American Journal of Surgical Pathology最新文献

Inverted papilloma (IP) is a benign neoplasm of the nasal cavity and paranasal sinuses, known for its variable risk of recurrence and potential for developing carcinoma. Emerging evidence has shown high rates of activating EGFR mutation, and a smaller subset is associated with low-risk human papillomavirus (lrHPV). While certain morphologic features, including an inverted growth pattern, are well-established, the presence of condylomatous features, such as large fungating lesions with thick undulating surface epithelium, hyperkeratosis, cytoplasmic clearing, raisinoid nuclei, and binucleation (koilocytic changes) in low-risk HPV-associated IP suggests that these tumors may be a distinct subtype of sinonasal papilloma (SP) with features similar to low-risk HPV-associated anogenital condylomas. This study presents a series of SP with condylomatous morphology and explores the association with lrHPV, the clinicopathologic features, and the rates of carcinoma development. In total, 17 cases of SP exhibiting condylomatous morphology were retrospectively identified. We performed lrHPV and high-risk HPV (hrHPV) RNA in situ hybridization and p16 immunohistochemistry and gathered detailed clinical and pathologic data along with treatment, disease follow-up, and outcomes. These condylomatous papillomas almost all developed in active smokers, were large, were primarily located in the nasal cavity (47%), and showed frequent transformation to invasive squamous cell carcinoma (29%). This malignant transformation rate is much higher than what has been reported for inverted, exophytic, and oncocytic papillomas. The tumors were almost uniformly associated with transcriptionally-active lrHPV (94%) and were consistently negative for p16 and hrHPV. This study shows that a subgroup of IPs with condylomatous morphology have a predilection for the nasal cavity, strong association with lrHPV, and high rates of carcinoma. These findings support the concept that these tumors are a distinct (fourth) type of SP with a higher risk of malignant transformation.

Osteoblastoma (OB) is a bone-forming tumor typically characterized by FOS rearrangements. When arising in the jawbone, the histologic features overlap with those of cementoblastoma (CB). We report the case of a 20-year-old man with a histologically uncategorized osteo-cementoblastic tumor in the jawbone. The tumor showed sheet-like or pseudopapillary structures with abundant calcifications, resembling psammoma body, cementum, or dot-like calcifications. Osteoid formation was minimal and the calcified materials displayed atypical features for OB, complicating definitive diagnosis. To elucidate the molecular basis of these unique features, we performed whole-genome sequencing and nanopore sequencing-based methylation analysis. These analyses confirmed the characteristic FOS rearrangement commonly observed in OB and revealed a novel fusion gene, FOS::FN1::FOS , which has not been reported previously. In addition, DNA methylation profiling confirmed clustering with OB, and genomic analysis demonstrated an almost flat copy-number profile, consistent with the typical features of OB. We hypothesize that this novel fusion gene, in combination with the unique anatomic site of the jawbone, may have contributed to the distinct histologic features. We propose this tumor as a hitherto undescribed morphologic variant of OB.

Inflammatory breast carcinoma (IBC) is an aggressive form of breast cancer. Prior studies have reported the presence of lobular histology in a small percentage of tumors from patients with IBC. However, the significance of these lobular features in IBC has yet to be fully characterized. We performed a comprehensive retrospective review of patients with IBC with lobular features (IBC-LF) to evaluate their clinicopathologic features. Our IBC program registry included 524 patients over a 20-year interval, 74 (14%) of whom had lobular features. Pathology material was available for review for 28 patients, and these patients were the focus of this study. On the basis of study criteria, 12 were classified as pure invasive lobular carcinoma (ILC) and 16 as invasive carcinoma with ductal and lobular features (IDLC). All were histologic grade 2-3. Receptor profiles included ER+/HER2- in 14/28 (50%), ER-/HER2- in 7/28 (25%), and ER(+/-)/HER2- in 7/28 (25%). In the 12 cases of pure ILC, 11 showed variant morphologic features, including 6 (50%) with pleomorphic apocrine features, 3 (25%) with a solid growth pattern, 1 with signet ring-cell, and 1 with histiocytoid features. All ILC cases showed negative or aberrant staining for E-cadherin, p120, and beta-catenin on immunohistochemical studies. Dermal lymphovascular invasion was seen in 13 (46.4%) cases, while direct dermal invasion was seen in 14 (50%) cases. Our study confirms that IBC may arise from pure ILC, with negative E-cadherin expression, and usually with variant morphology. This is the first study to detail the morphologic and immunophenotypic characteristics of IBC-LF.

