American Journal of Surgical Pathology最新文献

Pilomatrical skin tumors harbor mutations in CTNNB1, which encodes for β-catenin, a downstream effector of the Wnt signaling pathway responsible for the differentiation, proliferation, and adhesion of epithelial stem cells. Therefore, downstream molecules, such as CDX2, LEF-1, and SATB2, in the Wnt signaling pathway could be useful diagnostic markers. Here, we sought to investigate the potential of immunohistochemistry (IHC) to differentiate between pilomatricoma and pilomatrical carcinoma, as well as from other cutaneous adnexal tumors. We studied 88 cases of cutaneous tumors (14 pilomatrical carcinomas, 18 pilomatricomas, 13 basal cell carcinomas, 12 squamous cell carcinomas, 12 sebaceous carcinomas, 10 Merkel cell carcinomas, 7 trichoblastomas, and 2 hidradenocarcinomas) using a broad panel of IHC markers: β-catenin, SATB2, CDX2, LEF1, Ber-EP4, and PRAME. Pilomatricoma and pilomatrical carcinoma displayed >75% nuclear staining for β-catenin. CDX2 also strongly stained pilomatrical tumors; however, the staining distribution was limited in pilomatricoma and more widespread in pilomatrical carcinoma. But, overall, it was less than β-catenin. SATB2 and Ber-EP4 expressions were noted only in a subset of both pilomatrical carcinoma and pilomatricoma, whereas LEF-1 showed strong, diffuse nuclear positivity in both pilomatricoma and pilomatrical carcinoma. Among the IHC markers evaluated, none could distinguish between pilomatricoma and pilomatrical carcinoma. However, the combined use of β-catenin with CDX2 markers may assist in not only confirming the pilomatrical nature of the proliferation but also in differentiating benign from malignant cases when there is a significant presence of CDX2 staining. Despite these findings, the diagnosis should continue to primarily depend on a thorough histopathologic examination.

Immune checkpoint inhibitor therapy has demonstrated an overall survival benefit in patients with advanced melanoma. Though the significance of programmed death-ligand 1 (PD-L1) expression on melanoma cells as a predictive biomarker of response remains inconclusive, some reports indicate that a PD-L1 expression of <1% of tumor cells may be associated with better outcomes with dual immunotherapy. Adequate patient selection for combination therapy is critical given the higher frequency of adverse effects compared with monotherapy. Immunohistochemical (IHC) PD-L1 interpretation in tumor cells is challenging when inflammatory cells are present and cutoffs are low. We studied 36 metastatic melanoma biopsies from Immune checkpoint inhibitor-naive patients, previously stained and scored for PD-L1 IHC using the tumor proportion score (TPS). Cases were classified into 3 groups: <1%, 1% to 5%, and >5%. After de-coverslipping, SRY-related HMG-box-10 (SOX10) IHC was performed on PD-L1 IHC slides with a red chromogen, and subsequently scanned and scored by ≥2 dermatopathologists. This assessment determined that 25% of cases (9/36) had a TPS ≥ 1%, in contrast to the single IHC assay (63.8%). The majority of the 1-5% group (11/13, 84.6%) underwent a change of category to <1% TPS. In the >5% group, 60% of cases (6/10) were downgraded to <1% and 1% to 5% (4 and 2 cases, respectively). Our study suggests that PD-L1 IHC evaluation could benefit from dual PD-L1/SOX10 IHC. Dual IHC is expected to decrease the interference caused by PD-L1 expression on inflammatory cells, and digital imaging proves useful for the preservation and analysis of stains. Refining PD-L1 evaluation in metastatic melanoma may improve clinical decisions between single and combination immunotherapy, with potentially profound consequences in response and quality of life.

