The presence of oxyntic (body-type) glands in the duodenum is conventionally termed "gastric heterotopia" and is presumed to represent a congenital developmental anomaly. In contrast, gastric foveolar metaplasia of the duodenum is widely accepted as an acquired, reactive process. If duodenal gastric heterotopia were truly congenital, its prevalence should remain stable across age groups; if it is metaplastic in nature, prevalence should increase with age. A retrospective natural language search was performed for all cases diagnosed as "gastric heterotopia" in duodenal biopsies at a single academic medical center over a 10-year period (6/2013-4/2023). The prevalence of gastric heterotopia was calculated for each decade of life. Of 44,637 patients with duodenal biopsies, 846 (1.90%) had gastric heterotopia. The prevalence rose from 0.22% in patients aged 0-10 years to 4.05% in patients aged 91-100 years, representing an approximately 20-fold increase. The Spearman correlation between age group and prevalence was 0.988. The strong, monotonic relationship between patient age and prevalence of duodenal oxyntic glands is less consistent with a congenital process and instead supports a metaplastic etiology. The term "oxyntic metaplasia" is proposed as a more pathophysiologically accurate descriptor for this finding.
BACKGROUND:Solitary fibrous tumor (SFT) is a mesenchymal neoplasm characterized by NAB2::STAT6 fusion and nuclear STAT6 expression. Primary SFT of the prostate is rare, and its biological behavior remains incompletely defined. We present a multi-institutional cohort and comprehensive literature review to better characterize clinicopathologic features, management, and outcomes. DESIGN:We analyzed 33 patients with prostatic SFTs from multiple institutions, integrating clinical, radiologic, histopathologic, immunohistochemical, and follow-up data. A systematic review of published cases was performed, and findings were contextualized using established risk models. RESULTS:Patients ranged from 30 to 93 years (mean, 59; median, 61). Tumor sizes ranged from 0.6 to 19.5 cm (mean, 6.8; median, 5.75). Presenting symptoms included urinary obstruction, pelvic fullness, elevated PSA, or incidental detection. In two patients, the tumor caused urinary obstruction requiring transurethral resection. Location adjacent to the seminal vesicles was noted in several patients with one growing as a large mass into the pelvis. In several patients, the SFT was an incidental finding on needle biopsy performed for elevated PSA. Histologically, all tumors demonstrated classic SFT morphology with a spindle cell proliferation and patternless architecture. Tumor borders varied, with both well-circumscribed and infiltrative patterns observed. Cellularity ranged from low to high, and nuclear atypia was most often mild to moderate. Mitotic activity was generally low (<5 mitoses/10 HPF in most cases), although two tumors showed elevated indices (12 and 15/10 HPF). Necrosis was identified in 5 tumors and was focal in 3. STAT6 was positive in 27/27 tested cases (100%), and CD34 was positive in all cases with available results (31/31, 100%). Management was primarily surgical. Only three tumors in this cohort developed metastatic disease, limiting the ability to confirm or refute the applicability of the Demicco risk stratification model. Metastatic cases occurred in relatively older patients, two of the three were >5 cm with focal necrosis, and two had increased mitotic activity (>4/10 HPF), while the third was 4.5 cm without necrosis but showed a high mitotic count. No overtly high-grade morphology or consistent morphologic predictors of metastasis were identified in this series. Follow-up was available in 16 patients (10-171 months; mean, 38; median, 29). Aside from the three patients who developed metastatic disease, all others were alive and without recurrence or metastasis at last contact. CONCLUSIONS:This is among the largest reported cohorts of prostatic SFTs. These tumors, though rare in the prostate, appear to display similar morphologic and immunophenotypic features to SFTs in other anatomic sites. While generally indolent, rare cases may metastasize. Accurate diagnosis relies on a combination of morphologic evaluation and STAT6 IHC. This study expands the clinicopathologic spectrum of SFTs and emphasizes the need for long-term follow-up due to the potential for late recurrence or metastasis.
