American Journal of Surgical Pathology最新文献

A distinct type of pancreatic carcinoma (n=31; 6% of adenocarcinomas) is described, distinguished from conventional pancreatic ductal adenocarcinoma (PDAC) by: (1) solid/undifferentiated (sheet-like, stroma-poor) carcinomas lacking features of other entities (no osteoclasts, microsatellite stable, INI-1 retained, nonkeratinizing squamous <30%), often admixed with ordinary PDAC; (2) radiology/gross showing central necrosis/demarcation mimicking nonductal neoplasms, not scirrhous like PDAC; (3) marked intratumoral heterogeneity with divergent patterns, including basal/squamoid (81%), solid sheets punctuated with megavacuoles (77%), clear cell (68%), mucoepidermoid-like (36%), sarcomatoid (36%), and occasional choriocarcinomatous or angiosarcomatous patterns, and some with carcinomatous vasculitis; (4) cellular anaplasia with pleomorphic giant cells (55%), multinucleated nonosteoclastic (32%), and rhabdoid-like (32%); (5) immunohistochemically (n=16) consistently showing a basal phenotype with common GATA6 loss/depletion and/or CK5/6, p40, or p63 expression; (6) molecular-genetic profile (n=13) showing altered frequencies: ARID1A (31% vs. 4%) and CDKN2A/p16 (92% vs. 30%) alterations, universal KRAS mutations with enrichment in KRAS G12D, frequent TP53, and lower SMAD4 loss (8% vs. 55%). Limited follow-up suggests comparable or more favorable outcomes. In conclusion, this is a distinct type of carcinoma in the pancreas that is prone to being misdiagnosed as nonductal/non-PDAC cancers. It is the first pancreatic carcinoma type in which a basal molecular phenotype can be indicated clinically by both imaging and histopathology, with major potential management implications (as it is also enriched in actionable targets like ARID1A). Recognition of this category is critical for cancer research, as it offers an invaluable group to study plasticity, stroma versatility, necrosis mechanisms, and the basal type in pancreatic cancer.

The grading of intraductal carcinoma of the prostate (IDC-P) associated with conventional prostatic adenocarcinoma (CPA) remains controversial, particularly regarding whether IDC-P exhibiting a solid nest pattern is prognostically equivalent to Gleason grade 5 CPA. We retrospectively analyzed consecutive radical prostatectomy patients with grade 5 CPA as a primary, secondary, or tertiary pattern, as well as cribriform IDC-P, while excluding cases exhibiting comedonecrosis within IDC-P. We then compared clinicopathologic features and long-term oncologic outcomes between those with (n=28 [24.3%]) and without (n=87 [75.7%]) solid-pattern IDC-P. Solid IDC-P cases were significantly associated with a higher incidence of lymph node metastasis, larger estimated tumor volume, and more frequent administration of adjuvant therapy immediately after prostatectomy. No significant differences were observed in preoperative prostate-specific antigen, Grade Group, pT stage, or surgical margin status between the 2 groups. Univariate analysis revealed significantly worse biochemical recurrence-free survival ( P =0.010) and cancer-specific survival ( P =0.003) in patients with solid IDC-P. In multivariable Cox regression analyses, solid IDC-P remained significantly predictive of postoperative recurrence when adjusting for prognostic factors, including Grade Group (hazard ratio 1.902, P =0.039) or the percentage of pattern 5 (hazard ratio 1.986, P =0.028). Solid-pattern IDC-P was thus found to represent an independent adverse prognostic indicator in men undergoing radical prostatectomy, further suggesting that the clinical impact of solid IDC-P versus Gleason grade 5 CPA (or cribriform IDC-P) was not comparable. It might therefore be inadequate to simply translate solid IDC-P as a grade 5 pattern.

