American Journal of Surgical Pathology最新文献

E-cadherin (E-cad) immunohistochemistry is commonly used to distinguish lobular carcinoma in situ (LCIS) from ductal carcinoma in situ in histologically uncertain or ambiguous cases. Although most LCIS cases show an absence of E-cad expression on the neoplastic cell membranes, some show aberrant E-cad expression which can lead to diagnostic confusion. Awareness and understanding of the frequency, patterns, and distribution of aberrant E-cad staining in LCIS is crucial to achieving a correct diagnosis. We studied 55 LCIS cases diagnosed on core needle biopsy, classified each case by WHO subtype (classic, pleomorphic, or florid), and evaluated the frequency and patterns of aberrant E-cad expression using 3 different E-cad antibodies targeting the N-terminal (N), extracellular (EC), and C-terminal domains (C). Aberrant E-cad expression in one or more of the E-cad domains was identified in 17 cases (31%) and was significantly more frequent among LCIS variants (10/19, 56%) than among classic cases (7/36, 19.4%) (P=0.02). Among these 17 cases, aberrant E-cad expression was seen for all 3 domains in 10 cases, for EC+C in 4, for EC+N in 2, and for N only in 1. These results indicate that about one-third of cases of LCIS can show aberrant E-cad expression, that this is more common in variants than classic types of LCIS, and that this may be seen in different E-cad domains, most often in combination. These different patterns of aberrant E-cad expression may reflect different mechanisms of E-cad alterations in LCIS, the underlying nature of which merits further studies.

According to histopathology and molecular genetics, there are 5 major subtypes of ovarian carcinomas: high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3% to 4%), and low-grade serous (<5%) carcinomas. These tumors, which constitute over 95% of cases, represent distinct diseases with different prognoses and therapy. This review outlines contemporary advances in molecular pathology, which have expanded our knowledge of the biology of epithelial ovarian cancer and are also important to patient management. We also comment on some controversial points of the FIGO staging classification that we proposed in 2014.

The mechanism of tumor budding (TB) in gastric adenocarcinoma (GAC) and its relationship with biological indicators and prognostic significance, remains unclear. In this study, we conducted a comprehensive analysis using whole-slide imaging to evaluate TB in 75 cases of GAC. Our findings revealed the risk factors associated with TB in GAC and their impact on patient prognosis. The results indicate that the majority of cases exhibited a TB grade exceeding 10 (n=41), followed by 6-10 (n=15). Histologic grade (R=0.26, P=0.06), pT stage (R=0.56, P=0.00), neural invasion (R=0.29, P=0.01), marginal zone growth pattern (R=0.25, P=0.02), and basal zone growth pattern (R=0.38, P=0.001) are associated with TB in GAC. Logistic regression analysis revealed that the infiltrative growth pattern in both the marginal zone (odds ratio=5.90, 95% CI: 1.04-33.44, P=0.05) and basal zone (odds ratio=12.80, 95% CI: 2.03-80.68, P=0.01) were identified as risk factors for TB in GAC. Univariate analysis demonstrated a negative correlation between TB and TB grade with overall survival and progression-free survival in GAC patients. Furthermore, the multivariate COX analysis revealed that TB and TB grade, along with American Joint Committee on Cancer stage, lymph node metastasis, and pT stage, independently influenced the prognosis of GAC patients. In conclusion, a comprehensive evaluation of TB could serve as a significant histologic marker for risk stratification in GAC.

Although sialoblastoma (SBL) is defined as a low-grade malignant salivary gland anlage neoplasm in the 2022 World Health Organization (WHO) Classification of Head and Neck Tumors, its histology, genetics, and behavior remain controversial due to the rarity of the tumor. Here, we performed the first comprehensive clinical, histologic, and molecular analyses of 8 SBLs to better understand their pathogenesis and prognosis. This cohort consisted of 5 boys and 3 girls, with ages ranging from birth to 9 years at diagnosis. Tumors occurred in the parotid (4), cheek (3), and submandibular glands (1). Histologically, 5 tumors primarily presented as a solid pattern consisting of primitive basaloid epithelial cells, often with necrosis. Three tumors exhibited a non-solid pattern, with 1 tumor mainly showing epithelial-myoepithelial carcinoma (EMC)-like histology, whereas the other 2 tumors exhibited basal cell adenoma (BCA)-like histology. All 5 solid SBLs harbored FGFR2 mutations, and 1 also harbored mutations in PALB2, AR, and MAP2K1. In contrast, non-solid pattern tumors were characterized by HRAS mutations or significant β-catenin nuclear positivity. All 5 solid tumors recurred, 3 of them developed distant metastases, and 2 died 40 and 44 months after diagnosis. Three non-solid tumors showed no evidence of disease recurrence at 49, 144, and 132 months, suggesting a relatively favorable prognosis. Overall, SBLs can be stratified into solid and non-solid patterns, with solid pattern tumors usually having FGFR2 mutations, increasing the risk of recurrence and metastasis. This stratification underscores the importance of genetic and morphologic profiling for predicting the prognosis of SBLs.