Acute myeloid leukemia (AML) is increasingly defined by recurrent genetic alterations that determine disease classification, prognosis, and therapeutic strategy. Although definitive diagnosis of genetically defined subtypes relies on cytogenetic and molecular techniques, careful evaluation of bone marrow and peripheral blood morphologic findings remains an essential and immediate component of the diagnostic process. Many genetic lesions in AML are associated with reproducible morphologic findings that can guide early diagnostic suspicion, inform triage of ancillary testing, and anticipate biologic behavior. This review summarizes the major genetically defined subtypes of AML and delineates their characteristic morphologic correlates, emphasizing how integration of microscopic findings with cytogenetic and molecular data enhances diagnostic precision. By revisiting morphology through a genomic lens, we underscore its continued central role in contemporary hematopathology.
BACKGROUND:Pagetoid involvement of the rete testis (RT) in seminoma is widely interpreted as spread of germ cell neoplasia in situ (GCNIS) rather than true invasion; however, this concept is based largely on morphologic observations. Assessment of isochromosome 12p [i(12p)], a hallmark of invasive germ cell tumors that is absent in GCNIS, was used to determine the nature of pagetoid RT involvement. METHODS:We retrospectively identified orchiectomy specimens with pure seminoma and pagetoid RT involvement from institutional archives. Isochromosome 12p status was assessed on formalin-fixed, paraffin-embedded tissues using fluorescence in situ hybridization (FISH) with a dual-color PKP2/D12Z3 probe. Pagetoid RT involvement, invasive seminoma, and intratubular seminoma (ITS) components were analyzed separately when present. RESULTS:Sixteen tumors were included, with successful FISH analysis in 15 (94%). Pagetoid RT involvement was evaluable in 14 cases and demonstrated i(12p) in only 1 (∼7%), while the remaining 13 were negative. In contrast, invasive seminoma showed i(12p) in 5/14 cases (∼36%). All seminoma components negative for i(12p) showed polysomy 12, suggesting that these are mutually exclusive alterations. Cases with discordant results contained i(12p)-positive seminoma and i(12p)-negative pagetoid RT involvement. Intratubular seminoma (ITS) was present in 6 tumors, being positive for i(12p) in 2 (∼33%). CONCLUSIONS:The absence of i(12p) in pagetoid RT involvement supports its interpretation as spread of GCNIS rather than invasive tumor. Rare detection of i(12p) in RT involvement suggest that, occasionally, this lesion may represent retrograde invasion by seminoma or, more likely, in-situ progression of GCNIS.
Thyroid tumors of uncertain malignant potential (UMP) are recognized by the World Health Organization (WHO) as tumors of borderline malignancy, encompassing follicular tumor of uncertain malignant potential (FT-UMP) and well-differentiated tumor of uncertain malignant potential (WDT-UMP). Tumors classified as UMP have questionable capsular invasion (CI) and/or angioinvasion (AI); however, biological uncertainty extends beyond the possibility for invasiveness alone. We conducted a retrospective, single-center study of all thyroid tumors diagnosed as UMP (2005-2025). Upon review of our institutional UMP cohort, we identified 39 tumors that lack questionable CI and/or AI, and therefore, would not meet WHO-defined UMP criteria. This retrospective analytic group of borderline thyroid nodules (BTN) was used to interrogate the overlap between non-invasive follicular-patterned thyroid lesions and worrisome morphologic and/or molecular features. BTN show features of neoplasia (solid growth or microfollicular architecture, papillary thyroid carcinoma (PTC)-like nuclear atypia, oncocytic morphology, conspicuous mitoses, and/or abnormal molecular results) with or without procedural artifacts (mechanically disrupted capsule, squamous metaplasia or ischemic necrosis). BTN were diagnosed in 0.1% of thyroid surgeries; median age 55 years and 1.3:1 female-to-male ratio. Median tumor size was 4 cm. RAS or RAS-like variants were most frequent (25%), followed by gene fusions (10%). Negative molecular testing was identified in 10% of BTN and high-risk gene alterations, including TERT promoter and PIK3CA, were seen in 20%. Most patients underwent hemithyroidectomy (62%), with median follow-up of 2.5 years (range 1-12.5 years), and no recurrences or metastases were documented. Our findings suggest indolent behavior of BTN and support conservative management, such as hemithyroidectomy. Longer-term, multi-institutional studies will refine risk stratification and management strategies, with possible consideration for expanding UMP diagnostic criteria.