Placental site nodule (PSN) and atypical placental site nodule (APSN) are chorionic-type intermediate trophoblastic lesions, the latter characterized by worrisome histologic characteristics and risk for subsequent trophoblastic neoplasia, mainly epithelioid trophoblastic tumor (ETT). There is no consensus or evidence-based criteria on which and how many features are needed for APSN diagnosis. We assessed interobserver reproducibility of APSN, PSN, and ETT. Five expert pathologists evaluated representative whole slide images (1 hematoxylin-and-eosin and 1 Ki-67/AE1-AE3 immunohistochemical stain) of 50 cases with APSN, PSN, or ETT index diagnosis and recorded independently diagnostic impressions and worrisome histologic characteristics (extensive lesional tissue, severe nuclear atypia, hypercellularity, mitotic activity, irregular borders, tumor necrosis, and Ki-67 index ≥5%). Diagnostic consensus was reached in 96% (agreement of ≥3 experts), and there was agreement with the index diagnosis in 75%. Overall, Fleiss' kappa score (κ) was 0.46 (highest for PSN [κ=0.58] and lowest for APSN [κ=0.34]). Substantial agreement was reached in evaluating extensive lesional tissue (lesional tissue exceeding normal, κ=0.76) and Ki-67 in the entire lesion (intraclass correlation coefficient=0.62). Most other features showed moderate reproducibility. In cases with a higher degree of agreement, most APSN harbored 3 to 6 worrisome features, while most PSN had <2 and all ETTs had ≥6. In conclusion, APSN diagnosis is challenging, reflected by fair reproducibility among experts. However, agreement was reached in most instances, highlighting the beneficial role of consultation. Criteria refinement may increase reproducibility with the highest agreement of extensive lesional tissue and proliferation in the entire lesion with Ki-67/AE1-AE3. The presence of ≥3 worrisome features might be a reasonable threshold to avoid APSN overdiagnosis.

A subset of uterine smooth muscle tumors and PEComas has been recently shown to harbor RAD51B rearrangement. To date, occurrence of RAD51B -rearranged mesenchymal neoplasms in sites outside the uterus is exceedingly rare. In this study, we describe a series of 10 extrauterine RAD51B -rearranged soft tissue tumors to further expand the clinicopathologic and molecular spectrum of this emerging entity. Patients included 4 males and 6 females with age at presentation ranging from 4 months to 72 years (median: 53.5 y). Seven tumors occurred in the somatic soft tissues, including the scalp, nuchal region, abdominal wall, perineum, vulva, pelvic cavity, and palm. Three tumors originated in non-uterus visceral organs, including the lung, gastric cardia, and kidney. Grossly, they ranged from 2 to 20 cm (median, 7 cm) in size. Histologically, 5 cases were composed predominantly of round to epithelioid cells, whereas 4 cases consisted of spindled to ovoid cells and 1 case comprised of primitive small round cells. Tumor cells showed variable degree of cytological atypia, pleomorphism, and mitotic activity. By immunohistochemistry, among the 10 cases, 9 showed variable expression of at least one myogenic marker (smooth muscle actin, desmin, and h-caldesmon), 4 expressed at least 2 markers, and 2 were positive for all 3 markers. None of the tumors expressed melanocytic markers (HMB45, Melan-A). One case did not show any cell lineage differentiation. Targeted RNA-sequencing identified CEP170 :: RAD51B fusion in 6 cases, and NUDT3::RAD51B, PUM1 :: RAD51B, RBM43::RAD51B, ZFYVE26::RAD51B fusion in 1 case each. RAD51B rearrangement was confirmed by subsequent fluorescence in situ hybridization analysis. Targeted DNA-sequencing performed in 8 cases revealed pathogenic/likely pathogenic variants in 3 cases, involving TERT , CDKN2A , TP53 , RB1 , CDH4 , and NF1 genes, liked to high-grade morphology and aggressive behavior. DNA methylation profiling demonstrated that RAD51B -rearranged soft tissue tumors form a distinct epigenetic cluster separate from leiomyosarcoma, leiomyoma, and angioleiomyoma/myopericytoma, supporting their classification as a unique molecular subtype. At follow-up, 3 patients (30%) died of disease, whereas the other 7 patients were alive without disease. Our study demonstrates that RAD51B -rearranged soft tissue tumors represent a distinct clinicopathologic entity with a broad morphologic spectrum. Despite significant heterogeneity in histology and biological behavior, the shared DNA methylation profile underpins their unified identity. RAD51B -rearranged soft tissue tumors should be included in the differential diagnosis of morphologically undifferentiated or unclassified mesenchymal neoplasms with myogenic differentiation.