Extranodal marginal zone lymphomas (eMZL) can occur in any organ and site of the body. Recent research has shown that they differ from organ to organ in terms of their mutational profile. In this study, we investigated a cohort of primary breast marginal zone lymphomas (PBMZL) to get a better insight into their morphologic and molecular profile. A cohort of 15 cases (14 female and 1 male) was characterized by immunohistochemistry (IHC) for 19 markers, fluorescence in situ hybridization (FISH), and high throughput sequencing (HTS) using a lymphoma panel comprising 172 genes. In addition, PCR for the specific detection of Borrelia spp. and metagenomics whole genome sequencing were performed for infectious agent profiling. Follicular colonization was observed in most cases, while lymphoepithelial lesions, though seen in many cases, were not striking. All 15 cases were negative for CD5, CD11c, and CD21 and positive for BCL2 and pan B-cell markers. There were no cases with BCL2 , BCL10 , IRF4 , MALT1 , or MYC translocation; only 1 had a BCL6 rearrangement. HTS highlighted TNFAIP3 (n=4), KMT2D (n=2), and SPEN (n=2) as the most frequently mutated genes. There were no Borrelia spp. , and no other pathogens detected in our cohort. One patient had a clinical history of erythema chronicum migrans affecting the same breast. PBMZL is a mutation-driven disease rather than fusion-driven. It exhibits mutations in genes encoding components affecting the NF-κB pathway, chromatin modifier-encoding genes, and NOTCH pathway-related genes. Its mutational profile shares similarities with ocular adnexal and nodal MZL.

National Comprehensive Cancer Network guidelines state that clinical stage III melanoma patients may undergo ultrasound surveillance of the nodal basin in lieu of complete lymph node dissection (CLND). This has led to an inability to accurately classify patients according to the American Joint Committee on Cancer (AJCC) eighth edition staging system because it uses the total number of positive lymph nodes from the CLND to assign a pathologic N stage. We propose a new model for clinical stage III melanoma patients that does not rely on the total number of positive lymph nodes. Instead, it uses Breslow depth, ulceration status, sentinel lymph node metastasis size, and extracapsular extension to stratify patients into groups 1 to 4. We compared our model's ability to predict melanoma-specific survival (MSS), distant metastasis-free survival (DMFS) and locoregional recurrence, and distant metastasis-free survival (DMFS-LRFS) to the current AJCC system with and without CLND-data using a Cox proportional hazards model and Akaike Information Criteria weights. Although not reaching our predetermined level of statistical significance of 95%, our model was 5 times more likely to better predict MSS compared with the AJCC model with CLND. In addition, our model was significantly better than the AJCC model without CLND in predicting MSS. Our model performed significantly better than the AJCC model in predicting DMFS and DMFS-LRFS regardless of whether data from CLND were included.

Tumor necrosis has been reported to represent an independent prognostic factor in colorectal cancer, but its evaluation methods have not been described in sufficient detail to introduce tumor necrosis evaluation into clinical use. To study the potential of tumor necrosis as a prognostic indicator in colorectal cancer, criteria for 3 methods for its evaluation were defined: the average percentage method (tumor necrosis percentage of the whole tumor), the hotspot method (tumor necrosis percentage in a single hotspot), and the linear method (the diameter of the single largest necrotic focus). Cox regression models were used to calculate cancer-specific mortality hazard ratios (HRs) for tumor necrosis categories in 2 colorectal cancer cohorts with more than 1800 cases. For reproducibility assessment, 30 cases were evaluated by 9 investigators, and Spearman's rank correlation coefficients and Cohen's kappa coefficients were calculated. We found that all 3 methods predicted colorectal cancer-specific survival independent of other prognostic parameters, including disease stage, lymphovascular invasion, and tumor budding. The greatest multivariable HRs were observed for the average percentage method (cohort 1: HR for ≥ 40% vs. <3% 3.03, 95% CI, 1.93-4.78; cohort 2: HR for ≥ 40% vs. < 3% 2.97; 95% CI, 1.63-5.40). All 3 methods had high reproducibility, with the linear method showing the highest mean Spearman's correlation coefficient (0.91) and Cohen's kappa (0.70). In conclusion, detailed criteria for tumor necrosis evaluation were established. All 3 methods showed good reproducibility and predictive ability. The findings pave the way for the use of tumor necrosis as a prognostic factor in colorectal cancer.