AIMS:Histologic grading of the primary tumor (PT) is an established prognostic factor in lung adenocarcinoma; however, the clinical relevance of histologic patterns in metastatic lymph nodes (MLNs) remains unclear. This study investigated whether MLN histology is associated with recurrence patterns after complete resection. METHODS:We retrospectively analyzed 120 patients with pN1-2 lung adenocarcinoma who underwent complete resection at a single institution. Predominant histologic patterns of PTs and MLNs were categorized as low grade (lepidic), intermediate grade (papillary or acinar), or high grade (solid or micropapillary). Survival outcomes and recurrence patterns (locoregional vs distant) were compared across MLN histologic groups. RESULTS:Predominant histologic patterns were frequently discordant between PTs and MLNs (McNemar test, P = 0.01; κ = 0.25). High-grade PTs were associated with significantly shorter recurrence-free survival (RFS) than intermediate-grade tumors (P = 0.02), whereas MLN histology was not associated with RFS (P = 0.70). PT histology was not significantly related to recurrence site. In contrast, intermediate-grade MLNs showed a significantly higher incidence of locoregional recurrence than high-grade MLNs (P = 0.04), which was confirmed by cumulative incidence analysis (P = 0.02). Distant recurrence rates were comparable between the two groups (P = 0.39). CONCLUSIONS:While histologic grading of the primary tumor reflects overall tumor aggressiveness and prognosis, the histologic architecture of metastatic lymph nodes may be associated with recurrence patterns rather than survival outcomes. These findings suggest that MLN morphology may provide complementary pathological information regarding patterns of locoregional recurrence after surgical resection.
Fibrotic interstitial lung diseases (ILDs) are classified into histopathological patterns by the idiopathic interstitial pneumonia (IIP) classification, and not only IIP but also secondary interstitial pneumonia (SIP) are evaluated based on the classification system, and the final integrated diagnosis is established through multidisciplinary discussion. However, distinguishing IIP from SIP is often challenging. This study aimed to investigate differences in collagen and elastic fiber composition between idiopathic and secondary ILDs using machine-learning-based quantitative analysis. We analyzed 780 Elastica van Gieson (EVG)-stained whole-slide images obtained from 93 patients with fibrotic ILDs who underwent lung transplantation using the HALO-AI. Fibrotic areas were identified, and collagen and elastic fiber areas were quantitatively measured. Among the elastic fibers, the area of elastic fiber aggregation was identified based on the increased density and dark staining intensity on EVG staining. Although no significant differences were observed between IIP and SIP in the collagen fiber area or total elastic fiber area, the elastic fiber aggregation area/fibrosis area ratio was significantly higher in SIP, particularly in the lower lobes (P = 0.0010). Similar findings were observed in the subgroup analyses of usual interstitial pneumonia pattern and nonspecific interstitial pneumonia pattern, in which secondary cases demonstrated significantly greater elastic fiber aggregation than idiopathic cases in both the upper and lower lobes. In conclusion, SIPs exhibit greater elastic fiber aggregation than IIPs. These findings suggest that assessments of the quantity and structural characteristics of elastic fibers help to facilitate the differential diagnosis of ILDs and provide novel insights into disease pathogenesis.