Low-grade gliomas and reactive piloid gliosis can present with overlapping features on conventional histology. Given the large implications for patient treatment, there is a need for effective methods to discriminate these morphologically similar but clinically distinct entities. Using routinely available stains, we hypothesize that a limited panel including SOX10, p16, and cyclin D1 may be useful in differentiating mitogen-activated protein (MAP) kinase-activated low-grade gliomas from piloid gliosis. Reviewers blinded to clinical and pathologic data reviewed and quantified immunohistochemical expression patterns across 20 cases of piloid gliosis and 37 cases of MAP kinase-activated low-grade gliomas, including pilocytic astrocytoma and ganglioglioma. The majority of MAP kinase-activated low-grade glioma cases demonstrated extensive immunoreactivity for at least 2 of the 3 immunohistochemical markers, whereas none of the gliosis cases demonstrated significant immunoreactivity for more than one individual immunohistochemical marker. SOX10 and p16 demonstrated the highest individual sensitivity whereas cyclin D1 demonstrated the highest individual specificity to discriminate neoplastic from nonneoplastic cases in this cohort. A composite panel score based on significant immunoreactivity of at least 2 of the 3 markers provided specificity and a positive predictive value of 100% in differentiating MAP kinase-activated low-grade glioma from gliosis, as 0/20 (0%) of gliosis cases were scored positive compared with 24/37 (65%) of MAP kinase-activated low-grade glioma cases. We conclude that while the immunoreactivity of these markers may be suggestive of a low-grade glioma diagnosis, SOX10, p16, and cyclin D1 should be applied in combination to maximize diagnostic value.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive malignancy that frequently presents with extranodal involvement. Cutaneous tropism is clinically and histopathologically variable, which may pose a diagnostic challenge. We conducted a retrospective analysis of 40 samples of 20 cases of cutaneous AITL, focusing on the clinicopathologic and molecular correlations between skin and lymph node (LN) samples. In all cases, cutaneous involvement was concurrent with or followed the diagnosis of nodal AITL, with no cases preceding systemic involvement. Clinically, cutaneous AITL presented in 2 main forms: an evanescent rash and persistent lesions, with histopathology revealing diverse infiltration patterns, including perivascular, nodular, granulomatous, panniculitic, vasculitis, and epidermotropic. Clinical presentation and histologic patterns tend to correlate. Histopathologically, plasma cells were present in 15/22 skin samples, 5 of them being kappa-light restricted but polytypic in corresponding LNs. Epstein-Barr virus+ B cells were present in 10 cutaneous lesions and were already present in corresponding LNs. Molecular studies found correlations in all but one case between LN and skin, particularly in the presence of RHOA and TET2 mutations, which were identified in 8 of 12 cases. Molecular analysis was also informative in 4 cases with low levels of infiltration. The study also highlighted unique cases with distinct clinical and histopathologic patterns coexisting in the same patient over time. One case exhibited simultaneous granulomatous and epidermotropic patterns in different skin lesions. Four cases of cutaneous B-cell lymphomas associated with AITL were identified. Our study underscores the importance of integrating clinical, histopathologic, and molecular data to accurately diagnose cutaneous AITL.

Determining whether an ipsilateral breast carcinoma recurrence is a true recurrence or a new primary remains challenging based solely on clinicopathologic features. Algorithms based on these features have estimated that up to 68% of recurrences might be new primaries. However, few studies have analyzed the clonal relationship between primary and secondary carcinomas to establish the true nature of recurrences. This study analyzed 70 breast carcinomas from 33 patients using immunohistochemistry, FISH, and massive parallel sequencing. We compared 35 primary carcinomas with the associated recurrences, identifying 24 (68.6%) as true recurrences, 7 (20%) as new primaries, and 4 (11%) as undetermined. Twenty-eight primary carcinomas were invasive carcinomas (22 of no special type, 5 invasive lobular, and 1 invasive micropapillary carcinoma), and 7 were in situ (6 ductal and 1 lobular). Time to recurrence was longer for new primaries (median 12.8 y) than for true recurrences (median 6.8 y). Among the new primary cases, 6 of 7 (85%) patients had undergone mastectomy as their initial treatment. Clinicopathologic classifications of invasive carcinomas overestimated the number of new primaries (41.6% to 68.6%), partially due to phenotype conversion in 14% of true recurrences. Although 41.7% of recurrences showed private mutations or amplifications relevant to tumor progression, such as PIK3CA, PIK3R1, MAP3K1, AKT1, GATA3, CCND1, MDM4, or T P 5 3; a common mutational progression pattern was not identified. Further studies, including larger series, are necessary to evaluate the prognostic significance of the molecular classification of recurrences.

