American Journal of Surgical Pathology最新文献

As novel human epidermal growth factor receptor-2 (HER2) and drug conjugates have proven to be effective treatments for both HER2-positive breast cancer (BC) and HER2-low BC, the need to develop more accurate methods to quantify HER2 status has increased. We compared the correlation between the HER2 mRNA score (HS), obtained using the Oncotype DX (ODX) test, and HER2 immunohistochemistry (IHC) to verify the accuracy of HER2 quantification and its correlation with clinicopathologic characteristics. We retrospectively collected ODX test data from 1524 estrogen-receptor positive, HER2-negative patients with BC. No significant differences in clinicopathologic characteristics, including ODX Recurrence Score (RS), were observed between HER2-0 and HER2-low BC. The median HS value of the HER2-low subgroup was significantly higher than that of the HER2-0 subgroup ( P <0.001) and increased significantly between the 4 subgroups classified by HER2 IHC ( P <0.001). The receiver operating characteristic curve showed acceptable utility in distinguishing HER2-0 from HER2-low (area under the curve=0.76) and HER2-null and HER2-ultralow subgroups (area under the curve=0.81), but the overlap between subgroups was also prominent. After defining 8.9 as a suboptimal cutoff mRNA score, multivariate analysis revealed that low Ki-67 (<20%) and RS (≤25) were statistically associated with higher HS (>8.9), whereas progesterone receptor negativity, high Ki-67, high nuclear grade, lower HS, and older age (>50 y) were statistically associated with high RS. Our study revealed that HS is significantly associated with HER2 IHC results and clinicopathologic parameters other than HER2 IHC.

Pilomatrix-like high-grade endometrial carcinoma (PiMHEC) is a rare and aggressive variant of endometrial carcinoma often misdiagnosed due to overlapping features with other high-grade malignancies. This study characterizes its clinicopathologic, immunophenotypic, and molecular features to establish key diagnostic criteria and propose a standardized terminology. Ten tumors were analyzed using histopathologic examination, immunohistochemistry, and next-generation sequencing. All but 1 tumor exhibited both low-grade endometrioid and high-grade basaloid components, the latter characterized by either geographic or comedo-type necrosis and shadow cells. Although shadow cells are a hallmark feature, they may be focal or absent, necessitating careful evaluation. High-grade areas consistently showed ER and PR negativity with diffuse nuclear β-catenin staining, correlating with CTNNB1 exon 3 mutations in all tumors. Identical CTNNB1 mutations in spatially distinct tumor components suggest a clonal progression from a low-grade precursor. Additional mutations in ARID1A, PTEN, and PIK3CA were identified. Clinically, PiMHEC exhibited aggressive behavior, with 7 patients experiencing recurrence and 1 succumbing to the disease within 9 months. Metastatic sites included the lungs, liver, lymph nodes, and abdominal wall. PD-L1 expression in 4 tumors suggests potential responsiveness to immune checkpoint inhibitors, whereas low-level HER2 expression (1+ to 2+) in 5 tumors raises the possibility of HER2-targeted therapies. Folate receptor alpha was not expressed in any tumor. In conclusion, PiMHEC is a distinct and highly aggressive endometrial carcinoma with unique histopathologic and molecular features that differentiate it from high-grade endometrioid and other high-grade endometrial cancers including squamous cell carcinoma in rare situations. Its key diagnostic features include high-grade basaloid tumor cells associated with shadow cells, tumor necrosis, and diffuse nuclear β-catenin staining. To improve diagnostic accuracy and reduce ambiguity, we propose adopting "pilomatrix-like high-grade endometrial carcinoma" as a standardized term.

Gynecologic yolk sac tumors (YSTs) are more commonly encountered in children and young women as pure or mixed germ cell tumors and are rarely observed in older women. YSTs in older women are sometimes accompanied by a Müllerian-type carcinoma component, indicating a likely somatic rather than germ-cell origin. Studies of YSTs of germ cell and somatic types in this age group are limited. Analysis of additional pure and mixed tumors with YST differentiation could elucidate differences between these tumor subtypes and the relationship between components in mixed tumors. Clinicopathologic features of 32 malignant neoplasms with YST differentiation in women aged 40+ were analyzed. There were 11 pure YSTs, 7 mixed germ cell tumors, and 14 YSTs with a malignant non-germ cell tumor component (somatically derived yolk sac tumor [SDYST]). Targeted next-generation sequencing (NGS) was performed in 4/11 pure YSTs, 0/7 mixed germ cell tumors, and 4/14 SDYSTs. For the pure YSTs, alterations in DICER1 (1/4), PIK3R1 and PTPRT (1/4), PMS1 (1/4), and TP53 (2/4) were identified. One other pure YST had alterations in PTEN, ARID1A, ARID1B, FGFR2, and CTNNB1 (alterations common in endometrioid carcinoma). SDYSTs demonstrated shared alterations between both components including TP53, KRAS, FBXW7, and KMT2C, suggesting a common origin. The findings in the pure YSTs in older women suggest that for some, the origin could be germ cell as they harbor similar alterations as those described in pure YSTs in young women, whereas in other "pure" YSTs, the molecular profile aligns with previously described SDYSTs, which suggests a SDYST with an unsampled Müllerian carcinoma component rather than a germ cell origin. In SDYSTs, shared alterations are consistent with prior studies and suggest a somatic rather than germ-cell origin.