Atypical intraductal proliferations of the prostate encompass a spectrum from high-grade prostatic intraepithelial neoplasia (HGPIN) to intraductal carcinoma of the prostate (IDCP), the latter being strongly associated with aggressive prostate cancer. The recent WHO classification introduced atypical intraductal proliferation (AIP) to describe lesions intermediate between HGPIN and IDCP. To assess current diagnostic practice and variability prior to implementation of new consensus recommendations, we surveyed 541 pathologists from four national and international pathology societies (Genitourinary Society of Pathology (GUPS), International Society of Urological Pathology (ISUP), British Association of Urological Pathology (BAUP), and German Division of the International Academy of Pathology (GDIAP)). Participants widely supported the Guo/Epstein criteria for diagnosing IDCP and generally agreed that when IDCP is found in the absence of high-grade cancer on needle biopsy, unsampled high-grade cancer is almost always present, reinforcing its role as an exclusion criterion for active surveillance. However, opinions varied on whether IDCP is a precursor lesion or a growth pattern of invasive cancer. Participants reviewed 25 images of intraductal lesions classified as benign, HGPIN, AIP, or IDCP. Consensus (>2/3 agreement) was reached in only 36% of cases, and no AIP case achieved consensus. Grouping lesions into low-grade (benign/HGPIN) versus high-grade (AIP/IDCP) categories increased consensus to 88%. Consensus was higher for AIP + IDCP (60%) than for HGPIN + AIP (32%), suggesting closer diagnostic alignment of AIP with IDCP. These findings highlight persistent interobserver variability and the need for clearer diagnostic criteria, education, and further biological characterization of AIP and IDCP.
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME) and poor treatment responsiveness. Although neoadjuvant chemotherapy (NAC) can improve clinical outcomes, its effects on the TME, particularly the interplay between vascular remodeling and immune reprogramming, remain poorly understood. This study examined the impact of NAC on both the immune cell composition and vascular structure of PDAC. METHODS:Immunohistochemistry of immune cell infiltration was performed in PDAC tissues resected from 56 patients. In a separate cohort of 26 patients, three-dimensional vascular analysis using tissue clearing and confocal imaging was performed alongside immunohistochemistry-based evaluation of vessel proportions. Immunohistochemistry was used to evaluate CD4+ T cells, CD8+ T cells, FoxP3+ regulatory T cells, CD163+ macrophages, CD34+ pan-endothelial cells, and CD105+ tumor-associated endothelial cells. Vascular morphology, including vessel length, surface area, and volume, was quantified by three-dimensional reconstruction. All comparisons were performed at the patient level. RESULTS:NAC-treated tissues exhibited increased CD4+ and stromal CD8+ T cell infiltration, a reduced FoxP3+/CD4+ ratio, and an increased tumoral CD8+/CD163+ ratio. NAC was associated with shorter vessel length and a selective reduction in CD105+ tumor-associated vessels, with unchanged total CD34+ vessel density. These changes were generally more pronounced in patients with a better treatment response. CONCLUSION:NAC was associated with coordinated TME remodeling involving both immune and vascular components. This integrated remodeling might contribute to the development of an immunologically activated tumor phenotype and support the rationale for combination strategies with immunotherapy in PDAC.
Non-small cell lung carcinomas showing co-expression of TTF-1 and p40 in sampled tumor tissue are rare, diagnostically challenging, and not formally recognized in the current WHO classification of thoracic tumors. We analyzed 15 pulmonary carcinomas with TTF-1/p40 co-expression to characterize their clinicopathologic features and molecular alterations. The cohort consisted predominantly of male patients and was composed mainly of high-grade, poorly differentiated tumors. All cases demonstrated diffuse nuclear co-expression of TTF-1 and p40 by immunohistochemistry. Whole-exome sequencing, performed in 12 cases, revealed frequent TP53 alterations (9/12), occasional concurrent RB1 alterations, and a rare FGFR3::TACC3 fusion, which was further validated by FISH. Two tumors with prominent lymphoid stroma were positive for Epstein-Barr virus-encoded RNA and lacked TP53 alterations, suggesting additional biological diversity within this phenotype. Follow-up data were available for 13 patients (range, 1-29 months); 4 died of disease and 9 were alive at last follow-up. Two additional patients were lost to follow-up. Collectively, these findings suggest that pulmonary carcinomas showing TTF-1/p40 co-expression in sampled tissue comprise a heterogeneous clinicopathologic and molecular group rather than a currently definable distinct entity. Despite the small sample size and the inclusion of several biopsy-only cases, this study provides a descriptive basis for future investigation of this unusual immunophenotypic pattern.
