Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is defined by mutations in SDH subunits (A, B, C, or D) and is associated with hereditary paraganglioma-pheochromocytoma syndrome and gastrointestinal stromal tumors (GISTs) in some patients. This multi-institutional study analyzed 5 SDHA-deficient RCCs using morphology, immunohistochemistry (IHC), and next-generation sequencing (NGS). Patients had a median age of 40 years with male predominance (4:1). Initially, tumors were diagnosed as SDHA-deficient RCC (1), collecting duct carcinoma (1), or high-grade RCC, NOS (3). NGS subsequently identified 4 tumors as SDHA-deficient RCC. Common histologic features included papillary (100%) and nested (100%) architecture, solid growth (80%), eosinophilic/flocculent cytoplasm (100%), cytoplasmic vacuoles with inclusions (80%), and nuclear grooves (20%). Four of 5 tumors were high-grade (ISUP/WHO grade 3) with desmoplastic stroma and occasional inflammation. All tumors showed loss of SDHB expression (5/5), while SDHA expression was lost in 4/5, demonstrating that SDHA IHC may be preserved despite SDHA mutation. NGS identified SDHA mutations in four tumors. During follow-up, 2 of 4 patients developed metastases within 14 to 34 months, whereas the remaining 2 had no spread after 11 to 19 months. SDHA-deficient RCC displays a spectrum from classic SDHB-deficient RCC morphology to heterogeneous high-grade tumors. It should be considered in high-grade RCCs, particularly RCC NOS with papillary or collecting duct carcinoma-like morphology and vacuolated tumor cells. NGS is recommended, especially when SDHB loss is detected, as SDHA IHC may be retained. Unlike most SDHB-deficient RCCs, SDHA-deficient RCC appears more aggressive, with increased metastatic risk and poorer prognosis.
Synovial sarcoma is a rare malignant mesenchymal neoplasm that typically occurs in soft tissue sites, and the kidney is an uncommon primary location. Previous studies of primary renal synovial sarcoma are limited by small sample sizes, and our understanding remains incomplete. Here, we present the largest multi-institutional case series to date of primary renal synovial sarcoma, with a focus on novel and molecular findings. A total of 70 cases were contributed by multiple institutions. Comprehensive clinical and histopathologic data were collected and analyzed. The mean patient age was 40 years, with a male-to-female ratio of 1.9:1. The most common presenting signs and symptoms were pain and hematuria. The mean tumor size was 11.6 cm (range: 2.3 to 26 cm), with frequent cystic change and necrosis. The mean follow-up was 29 months (range: 2 to 129 mo), and the rates of metastasis, recurrence, and death due to disease were 62.7%, 33.3%, and 50.0%, respectively. Histologically, 56.1% were monophasic synovial sarcoma, 15.1% were biphasic, and 28.8% were poorly differentiated or showed round cell features. Molecularly, SS18::SSX2 fusion was detected in the majority of cases assessed (n=19), followed by SS18::SSX1 fusion (n=6) and a rare SS18::NEDD4 fusion (n=1). Given the morphologic and immunohistochemical overlaps with many other neoplasms, accurate diagnosis with preferably molecular techniques is crucial for appropriate prognostication and treatment of this aggressive tumor.
ALK-negative anaplastic large cell lymphoma (ALK-negative ALCL) frequently expresses cytotoxic molecules, which may complicate its distinction from peripheral T-cell lymphoma NOS (PTCL-NOS), particularly in cytotoxic molecule-positive cases. Among these, nodal EBV-negative cytotoxic T-cell lymphoma (CTL) represents an important diagnostic consideration. We evaluated the clinicopathological features of ALK-negative ALCL in comparison with nodal EBV-negative CTL and ALK-positive ALCL, with a focus on the immunohistochemical expression of master transcription factors (RORγt, T-bet, and GATA3). RORγt expression was significantly more frequent in ALK-negative ALCL than in nodal EBV-negative CTL (11/21 [52%] vs. 2/25 [8%]; P=0.001), and was uniformly present in ALK-positive ALCL (10/10 [100%]; P=0.012 vs. ALK-negative ALCL). In contrast, T-bet expression was less frequent in ALK-negative ALCL (2/21 [10%]) than in nodal EBV-negative CTL (9/25 [36%]; P=0.045), and was absent in all ALK-positive ALCL cases. RORγt and T-bet expression were largely mutually exclusive across the cohort, with only one overlapping case. GATA3 expression was absent in all evaluable cases of nodal EBV-negative CTL and ALK-positive ALCL, and was detected in only 2 of 19 ALK-negative ALCL cases (11%). These findings suggest that ALK-negative ALCL shows a distinct transcription factor profile characterized by frequent RORγt expression and infrequent T-bet expression, in contrast to nodal EBV-negative CTL. Assessment of these markers may provide a useful adjunct in the differential diagnosis of cytotoxic T-cell lymphomas, particularly in diagnostically challenging cases.
