American Journal of Surgical Pathology最新文献

Somatic or germline pathogenic/likely pathogenic variants in DICER1 have known associations with certain neoplasms in the gynecologic tract, including Sertoli-Leydig cell tumors, embryonal rhabdomyosarcoma, and adenosarcoma. However, recent studies have highlighted DICER1-related malignant neoplasms with complex admixtures of sarcomatous, primitive glandular, and/or neuroectodermal elements, which are underrecognized and lack consistent nomenclature. We report the largest series of these primitive polyphenotypic DICER1-related neoplasms arising in the gynecologic tract or peritoneum. The 15 patients were aged 10 to 77 (median: 37) years. Tumors involved the endometrium (n=6), cervix (n=3), endometrium and cervix (n=2), ovary (n=2), or pelvic peritoneum (n=2). Twelve were organ-confined and 3 were at an advanced stage at presentation. All contained sarcomatous elements composed of sheets and aggregates of ovoid/spindled cells with rhabdomyoblastic differentiation in 13. Periglandular condensation (n=13), cambium layer (n=12), fetal-type cartilage (n=11), and anaplasia (n=4) were also identified. Primitive glands were present in 14 (abundant in 8) and comprised single or clustered simple (n=14) or variably dilated/elongated glands resembling those seen in adenosarcoma (n=9). The epithelium had a primitive appearance with frequent subnuclear vacuoles (n=14), intracytoplasmic granules (n=7), or minimal amphophilic cytoplasm (n=3), and frequently stained for SALL4, glypican-3, and AFP. Neuroectodermal elements were seen in 12, composed of compact small round blue cells punctuated by neuroepithelial tubules. DICER1 alterations were present in all tumors. DICER1-related primitive polyphenotypic neoplasms present significant diagnostic difficulty due to their varied appearances and lack of consistent nomenclature in the rare reports to date. Recognition of the morphologic features of these unusual neoplasms should prompt confirmatory DICER1 testing and consideration of germline evaluation, particularly in young patients.

Due to its heterogeneous morphology and its rarity, anaplastic lymphoma kinase gene-rearranged renal cell carcinoma (ALK RCC) is a diagnostically challenging entity, often leading to labelling these tumors as RCC, not otherwise classified. This may have clinical and managerial implications, given that patients with ALK oncogene rearrangement may benefit from ALK-inhibitors. Therefore, we attempted to elucidate the clinicopathologic and immunophenotypical characteristics of ALK RCC in a large international cohort. Sixteen multi-institutional tumors were included in the study. Clinical, macroscopic, microscopic, immunohistochemical (IHC), molecular (DNA and RNA sequencing, FISH) and follow-up data were evaluated. There were 9 male and 7 female patients with tumor size ranging from 2 to 12.2 cm (mean=7.1 cm). All tumors had solid, tan-white with focal cystic changes and gelatinous appearance. Cystic changes and necrosis were seen in 7 and 6 tumors, respectively. Microscopically, a heterogeneous growth pattern was observed including solid (12), tubular (7), papillary (5), tubulocystic (2), pleomorphic epithelioid cells (6), sarcomatoid (2), rhabdoid (4), and intranuclear pseudoinclusions. All tumors were ALK-positive, coexpressing PAX8, KRT7, SDH, FH, and variably CD10, Vimentin, and AMACR. Molecular analysis through next-generation sequencing (NGS) was performed on 14/16 tumors. EML4::ALK (n=5) was the most common gene fusion observed; others included TPM1::ALK(n=4), TPM3::ALK(n=2), SLIT1::ALK(n=2)and VCL::ALK(n=1). Despite focal TFE3 immunoreactivity in 4/13 cases, the absence of TFE3 gene rearrangement by molecular analysis excludes TFE3- rearranged RCC as a differential diagnosis. Our study further expands the clinicopathologic, morphologic, and molecular genetic spectrum of ALK-RCC. ALK-RCC can be morphologically heterogeneous and mimic other well-established entities posing a misdiagnosis if appropriate IHC and/or molecular studies are not performed. Accurate diagnosis is of clinical significance as patients with this neoplasm may potentially benefit from ALK-inhibitors, particularly in a metastatic setting. As TFE3 immunoreactivity is not uncommon in ALK-RCC, documentation of ALK gene rearrangement is critical, either by surrogate IHC staining or cytogenetic/molecular analysis is essential.

Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX, KMT2C, ARID1A, and ARID1B. Other frequently mutated genes included ATM, NF1, and ERBB2. Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.