Myeloid sarcoma is defined as a neoplasm of myeloid blasts that involves an extramedullary site as a mass and effaces tissue architecture. Myeloid sarcoma is considered clinically to be equivalent to acute myeloid leukemia (AML) and requires appropriate therapy. As currently defined, extramedullary AML that does not form a mass is inconsistent with the diagnosis of myeloid sarcoma and the management of patients with extramedullary AML is less well defined. Furthermore, the pathogenetic relationship and clinical importance of extramedullary AML versus myeloid sarcoma is under explored. Recent studies have shown the importance of the MAPK/ERK pathway in pathogenesis of myeloid sarcoma and extramedullary AML. These studies also have shown that extramedullary sites of myeloid disease often evolve independently from medullary AML, likely related to microenvironmental clonal selection pressures and immune evasion mechanisms at extramedullary sites that differ from bone marrow disease. Here we review the clinicopathologic, immunophenotypic and molecular findings of myeloid sarcoma as currently defined. We also discuss the differential diagnosis of myeloid sarcoma and its relationship to non-mass forming extramedullary AML.
Colorectal dysplasia in inflammatory bowel disease (IBD) includes conventional and diverse nonconventional morphologic patterns, the latter of which are often endoscopically invisible or flat and are associated with an increased risk of advanced neoplasia. However, the prevalence and significance of nonconventional dysplasia in patients without IBD remain unclear. We analyzed 669 sporadic colorectal dysplastic lesions from 211 patients without IBD or syndromic polyposis, including 103 patients with colorectal cancer (CRC) (293 dysplastic lesions) and 108 without CRC (376 dysplastic lesions). Sporadic lesions were also compared with 317 dysplastic lesions from 168 patients with IBD. In the sporadic cohort, conventional dysplasia predominated (89%), whereas 11% were nonconventional, most commonly Paneth cell-rich dysplasia (9%). Goblet cell-deficient (1%) and hypermucinous (0.4%) patterns were rare, and no cases of basal crypt dysplasia, crypt cell dysplasia, or serrated dysplasia not otherwise specified were identified. Most sporadic lesions were tubular (93%), low-grade (95%), polypoid (97%), and right-sided (60%). Compared with lesions in the non-CRC group, those in the CRC group were more frequently nonconventional (14% vs. 9%, p = 0.045), larger (mean: 1.0 vs. 0.7 cm, p < 0.001), and more likely to show tubulovillous/villous architecture (10% vs. 5%, p = 0.016), high-grade dysplasia (HGD; 10% vs. 2%, p < 0.001), and invisible gross appearance (2% vs. 0%, p = 0.023). When compared with IBD-associated lesions, sporadic lesions occurred at an older age (mean: 61 vs. 53 years, p < 0.001) and showed significantly lower rates of nonconventional morphology (11% vs. 25%, p < 0.001), HGD (5% vs. 16%, p < 0.001), invisible/flat appearance (3% vs. 24%, p < 0.001), and left-sided location (39% vs. 48%, p = 0.006). In conclusion, although nonconventional dysplasia is not exclusive to IBD, several patterns, including hypermucinous, goblet cell-deficient, and basal crypt dysplasias, are rare or absent in patients without IBD. Although their low prevalence suggests that these patterns are unlikely to be major contributors to CRC risk in patients without IBD, a potential association with an increased risk of concurrent or subsequent CRC cannot be excluded, given the paucity of random colonic biopsies in this population.
