carcinoma occurring in axillary lymph node(s) without a detectable primary breast cancer. Prior studies of OBC have focused on treatment regimens. We sought to study the clinical, morphologic, and immunohistochemical features of OBCs. We retrospectively identified cases of OBC treated at our center between 1996 and 2021. All patients included in the study had biopsy-proven axillary metastatic breast carcinoma and underwent MRI after a noncontributory mammogram/ultrasound. Patients with a prior history of breast carcinoma were excluded. The study included 68 patients with a median age of 56 years (range: 31 to 84 y). The morphology in 55 cases (81%) was poorly-differentiated carcinoma, no special type (ductal). The remaining tumors showed lobular, micropapillary, apocrine, clear cell, and signet ring cell morphology. Thirty-nine (57.4%) OBC were hormone receptor positive, 19 (33.3%) were HER2 positive and 13 (22.8%) tumors were triple negative. Fifty (74%) patients had a breast sampling procedure while 18 (26%) did not. Thirty-four (50%) patients underwent neoadjuvant chemotherapy. Fifty-nine (87%) patients underwent axillary lymph node dissection while 9 (13%) had sentinel lymph node biopsy only. Nineteen (56%) patients achieved a complete pathologic response in the axilla. Fourteen (21%) patients developed a recurrence: 5 in the ipsilateral breast or axilla, 1 in the contralateral axilla and mediastinum, and 8 in distant metastatic sites. The median time to recurrence was 51.9 months. The final pathologic lymph node stage was the only feature found to be significantly associated with the development of recurrence.

CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change.

Classic Hodgkin Lymphoma (CHL) remains difficult to treat in patients with relapsed and refractory disease. The utility of immunotherapies, many of which target B-cell markers, is still under investigation. Although the neoplastic Hodgkin and Reed-Sternberg (HRS) cells are thought to lose most B-cell markers, studies have shown retention of these markers, mainly CD20, in some cases. However, the CD19 staining profile of HRS cells has not been thoroughly assessed and warrants exploration in the era of CD19-directed immunotherapies. We assessed CD19 immunohistochemical staining in 41 cases of CHL and correlated with histologic subtype, other markers, and clinical parameters. 13/41 cases (31.7%) demonstrated CD19 staining in HRS cells, with variation in staining pattern and intensity. When compared with CD19-negative cases, CD19 positivity correlated significantly with mixed-cellularity subtype (53.8% vs. 7.1%, P=0.002), CD20 (46.2% vs. 14.3%, P=0.0485), CD79a (53.8% vs. 9.1%, P=0.006), Epstein-Barr Virus (EBV) positivity (53.8% vs. 7.1%, P=0.002), and older age (median age 52 vs. 28.5 y, P=0.0006). 7/9 (77.8%) EBV+ cases demonstrated CD19 expression on HRS cells. By Kaplan-Meier analysis, CD19+ cases demonstrated worse overall survival compared with CD19- cases (P=0.011), with EBV-, CD19- cases demonstrating the best overall survival. On the basis of these findings, CD19 expression on HRS cells should not preclude the pathologic diagnosis of CHL, particularly in the context of mixed-cellularity or EBV+ disease. In addition, older patients with mixed-cellularity and/or EBV+ disease may represent a subgroup of patients with CHL who could benefit from CD19-directed therapies.

Clear cell papillary renal cell tumor (CCPRCT), formerly known as clear cell papillary renal cell carcinoma, is a low-grade renal neoplasm characterized by cytokeratin 7 and cup-like carbonic anhydrase 9 immunopositivity and absence of von Hippel-Lindau (VHL) abnormalities. Given the prognostic differences, distinguishing CCPRCT from clear cell renal cell carcinoma (CCRCC) is clinically important. However, some tumors diagnosed morphologically and immunohistochemically as CCPRCT have been found to harbor VHL abnormalities, which complicates clinical management. This study aimed to clarify how clinical, histologic, and immunohistochemical characteristics varied based on VHL status. Among 17 CCPRCTs analyzed, VHL abnormalities were identified in 10 (58.8%) cases, including VHL mutations in 6 cases and 3p loss of heterozygosity in 7 cases. Tumors were stratified into 3 groups based on VHL allele status: 3 cases with biallelic VHL inactivation (CCPRCT-biVHL), 7 with monoallelic VHL inactivation (CCPRCT-monoVHL), and 7 with wild-type VHL (CCPRCT-wtVHL). We integrated the molecular with morphologic and immunohistochemical findings, and reclassified 17 cases into 5 CCRCCs mimicking CCPRCT, 5 CCPRCTs-monoVHL, and 7 CCPRCTs-wtVHL cases. All tumors exhibited favorable clinical courses, with no instances of metastasis or recurrence. No significant differences in clinical, pathologic, or immunohistochemical features were observed among the 3 groups or between CCRCCs mimicking CCPRCT and CCPRCTs. This study demonstrated that strict morphologic and immunohistochemical criteria can distinguish most CCRCCs mimicking CCPRCT from CCPRCT. The diagnosis of CCPRCT should be expanded to include tumors with monoallelic VHL alteration exhibiting typical morphologic and immunohistochemical features.