Adenoid cystic carcinomas (AdCC) of salivary gland origin have long been categorized as fusion-defined carcinomas owing to the almost universal presence of the gene fusion MYB::NFIB, or less commonly MYBL1::NFIB. Sinonasal AdCC is an aggressive salivary gland malignancy with no effective systemic therapy. Therefore, it is urgent to search for potentially targetable genetic alterations associated with AdCC. We have searched the authors' registries and selected all AdCCs arising in the sinonasal tract. The tumors were examined histologically, immunohistochemically, by next generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) looking for MYB/MYBL1 and/or NFIB gene fusions or any novel gene fusions and/or mutations. In addition, all tumors were tested for HPV by genotyping using (q)PCR. Our cohort comprised 88 cases of sinonasal AdCC, predominantly characterized by canonical MYB::NFIB (49 cases) and MYBL1::NFIB (9 cases) fusions. In addition, noncanonical fusions EWSR1::MYB; ACTB::MYB; ESRRG::DNM3, and ACTN4::MYB were identified by NGS, each of them in 1 case. Among nine fusion-negative AdCCs, FISH detected rearrangements in MYB (7 cases), NFIB (1 case), and EWSR1 (1 case). Six AdCCs lacked fusions or gene rearrangements, while 11 cases were unanalyzable. Mutational analysis was performed by NGS in 31/88 (35%) AdCCs. Mutations in genes with established roles in oncogenesis were identified in 21/31 tumors (68%), including BCOR (4/21; 19%), NOTCH1 (3/21; 14%), EP300 (3/21; 14%), SMARCA4 (2/21; 9%), RUNX1 (2/21; 9%), KDM6A (2/21; 9%), SPEN (2/21; 9%), and RIT1, MGA, RB1, PHF6, PTEN, CREBBP, DDX41, CHD2, ROS1, TAF1, CCD1, NF1, PALB2, AVCR1B, ARID1A, PPM1D, LZTR1, GEN1, PDGFRA, each in 1 case (1/21; 5%). Additional 24 cases exhibited a spectrum of gene mutations of uncertain pathogenetic significance. No morphologic differences were observed between AdCCs with MYBL1::NFIB and MYB::NFIB fusions. Interestingly, mutations in the NOTCH genes were seen in connection with both canonical and noncanonical fusions, and often associated with high-grade histology or metatypical phenotype, as well as with poorer clinical outcome. Noncanonical fusions were predominantly observed in metatypical AdCCs. These findings emphasize the value of comprehensive molecular profiling in correlating morphologic characteristics, genetic landscape, and clinical behavior in AdCC.

To survey and characterize intraductal polypoid neoplasms in the intrahepatic large bile ducts of small duct-type intrahepatic cholangiocarcinoma (small duct-iCCA), a total of 121 cases of small duct-iCCA presenting mass-forming growth were surveyed for intraductal polypoid neoplasms that were compared with mass-forming tumors in individual cases and with intraductal papillary neoplasm of bile duct (IPNB) (20 cases). Polypoid neoplasms were found in intrahepatic bile ducts in 8 (6.6%) of 121 cases of small duct-iCCA. They showed cast-like growth involving several adjoining bile ducts adjacent to or in the peripheries of mass-forming tumors as well as well-differentiated papillary or tubular/cribriform patterns and no stromal invasion. Intraductal polypoid neoplasms were histologically and immunohistochemically similar to mass-forming tumors in individual cases, and both components were of biliary subtype. There was an abrupt transition between these polypoid neoplasms and normal lining epithelia in the affected bile ducts, suggesting that intraductal polypoid neoplasms reflect the cancerization of ducts. IPNB presented with biliary (5 cases), intestinal (8 cases), gastric (5 cases), and oncocytic subtypes (2 cases), and about half of IPNBs were noninvasive, thus differing from intraductal polypoid neoplasms of small duct-iCCA. In conclusion, small duct-iCCA occasionally presents as intraductal polypoid neoplasms in adjoining bile ducts, reflecting the cancerization of ducts. These intraductal polypoid neoplasms should be considered in the differential diagnosis of heterogeneous intraductal tumors of bile ducts.

Tandem duplications (TDs) in exons of upstream binding transcription factor (UBTF-TD) are a rare recurrent alteration in pediatric and adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/neoplasm. Although recently identified, AML with UBTF-TD is now considered a distinct subtype of AML. To further our understanding of myeloid neoplasms with UBTF-TD, we analyzed clinical, morphologic, and immunophenotypic characteristics of 27 pediatric patients with UBTF-TD-positive myeloid neoplasm, including 21 diagnosed as AML and 6 as MDS. Our data demonstrated that UBTF-TD is frequently associated with cytopenia, hypercellular marrow with erythroid hyperplasia, and trilineage dysplasia. Blasts and maturing myeloid cells show a characteristic dysplastic feature with condensed eosinophilic cytoplasm. Blasts have a myeloid or myelomonocytic immunophenotype with a variably dim expression of CD34 and/or CD117, and except for CD7 expression lack a consistent pattern of aberrant lineage-specific antigen expression. Patients with MDS had a lower blast count in the peripheral blood (P = 0.03) and bone marrow (P <0.001) but otherwise had no significant differences in other hematological parameters. Three patients with MDS rapidly progressed to AML in 33, 39, and 210 days from the initial diagnosis and there was no difference in overall survival between patients with MDS and AML (P = 0.18). Our data suggest that MDS with UBTF-TD is prognostically equivalent to AML with UBTF-TD and thus should be considered as a continuum of the same molecularly defined myeloid neoplasm. These collective data also provide morphologic and immunophenotypic clues that can prompt screening for UBTF-TD in patients with MDS or AML.