OBJECTIVE:Breast MRI is widely used for screening high-risk patients and for assessing the extent of disease in patients with breast cancer. The goal of this study was to determine the pathologic findings associated with MRI-guided core needle biopsies performed for non-mass enhancement (NME) lesions of the breast. METHODS:We retrospectively identified 270 MRI-guided core needle biopsies from 225 women performed at our institution between January 1, 2024, and Dec 30, 2025. All included cases demonstrated non-mass enhancement on MRI. Radiologic and pathologic findings were reviewed. Cases were divided into two groups: those with a recent diagnosis of ipsilateral malignancy (n = 74) and those without a recent diagnosis of malignancy (n = 196). RESULTS:Biopsies from patients with a known ipsilateral malignancy demonstrated a higher frequency of invasive carcinoma (20% vs. 7%, p = 0.003) and in situ carcinoma (27% vs. 9%, p = 0.0002) compared with those without ipsilateral malignancy, and a lower frequency of benign findings (46% vs. 77%, p = 0.0001). NME-associated invasive carcinomas were predominantly well-to moderately-differentiated carcinomas (96%) and were ER-positive/HER2-negative (>90%). NME-associated DCIS were 57% high grade, 43% intermediate grade, with 36% showing an ER-negative staining. CONCLUSION:MRI-guided biopsies for NME lesions demonstrate a significant rate of malignancy, particularly in patients with known ipsilateral breast cancer. Most NME-associated malignancies are well-to moderately-differentiated, hormone receptor-positive/HER2-negative carcinomas, while a subset of high-grade, ER-negative DCIS highlights the heterogeneous nature of these lesions.
BACKGROUND:HER2 represents an actionable target in a subset of biliary tract cancers (BTCs), particularly extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC). Recent approval of zanidatamab for HER2-positive BTC has further highlighted the clinical relevance of accurate HER2 assessment. METHODS:HER2 status was evaluated in 140 consecutive surgically resected BTCs collected between 2020 and 2025 (87 eCCAs and 53 GBCs) using immunohistochemistry (IHC) and dual chromogenic in situ hybridization (DISH). HER2 expression was scored according to gastric cancer criteria, and HER2 positivity was defined following HERIZON-BTC-01 criteria. Selected cases were additionally analyzed using a combined IHC-DISH approach. RESULTS:HER2 expression was 0 in 72.9% of cases, 1+ in 12.1%, 2+ in 8.6%, and 3+ in 6.4%. HER2 positivity was observed in 9.2% of eCCAs and 9.4% of GBCs. ERBB2 amplification was consistently identified in all IHC 3+ tumors and in a subset of IHC 2+ and, rarely, 1+ cases. The mean ERBB2/CEP17 ratio was significantly higher in HER2 3+ tumors than in amplified HER2 2+/1+ tumors (6.2 vs 3.9; p = 0.001). Combined IHC-DISH analysis confirmed concordance between HER2 overexpression and ERBB2 amplification within the same tumor cells. HER2 expression frequently showed intratumoral heterogeneity, often involving less than 50% of tumor cells. CONCLUSIONS:HER2 alterations occur in a subset of eCCA and GBC and show substantial biological heterogeneity, including lower-level amplification and intratumoral heterogeneity, with potential implications for HER2 assessment and patient selection.
BACKGROUND:SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) have been included in the latest WHO classification of tumors. This study examined the cytomorphology, management, molecular features and prognosis of malignancies harboring SMARCA4 alterations. METHODS:Biopsied cytologic slides were reviewed. Next-generation sequencing (NGS) and clinical data were analyzed. RESULTS:Thirty-four cases with SMARCA4 alterations were identified, including 13 primary and 21 metastatic tumors, sampled primarily from lung (35%), lymph nodes (26%) and liver (15%). Tumor origins were predominantly the lung (61%) and gallbladder (9%). The most common tumor type was adenocarcinoma (70%). Predominant architectures included nested, single-cell, tubular/acinar, and 3D clusters. Cells were most commonly round and columnar, with medium cytoplasm mostly showing vacuoles and granular features. Nuclear grade 2-3 was seen in 93% of cases, with prominent nucleoli and coarse chromatin. SMARCA4 alteration included mutations (32) and loss (2). These tumors are characterized by a high co-mutation burden, including TP53 (62%), KRAS (35%), and STK11 (15%). Prognosis is further modulated by allelic status (biallelic vs. monoallelic vs. subclonal), and mutations in DDR pathway (24%). Most tumors presented as stage IV. 26% received surgical resection. Overall, 74% underwent chemotherapy and 29% radiotherapy. Mean follow-up was 17 months, with 2-year OS of 49.1%. Twenty-three (68%) patients were current or former smokers. CONCLUSION:SMARCA4-altered malignancies show diverse differentiation and lack consistent cytomorphologic features. Majority of cases were differentiated malignancies and only four cases (12%) were undifferentiated, suggesting SMARCA4 alterations were associated with poor prognosis but were not exclusive drivers of undifferentiated malignancy.