IgA vasculitis (IgAV) and IgA nephropathy (IgAN) are closely related disorders that usually present in childhood. Pulmonary involvement is rare and histopathologic features thereof in adults are poorly understood. Institutional archives were searched for adults with IgAV or IgAN and diffuse parenchymal lung disease. Ten patients (6 men, median age 59 years) with lung tissue sampling were enrolled. Clinical history and pathology slides were reviewed. All patients were diagnosed with IgAV or IgAN before or concurrently with lung disease. Symptoms were nonspecific but hemoptysis was common. Radiologically, bilateral ground-glass opacities, consolidation, and reticulonodular densities were typical. Histologically, 6 cases (60%) featured acute or subacute diffuse alveolar hemorrhage (DAH) accompanied by definite (40%) or probable (20%) capillaritis. Two cases (20%) featured resolved DAH only, manifesting as alveolar hemosiderosis without other changes. And 2 cases featured organizing pneumonia without DAH. Five patients had a chronic interstitial pneumonia in the background, including 3 with nonspecific interstitial pneumonia (NSIP) and 2 with unclassifiable fibrosis. Findings were similar in IgAV versus IgAN. Of 4 patients with follow-up information, 2 died during hospitalization, one died 9 weeks later of secondary complications, and one was treated with rituximab and nintedanib and is alive 2 years later. To our knowledge, this is the largest series detailing pulmonary histopathologic findings in adults with IgAV or IgAN. Most cases show acute DAH with capillaritis; less commonly, old DAH, organizing pneumonia, NSIP, or unclassifiable fibrosis may be observed. Some patients do well with treatment but fatal cases also occur.

Radiologic-pathologic correlation is essential for diagnostic accuracy, particularly when dealing with primary bone tumors. This investigation explores the unique radiographic and pathologic features of NFATC2-rearranged bone sarcomas. Inclusion criteria focused on primary bone sarcomas with NFATC2 fusions while excluding soft tissue sarcomas, benign bone cysts, and vascular neoplasms with similar fusions. Our cohort comprised 16 patients (12 males, 4 females) with a mean age of 45.6 years (range: 15 to 77 y). Tumors were located in the femur (n=9), tibia (n=3), humerus (n=2), ulna (n=1), and radius (n=1). Symptoms generally followed a long latency period and several were incidentally discovered for other reasons, with a mean tumor size of 9.7 cm (range: 3.0 to 19.7 cm). Histologic examination revealed typical features of NFATC2-rearranged sarcomas, including uniform epithelioid, round, or spindle cells growing in cords, chains, clusters, and sheets suspended in a richly vascularized fibromyxoid to variably sclerotic stroma. Mitotic activity varied dramatically between and within tumors (from <5 to >50 per 10 HPF). By immunohistochemistry, positive stains included CD99 (12/14), NKX2.2 (7/7), AGGRECAN (3/3), SMA (6/7), CAM5.2 (3/4), SATB2 (8/9), and ERG (5/8) with more limited expression of CK AE1/AE3 (3/12) and NKX3.1 (2/8). All had an NFATC2 gene fusion, with 9 harboring FUS and 7 EWSR1 as 5' partners. Additional genetic analysis beyond the targeted fusion panel (n=7) demonstrated that all cases harbored a range of secondary genomic alterations in addition to the driver NFATC2 fusion. On radiography and CT imaging, all showed lucent lesions with peripheral sclerosis and narrow transition zones. Expansile cortical remodeling (n=8; 50%) varied from minimal to extensive. Despite generally indolent-appearing radiographic features, 87.5% (14/16) demonstrated soft tissue extension, ranging from focal to extensive. Internal septations were present in 62.5% (10/16). MRI, performed on 15 tumors, revealed hypointensity on T1-weighted images and heterogeneously hyperintense on fluid-sensitive sequences. After contrast administration, avid enhancement was seen in all tumors with perilesional edema and enhancement in 26.7% (4/15). In summary, the imaging of NFATC2-rearranged bone sarcomas differs significantly from Ewing sarcoma, suggesting a tumor of longer duration characterized by a lytic nature, areas of peripheral sclerosis, expansile cortical remodeling, and frequent extraosseous extension. However, these features may not correlate with prognosis. This study represents the first systematic radiologic evaluation of NFATC2-rearranged bone sarcomas, highlighting distinctive characteristics that may aid pathologists in their initial diagnostic assessments.