Diagnosis and classification of oral epithelial dysplasia (OED) is critical to identifying and prognosticating patients at risk of squamous cell carcinoma (SCC). However, conventional 3-tiered and 2-tiered grading systems suffer from poor inter-pathologist agreement, and SCC may arise from all grades of OED. This study evaluated pathologist agreement in OED classification as p53 wildtype, p53 abnormal, and HPV-associated based on recent evidence demonstrating the utility of p53/p16 immunohistochemistry (IHC) in this setting and increased risk of p53 abnormal OED progression to SCC, regardless of histologic grade. Fifty digital biopsy specimens were evaluated for diagnosis by 18 subspecialty-trained pathologists, with OED graded utilizing 3-tiered, 2-tiered, and p53 wildtype/p53 abnormal/HPV-associated schemata. Cases were reviewed first without and subsequently with p53/p16 IHC. The cohort consisted of 8 cases of p53 wildtype, 24 cases of p53 abnormal, and 18 cases of HPV-associated OED. Inter-pathologist agreement in OED grading according to 3-tiered (κ=0.32) and 2-tiered (κ=0.39) systems by H&E was poor, but fair-to-good (κ=0.59) in classification as p53 wildtype/p53 abnormal/HPV-associated by H&E and IHC. Classification of OED as p53 wildtype, p53 abnormal, or HPV-associated using p53/p16 IHC outperformed conventional grading in this cohort enriched for p53 abnormal OED, which required correct interpretation of p53 IHC, historically deemed challenging. Routine use of IHC also identifies a wider histologic spectrum of HPV-associated OED than is currently appreciated. More work is needed to determine the efficacy of this classification system in predicting patient outcomes and in guiding management decisions in real-world cohorts.

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.

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.

"Mixed endometrioid adenocarcinoma and adenosarcoma" is a recently described malignancy of the uterus and ovary characterized by discrete components of Mullerian adenosarcoma and typically low-grade endometrioid adenocarcinoma. Its molecular biology, natural history, and proper classification remain uncertain. We analyzed clinicopathologic data and performed comparative molecular analysis on the adenocarcinomatous and adenosarcomatous components of 14 tumors using a 168-gene next-generation sequencing panel (n=11) and the MSK-IMPACT assay (n=3). Thirteen tumors were stage I, and 1 stage II. The epithelial component was endometrioid carcinoma in 12 (86%), endometrioid intraepithelial neoplasia in 1 (7%), and mesonephric-like adenocarcinoma in 1. The adenosarcomatous component showed sarcomatous overgrowth in 8 (57%), high-grade atypia in 4 (29%), heterologous differentiation in 10 (71%), and lymphovascular invasion in 3 (21%). The adenocarcinomatous and adenosarcomatous components shared molecular alterations in all cases, including mutations in ARID1A (10, 71%), KRAS (8, 57%), DICER1 (7, 50%), PIK3CA (7, 50%), PTEN (6, 43%), and PIK3R1 (4, 29%). Twelve tumors were of no specific molecular profile and 2 were microsatellite instability-high. Four (31%) patients recurred, and 3 (23%) died of disease 7, 8, and 18 months after hysterectomy. Prognosis correlated with high-risk morphologic features in the adenosarcomatous component, including sarcomatous overgrowth, extensive rhabdomyosarcomatous differentiation, vascular invasion, and high-grade nuclear atypia. "Mixed endometrioid adenocarcinoma and adenosarcoma" is a clonal biphasic malignant neoplasm of uncertain histogenesis, with a high frequency of DICER1 mutations.