This retrospective diagnostic concordance study evaluated the feasibility and performance of PMS2/MSH6 double immunohistochemistry (DIHC) as a single-section screening tool for deficient mismatch repair (dMMR). The study was conducted at a single academic tertiary care center in Japan and included 1025 consecutive Japanese patients surgically treated for de novo primary colorectal cancer (CRC) or endometrial cancer (EC) between 2018 and 2021, using tissue microarrays (TMA) rather than whole-slide sections. Following a two-step exclusion process-qualitative assessment of original surgical FFPE blocks (65 CRC and 41 EC cases) and of constructed TMA blocks (125 CRC)-794 cases (580 CRC and 214 EC) were analyzed using 2-mm-diameter TMA cores. The primary outcome was concordance of mismatch repair status between the DIHC index test and single immunohistochemistry (SIHC) as a reference standard, rather than a true gold standard, for MMR deficiency. DIHC identified dMMR in 6.7% of CRC and 22% of EC cases, and McNemar's test showed no significant difference in sensitivity between DIHC and SIHC. For MSI-H detection, assessed in a limited subset (N = 163), DIHC showed a sensitivity of 100% (95% CI: 67.6%-100%) and specificity of 98.1% (94.5%-99.5%). dMMR status by DIHC was significantly associated with right-sided location and medullary histology in CRC. Although rare, in three cases (0.4%), DIHC visualized heterogenous MSH6 loss within PMS2-deficient clones in a section. PMS2/MSH6 DIHC provides diagnostic performance comparable to conventional SIHC while conserving tissue and resources, suggesting potential utility for small biopsies and investigation of intratumoral MMR protein expression heterogeneity.
CONTEXT:The Oncotype DX Recurrence Score (RS) is used to guide adjuvant chemotherapy decisions in estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer. Although RS is widely used in routine practice, the extent to which score distributions differ by histologic types- specifically invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC)- within the same pathologic anatomic AJCC stages is not well studied. DESIGN:We performed a retrospective study of ER+/HER2- invasive breast carcinomas with available RS results from 2020 to 2024 (n = 322, including IDC [n = 254] and ILC [n = 68]). RS distributions were evaluated by clinicopathologic features and histologic type. IDC and ILC were compared within pathologic anatomic AJCC stage and progesterone receptor (PR)-stratified subgroups. Moreover, two histologic types were compared for eligibility for the prespecified very-low RS endpoint (stage IA, node-negative tumors, RS < 11). Multivariable logistic regression was used to identify independent predictors of RS < 11. RESULTS:Mean RS was similar in IDC and ILC (17.2 vs 17.1), although the score range was broader in IDC (0-83) than in ILC (5-37). Overall, PR- tumors showed significantly higher RS than PR+ tumors in both stage IA and stage IIA disease (both p = 0.001). In subgroup analyses, IDC demonstrated a higher RS than ILC in the PR+ stage IIB subgroup only (p = 0.03). More IDC cases met the criteria for very-low RS endpoint relevant to AJCC prognostic-stage assignment (stage IA, node-negative tumors with RS < 11), which was statistically significant (28.9% of IDC versus 8.9% of ILC; p = 0.006). On multivariable analysis, ILC remained independently associated with lower odds of RS < 11 compared with IDC (adjusted OR, 0.25; 95% CI, 0.08-0.75; p = 0.013), and PR negativity was also independently associated with lower odds of RS < 11 (adjusted OR 0.12, 95% CI 0.02-0.94, p = 0.043). CONCLUSIONS:IDC and ILC showed similar mean RS values, but IDC had a wide range of score distribution. In-depth analysis also uncovered the subtle impact of histologic type at different pathologic anatomic AJCC stages. In particular, ILC was less likely than IDC to demonstrate a very-low RS (<11) in stage IA, node-negative ER+/HER2- disease. These findings suggest that histologic subtype may provide useful context for interpretation of RS, especially in pretest counseling regarding the likelihood of very-low genomic risk.