The advent of immune checkpoint inhibitors (ICIs), although associated with adverse events, has heralded a new era in cancer therapy. ICI-related pancreatitis is a rare adverse effect of ICIs. The nonspecific clinical manifestations have posed diagnostic challenges, and the detailed histologic features remain largely unknown. This study aims to characterize the clinical and histopathologic features of ICI-related pancreatitis to increase awareness and improve diagnostic accuracy. We retrospectively identified 5 specimens from 4 patients from our database and consultation practice. We reviewed demographic, clinical, serological, and radiologic data and examined each specimen's histologic features. Patients (2 female, 2 male) were all prescribed anti-PD-1 monoclonal antibodies (1 on Nivolumab and 3 on Pembrolizumab) for metastatic melanoma, unresectable colon cancer, metastatic pancreatic adenocarcinoma, and urothelial carcinoma. The onset of ICI-related pancreatitis ranged from 28 to 473 days after ICI initiation. All 4 patients showed elevated amylase and/or lipase. Two patients presented with the chief complaint of abdominal pain. The other 2 initially asymptomatic patients showed hypointense mass lesions on imaging resembling malignant processes. The most common histologic findings were acinar-centric mixed inflammatory infiltrate (5/5 specimens) followed by atrophy (4/5 specimens) and fibrosis (4/5 specimens). Storiform fibrosis was identified in one patient who was biopsied twice. Other findings included edema (3/5 specimens) and acinar-to-ductal metaplasia (3/5 specimens). Granulocytic epithelial lesion was identified in 2 specimens. No obliterative phlebitis or granulomas were identified. By immunohistochemistry, the inflammatory infiltrates were predominately composed of CD3+ T cells with a variable CD4 to CD8 ratio. Neutrophils and eosinophils were readily identifiable with rare plasma cells. Management included stopping the ICI and starting steroids. Whereas 1 patient lacked follow-up information, 2 patients showed marked improvement. One patient succumbed to severe ICI-related myocarditis. In conclusion, ICI-related pancreatitis shows overlapping clinical-radiologic features with malignancy and autoimmune pancreatitis with the potential for chronic injury. Although ICI-related pancreatitis lacks the classic histologic features of autoimmune pancreatitis, there is considerable histologic overlap, particularly on small biopsies. Therefore, correlation with the patient's medications is critical when evaluating pancreatic specimens with nonspecific chronic pancreatitis histologic patterns.

Endometrial carcinomas (EC) show variable HER2 protein expression or gene amplification and may be eligible for HER2-directed therapy (trastuzumab or antibody-drug conjugates (ADCs) such as trastuzumab-deruxtecan). HER2 testing is currently recommended in advanced-stage/recurrent serous carcinomas and carcinosarcomas. However, no universally adopted reporting guidelines exist, and institutional practices vary. We aimed to analyze our experience with HER2 testing and compare gynecologic (GyC), gastric (GaC), and breast (BrC) criteria. We identified ECs with available HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) results where applicable. HER2 IHC was reassessed using GyC, GaC, and BrC. The overall HER2-positivity rates were 31% by GyC and BrC, and 35.7% by GaC. The scoring systems significantly differed, with 69.8% concordance between GaC and GyC ( P <0.001) and 99.2% concordance between BrC and GyC. Our results emphasize the importance of using the appropriate HER2 scoring criteria depending on the type of intended HER2-directed therapy as well as comprehensive yet perspicuous reporting of HER2 status to ensure optimal clinical outcomes in EC patients.

Verruciform/acanthotic vulvar intraepithelial neoplasia (vaVIN) is a rare, recently defined HPV-independent, TP53- wild type lesion of the vulva that predisposes to vulvar squamous cell carcinoma (VSCC). VaVIN encompasses a variety of histomorphologic subtypes, including verruciform lichen simplex chronicus (vLSC), differentiated exophytic vulvar intraepithelial lesion (DEVIL), and vulvar acanthosis with altered differentiation (VAAD). Given the rarity of the lesion, subtle histopathologic features, and overlap with other preneoplastic entities and benign dermatoses, vaVIN is a diagnostic challenge. Therefore, immunohistochemistry (IHC) may be a helpful diagnostic adjunct in differentiating vaVIN from mimickers. Cytokeratin 17 (CK17) immunohistochemistry has been previously described as a useful diagnostic tool in diagnosing differentiated vulvar intraepithelial neoplasia (dVIN) and VSCC and has only recently been applied to vaVIN. In this study, we identified a total of ten cases of vaVIN, including four classified as vLSC, five classified as DEVIL, and one classified as VAAD. CK17 was expressed by all vaVIN lesions, with superficial to suprabasal expression in the vLSC subtype and uniform suprabasal expression in the DEVIL and VAAD subtypes. The pattern of CK17 expression may be helpful in differentiating vaVIN subtypes, notably demonstrating only superficial expression in some cases of the least aggressive phenotype, vLSC. Suprabasal expression corresponds to the more aggressive phenotypes of DEVIL and VAAD. However, additional confirmatory studies in a larger cohort are needed to validate these findings.