Carboxypeptidase Z (CPZ) is a newly identified member of the metallopeptidase family, primarily reported in rats; however, its distribution in normal human tissues and expression characteristics in tumor tissues remain unclear. This study uses high-throughput and mass production technology for tissue microarray (TMA) to perform immunohistochemical staining of CPZ, for the first time delineating its distribution and expression in normal tissues and various tumors throughout the body, to discuss its potential pathologic value. CPZ exhibited varying degrees of cytoplasmic positive expression in the normal hepatocytes, pancreatic islets, and gallbladder epithelium, with no expression observed in other normal tissues. The positive expression rates of CPZ in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), metastatic liver tumors, and normal liver tissue were 90.8% (109/120), 27.7% (13/47), 0% (0/22), and 100% (81/81), respectively. The sensitivity and specificity for diagnosing HCC with any of the 3 markers (CPZ, arginase-1 (Arg-1), and hepatocyte paraffin antigen-1 (Hep Par-1)) positive were 96.7% (116/120) and 65.2% (45/69), respectively. The sensitivity and specificity for diagnosing HCC with all 3 markers positive were 70.8% (85/120) and 100% (69/69), respectively. The sensitivity and specificity for diagnosing HCC with both CPZ and Arg-1 positive were 79.2% (95/120) and 95.7% (66/69), respectively. The sensitivity and specificity for diagnosing HCC with both CPZ and Hep Par-1 positive were 76.7% (92/120) and 97.1% (67/69), respectively. The sensitivity and specificity for diagnosing HCC with both Arg-1 and Hep Par-1 positive were 72.5% (87/120) and 98.6% (68/69), respectively. The ROC curve indicated that the combined detection of CPZ, Arg-1, and Hep Par-1 had the best diagnostic value for HCC (AUC=0.939, P<0.001). However, for individual detection, CPZ had the highest AUC value among the 3 markers (AUC=0.908, P<0.001). CPZ was not observed to be positive in the majority of 897 cases of solid tumors. Utilizing the TMA repository, we propose for the first time that CPZ may serve as a useful adjunctive tool for the diagnosis or differential diagnosis of HCC in routine surgical pathology practice. CPZ shows a trend of superiority over Arg-1 and Hep Par-1, particularly in poorly differentiated HCC.

Primary cutaneous neoplasms that lack definitive histologic and immunophenotypic evidence of differentiation are a heterogeneous group of tumors with diverse prognoses and management options. These include undifferentiated and dedifferentiated melanoma (UM/DM), atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and sarcomatoid squamous cell carcinoma. Diagnosis requires careful correlation between the clinicopathologic and molecular features, and the finding of a MAPK pathway variant commonly associated with melanoma may support the diagnosis of melanoma over other tumors in this group. To examine the frequency of typical melanoma-associated MAPK pathway-related variants (BRAF, NRAS, KIT, GNAQ, GNA11) among a cohort of primary cutaneous sarcomatoid neoplasms, we conducted a retrospective analysis of 37 cases of immunohistologically unclassifiable primary cutaneous neoplasms, submitted for targeted NGS analysis. All cases lacked a history of a prior relevant tumor, were negative for melanocytic markers (S100, SOX10, HMB45, and Melan-A), or showed <5% staining with 1 or 2 of these markers. Other lineage markers were negative. We identified typical melanoma driver variants in 7 cases (7/37, 19%), including NRAS (5/37, 14%), KIT (1/37, 3%), and GNAQ (1/37, 3%). There were no significant differences in age, sex, tumor site, or mitotic rate between patients with and without a melanoma driver variant. Melanoma cases were thicker (16.3 vs. 9.25 mm, P=0.041) and more likely to show epithelioid cell phenotype (P=0.008). In our cohort, nearly 20% of patients with immunohistologically unclassifiable cutaneous tumors could be reclassified as having primary UM/DM after molecular testing, thereby opening alternative management pathways.

The cholangioblastic variant of intrahepatic cholangiocarcinoma is a distinctive neoplasm that typically affects young women without underlying liver disease. Morphologically, it demonstrates solid, trabecular, and tubulocystic architecture, biphasic small cell-large cell cytology, and immunoreactivity for inhibin, neuroendocrine markers, and biliary but not hepatocellular markers. In 2021, our group identified a characteristic NIPBL::NACC1 gene fusion in cholangioblastic cholangiocarcinoma, and since then ~20 genetically confirmed cases have been reported in the literature. We report 2 additional cases, both of which caused diagnostic challenges. The first was previously published as a "biliary adenofibroma with malignant features" which we now show recurred as a high-grade adenocarcinoma. Re-review of the original lesion demonstrated the morphologic and immunohistochemical features of highly cystic cholangioblastic cholangiocarcinoma, whereas the high-grade recurrence lacked many of these features. In addition to the characteristic NIPBL::NACC1 gene fusion, the recurrence demonstrated loss of the RB1 and PTEN genes which were found in the highly cystic, bland areas of the original tumor, suggesting that the recurrence was derived from this bland component. The second case was originally misclassified as metastatic well-differentiated neuroendocrine neoplasm and only focally demonstrated the characteristic biphasic small cell-large cell cytology. In addition, a review of 7 cholangioblastic cholangiocarcinomas in our files demonstrates that loss of chromosome 13q14.2 (where the RB1 gene resides) and loss of chromosome 6q15-q16.3 are recurrent secondary changes in these neoplasms. Expression profiling demonstrated alterations in the transforming growth factor receptor beta superfamily, and overexpression of MYC which was validated by immunohistochemistry. Our findings expand the morphologic and genetic spectrum of this neoplasm and provide insight into secondary genetic changes associated with progression.