Acinar cell carcinomas (ACCs) of the pancreas typically demonstrate distinct morphologic features including minimal fibrous stroma, acinar architecture, relative nuclear uniformity, single prominent nucleoli and eosinophilic cytoplasmic granules. We report seven cases of metastatic carcinomas to the liver with acinar cell differentiation (two acinar cell carcinomas, four carcinomas with mixed acinar and neuroendocrine differentiation, one mixed acinar ductal carcinoma) that lacked many of these features, and, as a result, were misclassified. The cases were prospectively identified in our routine confirming consultation service. Clinical data and histology were retrospectively reviewed. The seven patients ranged in age from 48-72 years with a male predominance (5 males, 2 females). Five patients had a known pancreatic mass, and all patients had multiple liver lesions on initial imaging, prompting liver biopsies. Three of seven liver tumors were diagnosed at the submitting institution as high-grade neuroendocrine tumors (NETs) as they all expressed synaptophysin and/or chromogranin, had a high Ki67 proliferation index, and lacked cytoplasmic granules or acinar architecture. The remaining four liver tumors were diagnosed as adenocarcinoma as they lacked prominent nucleoli, had prominent fibrotic stroma (3 cases), lacked eosinophilic cytoplasmic granules (3 cases), lacked acinar architecture (2 cases) and/or had significant nuclear pleomorphism (1 case). In all cases, reevaluation at the time of consultation with an extended immunohistochemical panel revealed the expression of pancreatic exocrine enzymes (trypsin, chymotrypsin, and/or BCL10), confirming acinar differentiation. All six patients with follow-up died within 1 to 24 months of initial diagnosis. In conclusion, metastatic ACC should be considered in differential diagnosis of the more common liver metastasis of pancreatic origin, NET and PDAC. ACC metastatic to the liver may lack hallmark morphologic features such as acinar architecture, prominent nucleoli and eosinophilic cytoplasmic granules and may express neuroendocrine markers (mimicking NET) or exhibit prominent fibrotic stroma and pleomorphism (mimicking PDAC). Immunolabeling for acinar cell markers is warranted for cases of purported PDAC/NET with atypical features, such as purported NET with high Ki67 index and/or only patchy neuroendocrine marker labeling, or purported PDAC with luminal proteinaceous secretions rather than mucin and/or minimal pleomorphism.
Unlike in hematologic malignancies like acute promyelocytic leukemia (APL), the tumorigenic role of RARA fusions in solid tumors, including melanomas, remains largely unknown. Here, we present a comprehensive clinicopathologic and molecular analysis of two cutaneous melanomas harboring RARA fusions. Both melanomas were of the acral subtype, affecting the feet of adults (median age: 60.5 years) without sex predilection. At diagnosis, Breslow thickness ranged from 1.2 to 5.5 mm, ulceration was present in one case, and the median mitotic rate was 4/mm2. Tumor cells exhibited variable cytomorphology, including spindled and epithelioid features, with occasional rhabdoid morphology. Molecular analysis revealed a consistently low tumor mutational burden (median: 4.5 mutations/Mb). One acral melanoma was triple wild-type (lacking mutations in BRAF, NRAS, and NF1) and showed no gene amplifications, but harbored a LOC107984974::RARA fusion. The other acral melanoma carried an NF1 loss-of-function mutation and multiple gene amplifications involving 11q13.3 (CCND1, FGF3, FGF4, FGF19), 11q13.5-q14.1 (PAK1), 12q15 (MDM2), and 6q24.3 (SHPRH), along with two RARA fusions: RARA::LRP5 and RARA::RNF169. Over a median follow-up of 23 months, one patient developed a distant metastasis involving the brain approximately 20 months after the initial diagnosis. At last follow-up, one patient was alive with disease, while the other remained alive without clinical or radiological evidence of recurrence. These findings expand the current understanding of the molecular landscape of acral melanomas and may provide insights into the potential utility of targeted therapies against RARA fusions in a subset of melanomas, analogous to their therapeutic role in APL.