Pediatric-type follicular lymphoma (PTFL) is a rare and indolent B-cell lymphoma that largely affects children and young adults. Although typically nodal, rare similar lesions have been reported in the conjunctiva, but differential diagnosis with follicular hyperplasia and other low-grade B-cell lymphomas is challenging. We identified 22 B-cell-derived conjunctival lesions in patients aged 7 to 33 years. All biopsies were characterized using morphologic, immunophenotypic, and molecular criteria. Cases showed a marked male predominance (20 males and 2 females). Final diagnoses included PTFL (n=8), PTFL with marginal zone differentiation (n=3), extranodal marginal zone lymphoma (EMZL, n=8), and reactive hyperplasia (n=3). PTFL cases showed expanded serpiginous follicles with a starry-sky appearance, high Ki67 proliferation index, CD10 and BCL6 positivity, and absence of BCL2 expression. Clonality studies were performed in all cases, revealing clonal immunoglobulin gene (IG) rearrangements in 18 cases and a polyclonal pattern in 4. Next-generation sequencing (NGS) provided confirmatory evidence for PTFL with detection of MAP2K1 mutations in 5/7 (71.4%) cases tested, observed in cases both with and without marginal zone differentiation. Our findings broaden the clinical and anatomic spectrum of PTFL. Like nodal PTFL, cases in the conjunctiva may show evidence of MZ differentiation, confirming that this is a spectrum of one disease. Integrated histologic and molecular assessment is key to accurate diagnosis of pediatric conjunctival lymphoid proliferations.

In this article, we describe a previously underrecognized pattern of aerogenous dissemination to the lungs, based on 2 cases of sinonasal DEK::AFF2 carcinoma. Over follow-up periods of 10 and 18 years, respectively, both patients exhibited recurrent multiple endotracheal and endobronchial metastases. These lesions were successfully managed with endoscopic tumor resection. No lymph node involvement or distant metastases beyond the trachea and bronchi were observed; they were entirely absent in one case and largely absent in the other. Based on these clinical courses, the tracheobronchial dissemination was most plausibly interpreted as aerogenous rather than lymphatic or hematogenous spread. DEK::AFF2 carcinoma appears to exhibit three key biological features favoring aerogenous dissemination: anatomic location of the primary tumor, loss of intercellular adhesion, and strong affinity for ciliated respiratory epithelium. These cases may help enhance our understanding of aerogenous tumor cell spread, including phenomena such as spread through air spaces (STAS).

Human papillomavirus (HPV)-independent oropharyngeal squamous cell carcinoma (OPSCC) is an aggressive cancer without established molecular prognosis. CDKN2A (encoding p16) deletion is a common genetic event in HPV-independent OPSCC. CDKN2A homozygous deletion is recognized as a poor prognostic factor in various tumors, such as gliomas, and methylthioadenosine phosphorylase (MTAP) immunostaining serves as a surrogate marker for it. Because MTAP is related to the methionine salvage pathway, various cancer cell lines with MTAP deletion have been reported to exhibit increased sensitivity to the pyrimidine analog 5-fluorouracil (5-FU). This study aimed to clarify the prognostic effect of the expressions and homozygous deletions of CDKN2A ( p16 ) and MTAP in 177 patients with OPSCC (106 HPV-positive and 71 HPV-negative) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). MTAP loss by IHC was observed in 25.3% (16/63) of HPV-negative/p16-negative OPSCCs, and FISH confirmed homozygous deletions of both CDKN2A and MTAP . All HPV-negative/p16-positive (n=8) and HPV-positive (n=106) OPSCCs did not exhibit MTAP deficiency. The prognosis of the HPV-negative/MTAP - loss group (n=16) was significantly better than that of the HPV-negative/MTAP-retained group (n=47) and was as favorable as that of the HPV-positive group (n=106). A similar trend was confirmed in patients with HPV-negative OPSCC who received pyrimidine-based chemotherapy (n=46). MTAP deficiency is closely associated with homozygous CDKN2A and MTAP deletions in HPV-negative/p16-negative OPSCCs. Furthermore, MTAP loss may be a favorable prognostic factor in HPV-negative OPSCC, and this paradoxical phenomenon might be explained by the enhanced efficacy of chemotherapy with pyrimidine analogs.