Silicone granulomas can have histologic features that mimic xanthogranulomatous inflammation, particularly in small samples or when the diagnosis is unsuspected. Histochemical stains for microorganisms may be performed to assess for infection in such cases. After observing diffuse Fite staining in a specimen exhibiting histologic features of silicone granuloma, the frequency of Fite staining in a series of confirmed silicone granulomas was assessed. Modified acid-fast (Fite) staining was performed in 20 silicone granuloma cases. In a subset (n=5), Ziehl-Neelsen (Z-N), Grocott's methenamine silver (GMS), and Brown & Brenn (B&B) stains, as well as mycobacterial immunohistochemistry were also performed. All 20 cases (100%) demonstrated Fite staining, ranging from patchy (45%) to diffuse (55%). Finely vacuolated histiocytes exhibited reticular to granular Fite staining, some morphologically resembling bacteria, whereas larger vacuolar spaces showed globular to crescent-like staining at their peripheral edges. Focal Z-N staining in a pattern similar to Fite staining was observed in 4 of the 5 cases examined. GMS, B&B, and mycobacterial IHC were negative. Silicone granulomas consistently show Fite staining. While the reason for this is uncertain, it is postulated that the hydrophobicity of silicone polymers may simulate the hydrophobic barrier of mycolic acids, preventing entry of decolorizer and removal of the primary stain. Recognition of this phenomenon is important to avoid misinterpretation of silicone granulomas as infectious. Fite staining may also serve as a potential diagnostic aid in cases with histologic features of silicone granuloma in which a history of silicone injection or silicone implant use is not established.

Proteus syndrome is a rare mosaic overgrowth disorder caused by somatic activating variants in AKT1 , most commonly the c.49G>A p.(Glu17Lys) variant. It predisposes individuals to asymmetric tissue proliferation and an elevated risk for both benign and malignant neoplasms. Among 64 males with genetically confirmed Proteus syndrome enrolled in a longitudinal natural history study, 12 (19%) underwent surgery for paratesticular masses. The average age at surgery was 9 years, most tumors were unilateral, small (median 1.6 cm), and slow growing, but 50% showed recurrence or metachronous tumor development, occasionally with progression to more atypical histology. Histologically, these tumors demonstrated a broad spectrum of differentiation. Eight reviewed cases included Müllerian-type papillary cystadenomas and low-grade papillary adenocarcinomas, a Brenner tumor, and one case of a papillary adenocarcinoma with spindle cell transformation. The epithelial components were typically arranged in papillary and glandular architectures, with variable degrees of cytologic atypia. Psammomatous calcifications were common. Immunohistochemistry showed consistent expression of PAX8(7/7), WT1(7/7), estrogen receptor (ER)(7/7), and progesterone receptor (PR)(6/7), supporting Müllerian lineage, while negative staining for germ cell and mesothelial markers excluded common paratesticular differential diagnoses. Four of the 7 tumors were positive for SF-1. All 7/7 sequenced tumors harbored the AKT1 c.49G>A variant with no additional oncogenic alterations identified by exome sequencing. This series is the largest series to date documenting the clinicopathologic features of paratesticular tumors, a poorly understood component of the Proteus syndrome phenotype.

Patients undergoing periods of starvation or malnutrition may develop degenerative and/or atrophic changes of various organs. These findings may manifest histologically and may cause confusion when first encountered, raising a differential that includes benign and malignant tumor entities. Herein, we report 16 cases of incidentally identified degenerative changes within abdominal-site fatty tissues that caused diagnostic difficulties. The patients were 11 males and 5 females, aged from 1 day to 82 years (mean: 58 years). The degenerative changes were all incidentally identified within adipose tissue of the abdominal cavity or adjacent to organs contained within the abdominal cavity in procedures done for unrelated reasons such as cancer, infection, or perforation. Cases were identified in the colon (n=6), small intestine (n=4), omentum (n=3), inguinal hernia sac (n=1), peritoneum (n=1), and retroperitoneal soft tissue (n=1). Patients had variable past medical histories with multiple comorbidities. Ten patients presented with some form of malnutrition and/or cachexia. Histologically, the lesions demonstrated lobules of atrophic-appearing fat with small signet-ring-like adipocytes that were sometimes bilobed. The nodules varied in size and were characterized in some cases by a variably myxoid stromal background, often with a prominent delicate capillary network. Immunohistochemistry was performed and was uniformly positive for S100 protein and negative for cytokeratins. The lesions were generally recognized as degenerative, but various differential diagnoses proposed at the time of sign-out included signet-ring cell carcinoma, liposarcoma, and vascular lesions, among others. Nomenclature to describe this phenomenon has been inconsistent in the literature, and thus, we suggest the term "pseudoneoplastic fat atrophy."