Spontaneous regression or a long-term lack of obvious progression is often observed in patients with low-tumor-burden (LTB) follicular lymphoma (FL). However, conventional prognostic risk models are unable to precisely identify the patients who will not require any antilymphoma treatment for a long term, especially at diagnosis. In this study, we identified genes whose expression levels were associated with the clinical outcome of LTB FL and verified their prognostic value using immunohistochemistry. Because the tumor microenvironment may influence FL pathogenesis, we used digital expression profiling to quantify the expression of 730 immune-related genes extracted from tumor tissue specimens collected from 55 untreated patients with LTB FL. Five genes were identified as potential transcriptomic predictive markers. Among these, FCGR2B , an inhibitory FC gamma receptor, was immunohistochemically stainable and identified as a reliable immunohistochemical prognostic marker mainly expressed in tumor cells but not in the surrounding reactive cells. Our findings could help identify patients with LTB FL who do not require any antilymphoma treatment for the long term.

Xanthogranuloma is the most common category of histiocytic neoplasia, with a range of clinical behaviors from solitary cutaneous lesions to multiple cutaneous lesions and less frequent cases with evolution to disseminated disease. Solitary lesions make up 78% to 81% of total cases. We encountered 2 consecutive index patients with solitary cutaneous xanthogranuloma with NTRK overexpression by immunostaining and confirmed the presence of an NTRK1 fusion with both RNA and DNA sequencing. We screened 55 additional patients by pan-TRK immunostain, and found that 26 of 48 (54%) with solitary xanthogranulomas had TRK overexpression, whereas 0 of 7 (0%) multifocal or disseminated xanthogranulomas had TRK overexpression. We sequenced a subset of 23 patients with solitary xanthogranuloma. In all 16 patients with a positive pan-TRK immunostain, we confirmed the presence of an NTRK1 fusion using RNA and DNA sequencing. In all 7 patients that were negative by immunostain we identified no NTRK fusion by sequencing. All patients with a fusion identified by sequencing had overexpression of the NTRK1 RNA transcript relative to wild-type tumors with a mean 58-fold increase over wild-type tumors ( P =8.77e-15). Further, all cases with fusions had a loss of the extracellular portion of NTRK1 , and fusion partners were limited to TPM3, PRDX1, IRF2BP2, LRRIP1 , and SQSTM1 . DNA sequencing identified additional recurrent loss of function mutations in DNA methylation genes DNMT3A, KDM5D , and SETD2, as well as the MTOR-PI3K pathway gene FLCN . Recurrent copy number gains were detected in MTOR-PI3K pathway genes PIK3CG , IL10Ra , as well as transcriptional regulator PAX8 . The frequency of NTRK1 fusions appears markedly higher in solitary compared with multifocal and disseminated xanthogranuloma (54% vs. 0%). The reduced proportion of NTRK1 fusions in disseminated cases relative to solitary cases suggests that NTRK1 fusions are less efficient than MAP kinase pathway point mutations at driving tumor evolution towards disseminated disease. As NTRK1 fusions are uncommon in other histiocytoses, pan-TRK immunostain may have utility to confirm the diagnosis of xanthogranuloma in a histiocytic lineage tumor and to screen for low-risk xanthogranuloma.

Pediatric Spitz melanoma (SM) with bonafide metastatic disease is rare. In this study, we assembled the largest cohort to date of pediatric SM with a verified Spitz-associated genomic driver and clinical follow-up demonstrating bonafide metastasis. We compared the clinical, morphologic, and molecular features of these SMs to a control cohort of 57 pediatric atypical Spitz tumors (ASTs). Pediatric SM patients were significantly older than AST patients (12 vs 8 years of age). While not statistically significant, SMs were more likely to be heavily pigmented (5/7 SMs vs 11/57 ASTs), to have a sheet-like growth pattern (3/7 SMs vs 8/57 ASTs), and have severe nuclear atypia (6/7 SMs vs 20/57 ASTs). SMs had significantly greater mitotic activity (avg of 4.3/mm 2 in SMs and 2.7/mm 2 in ASTs, P =0.008) and more frequent larger cell size ( P =0.006). However, none of these features were specific and could also be seen in ASTs. The presence of homozygous deletions of 9p21 in conjunction with TERT promoter hot spot mutations or PTEN deletions (n=2), as well as MYC overexpression or amplification (n=2) were only seen in the SMs and none of the ASTs. These findings were mutually exclusive in the SM group and mutually exclusive with the presence of complex chromosomal copy number aberrations, which were seen in the remaining 3 pediatric SMs. This study demonstrates that there are multiple pathways to malignancy for pediatric SMs and none of our commonly used biomarkers have a particularly high sensitivity. Hence, the optimal distinction of pediatric SM from ASTs will continue to require the integration of clinical, histologic, and molecular data.