Artificial intelligence diagnostic tools show promise for improving histotype classification in epithelial ovarian cancer but face challenges due to slide variability across institutions. To address this domain shift, the adversarial Fourier-based domain adaptation (AIDA) model was developed. This retrospective study evaluates AIDA's performance in classifying the 5 major ovarian cancer subtypes using an independent cohort. Surgically treated patients diagnosed with clear cell (CCC), endometrioid (EC), high-grade serous (HGSC), low-grade serous (LGSC), or mucinous (MC) ovarian cancer at Amsterdam University Medical Center (1985-2022) were included in the study. The deep learning method AIDA, trained on data from Vancouver General Hospital, was applied to all cases. Final histotype predictions were made through majority voting across 15 independently trained models. For misclassified cases, up to 3 additional slides were scanned, and the AIDA model was retrained. Classification was then assessed using single-slide and majority voting approaches. The AIDA algorithm achieved an overall balanced accuracy of 79.7% across all histotypes. Accuracy was highest for CCC (90.9%) and LGSC (89.8%), and lowest for EC (62.4%). Common misclassifications included MC as EC and EC as HGSC or LGSC. Retraining with additional slides improved balanced accuracy to 85.8% based on single-slide voting and 82.6% based on majority voting. This study highlights the future potential of the AIDA model in classifying epithelial ovarian cancer histotypes. With further refinement to improve performance on more challenging cases, the model could enhance diagnostic accuracy in clinical practice.

Distinguishing endometrial hyperplasia from endometrial adenocarcinoma remains a histopathologic challenge. Several retrospective studies have reported high interobserver variability when assessing the progestin-naive endometrium, while only one study has assessed interobserver variability of postprogestin endometrial biopsies. This study quantified the interobserver variability between trial site pathologists and central pathology review of endometrial specimens taken before treatment with the levonorgestrel intrauterine device (LNG-IUD), 3 months and 6 months post-treatment as part of the feMMe phase 2 randomized clinical trial (NCT01686126). Interobserver agreement was 73% (105/143, κ=0.50) at baseline, 80% (107/134, κ=0.72) at 3 months and 77% (98/127, κ=0.64) at 6 months post-LNG-IUD treatment. Overall, 42% (45/107) site-reported diagnoses of endometrial hyperplasia and 13% (21/161) site-reported diagnoses of endometrial adenocarcinoma were discordant. Site-reported diagnoses were upgraded to higher risk pathology on central review for 77% (72/94) discordant cases. This study confirms the high rate of interobserver variability when diagnosing endometrial hyperplasia or endometrial adenocarcinoma both before and after progestin treatment in specimens collected as part of a clinical trial. It emphasizes the value of confirming diagnosis by a gynecologic pathologist and comparing specimens from the progestin-treated endometrium with the pretreatment biopsy. This study highlights the importance of central pathology review for clinical trial reporting and when deciding on treatment options and assessing response, particularly in the context of progestin treatment.

Increasing availability and utilisation of high-throughput sequencing techniques has resulted in a rapidly expanding range of uterine mesenchymal lesions harbouring recurrent and nonrecurrent gene rearrangements. Within the literature, 3 molecularly confirmed FOXO1 -rearranged uterine corpus tumors have been reported, all representing alveolar rhabdomyosarcomas (ARMS). We report 5 cases of non-ARMS uterine mesenchymal tumors, in patients aged 36 to 71, harbouring novel FOXO1 rearrangements with different fusion partners ( JRK , PIK3R4, MEIS1 , and ATP7B); in the fifth case, FISH revealed a FOXO1 gene rearrangement with an unknown fusion partner. Although morphologically heterogenous, all 5 cases had a low-grade spindle cell component with 3 cases showing prominent myxoid stroma. Two cases were originally diagnosed as myxoid leiomyosarcoma, one as high-grade endometrial stromal sarcoma, one as an undifferentiated sarcoma with a fibrosarcoma-like appearance, and the other as a myxoid neoplasm of uncertain malignant potential. In 3 cases, the rearrangements showed similar breakpoints to known recurrent FOXO1 gene fusions; 2 rearrangements ( JRK::FOXO1 and MEIS1::FOXO1 ) incorporate both an intact transactivation domain and a DNA-binding domain akin to the rearrangements seen in ARMS, likely representing true oncogenic driver events. Although all 5 cases were confined to the uterine corpus at presentation, recurrences occurred in 2 patients indicating a potential for malignant behaviour and justifying the designation of sarcoma. These cases expand the landscape of FOXO1 -rearranged neoplasms and describe a potential new uterine mesenchymal entity. Further study of additional cases is needed to establish whether these rearrangements truly represent an initiating event for a distinct subset of uterine sarcomas, or whether FOXO1 rearrangements simply represent an additional noninitiating/nondriver event within other established tumor types.