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy, representing ~1% of all thyroid tumors. It is characterized by high-grade histologic features without the anaplastic characteristics observed in anaplastic thyroid carcinoma. Although rare in children and young adults, there is emerging evidence of clinical and genetic differences with PDTC in adults. We present a case of a 19-year-old female with a right thyroid lobe nodule classified as an EU-TIRADS 5 lesion. Subsequent FNAC showed a cellular aspirate of solitary cells and scant microfollicles with variable nuclear irregularities, which was designated a Bethesda class IV lesion. Thyroidectomy revealed histopathological features consistent with PDTC, including solid/trabecular growth, increased mitotic activity, central necrosis, and extensive vascular invasion. Molecular analysis identified germline and somatic DICER1 mutations in the absence of other established driver mutations of PDTC. This case report describes the fourth reported patient with a PDTC and germline DICER1 mutation. Our findings contribute to a limited body of literature on pediatric/young adult PDTC cases and highlight the pivotal role of DICER1 mutations. Emerging evidence suggests that pediatric PDTC may exhibit unique clinical and genetic characteristics, prompting further research into its molecular profile.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Risk factors include extensive sun damage, infection with Merkel cell polyomavirus, and an immunocompromised state. PRAME, also known as preferentially expressed antigen in melanoma, is a cancer-testis antigen recently found to be a useful diagnostic tool in the workup of melanocytic neoplasms. However, the expression pattern of PRAME in Merkel cell carcinoma is unknown. In this study, we examine PRAME expression in Merkel cell carcinoma and explore its prognostic implications. The institutional archives at the University of Virginia were used to search for tumors classified as Merkel cell carcinoma from 2004 to 2022. All potential cases were reviewed to confirm the diagnosis, and electronic medical records were searched for clinical and demographic data. Tumors were subsequently immunostained for PRAME and Merkel cell polyomavirus. Cox proportional hazards regression models were used to estimate relative (all-cause) survival of PRAME positivity and MCPyV positivity in our study as well as MCC-specific survival of PRAME positivity. Univariate and multivariable models were created for each outcome related to all-cause survival. A total of 39 cases were included in the study. Twenty-eight percent (11 cases) demonstrated strong PRAME expression, and 27% of cases were positive for Merkel cell polyomavirus. There was no statistically significant correlation between PRAME expression and virus positivity. With respect to PRAME, the adjusted all-cause mortality hazard ratio was 11.4 (95% CI: 1.8, 70.8). The unadjusted MCC-specific hazard ratio was 4.6 (95% CI: 0.8, 27.5). The adjusted hazard ratio pertaining to Merkel cell polyomavirus infection was 0.25 (95% CI: 0.02, 2.96). In this limited cohort, PRAME expression appears to correlate with worse outcomes in Merkel cell carcinoma.

Differences in risk factors (RF) of lymph node metastasis (LNM) and prognosis between submucosal early gastric cardiac (SEGCC) and noncardiac (SEGNCC) carcinomas remain unclear. In this study, we investigated and compared RF of LNM and prognosis in 891 patients with radical gastrectomy for SEGCC (n=217) or SEGNCC (n=674). Compared with SEGNCC, SEGCC displayed significantly higher proportion of elderly patients (70 y or above), the elevated macroscopic type, well/moderately differentiated tubular and low-grade papillary adenocarcinomas, as well as low-grade tumor budding, but lower prevalence of the depressed macroscopic type, poorly differentiated tubular adenocarcinoma, mixed adenocarcinoma, poorly cohesive carcinoma, lymphovascular invasion (LVI), perineural invasion, and high-grade tumor budding. By univariate analysis, significant RF for LNM of the cohort included female sex, poor differentiation, SM2 invasion, LVI, intermediate-grade and high-grade tumor budding, whereas tumor size, histology type, and perineural invasion were the significant RF for LNM in SEGNCC. By multivariate analysis, significant independent RF for LNM included female sex and LVI in SEGCC but were female sex, mixed adenocarcinoma, LVI, and high-grade tumor budding in SEGNCC. The 5-year overall survival was significantly worse in SEGCC than in SEGNCC for patients with LNM, but not for those without. For overall survival, LNM was the only significant independent RF in SEGCC, whereas age 70 years or above and LNM were independent RF in SEGNCC. The results of our study provided the clinicopathologic evidence for individualized clinical management strategies for these 2 groups of patients and suggested different pathogenesis mechanisms between SEGCC and SEGNCC.