Treatment effects in the urinary bladder are variable and range from localized post-transurethral resection changes to widespread systemic therapy effects. The International Society of Urological Pathology (ISUP) organized a consensus meeting in Vienna, Austria, in September 2025, focused on the evaluation of treatment effects in both the prostate and bladder. Working Group 2 was assigned the topic of the urinary bladder, and a group of pathologists and clinicians was convened. They worked cooperatively to develop a 30-question, premeeting survey for the ISUP membership, which covered the following topics: systemic therapy-related changes, intravesical therapy and radiotherapy-related changes, macroscopic examination and reporting of treated bladder specimens, and relevant ancillary testing methods for grossly residual and/or minimal residual disease. The premeeting survey results highlighted uncertainty about tumor regression grading (TRG), variability in reporting practices for post-resection and intravesical therapy cases, and divergent opinions on the potential utility of molecular testing. Based on findings from this crowd-sourced experience, the Working Group researched the primary medical literature to study the problematic premeeting survey topics, curated focused presentations of published experience for the consensus meeting participants and developed refined consensus questions for consensus voting. Consensus was achieved in 18/19 polling statements. Use of molecular tests to distinguish benign mimickers from carcinoma did not reach consensus. Overall, the surveys and in-person consensus voting supported standardized reporting practices and terminology for post-therapy cases, interdisciplinary development of a bladder TRG scheme, and the utility of select molecular and immunohistochemical testing in the post-treatment setting.
Thyroid carcinomas with mutations in the TSC2 gene have been described rarely. Here, we report a unique thyroid carcinoma that has somatic mutations in TSC2, follicular and melanocytic differentiation and distinct morphologic features, supported by a comprehensive molecular-genetic analyses. No other known pathogenic driver mutations were identified. The TSC2 mutations are predicted to be truncating and result in constitutive activation of mammalian target of rapamycin (mTOR) signaling that was confirmed by transcriptome expression profiling. This is the first demonstration of a thyroid follicular tumor with melanocytic differentiation and corresponding Melan-A expression may be a biomarker for this thyroid cancer. Its diffuse papillary architecture, macronuclei, multinuclear aggregates and intratumoral T lymphocytes are morphologic features not yet described in other TSC2-mutated thyroid carcinomas. Morphologic overlap with classic thyroid papillary carcinoma and known technical difficulties in sequencing the large TSC2 gene make it likely that TSC2-mutated thyroid carcinomas have been underdiagnosed so far. We suggest that TSC2-mutated thyroid carcinoma should be considered in the differential diagnosis of any thyroid tumor that has unusual morphologic and immunohistochemical features or lacks known driver mutations in thyroid cancer.
Metaplastic breast carcinoma (MBC) with squamous differentiation can often be diagnosed by routine histopathologic evaluation, but cutaneous squamous cell carcinoma (cSCC) may enter the differential diagnosis in selected pure squamous carcinomas involving the breast/chest, particularly in limited samples or cases lacking definitive epidermal connection, ductal carcinoma in situ, or complete clinical information. Determining the site of origin is clinically important because management strategies for breast and cutaneous carcinomas differ substantially. We sought to identify immunohistochemical and genetic features that could distinguish MBC with squamous differentiation from cSCC arising in breast/chest skin in cases of uncertain origin. To this end, we comprehensively characterized 15 MBC with pure to mixed squamous differentiation and 18 invasive/in situ cSCC arising in breast/chest skin. Comparisons between these cohorts and 48 SCC of other anatomic sites identified significant immunohistochemical differences, with CK7, SOX10, and TRPS1 expression more frequent in MBC than cSCC (P=0.0005, 0.0227, and 0.0290, respectively). HER2 overexpression was identified only in breast and esophageal carcinomas. Next-generation sequencing of the breast/chest tumors demonstrated more frequent PIK3CA/PIK3R1 alterations in MBC than cSCC (P=0.0040), whereas NOTCH1 mutations were exclusive to cSCC (P=0.0407). cSCC showed higher tumor mutational burden and percentage of ultraviolet-associated mutations than MBC (P=0.0002 and <0.0001, respectively). These distinguishing features were then applied to 9 additional breast cases of uncertain origin, demonstrating the added value of molecular data in diagnostically challenging cases. Overall, these findings support a stepwise diagnostic approach integrating immunohistochemistry, selected molecular features, and clinicopathologic context to aid in this distinction.
Folate receptor alpha (FRα) is highly expressed in tubo-ovarian high-grade serous carcinoma (HGSC), but its expression in serous tubal intraepithelial carcinoma (STIC) and earlier tubal lesions has not been systematically characterized. We evaluated FRα expression across the spectrum of fallopian tube lesions and assessed its potential as an adjunctive diagnostic biomarker. Immunohistochemistry was performed on 408 tubal epithelial samples from 262 patients, including 52 normal fallopian tube samples, 110 secretory cell expansions (SCE), 88 secretory cell outgrowths (SCOUT), 72 serous tubal intraepithelial lesions (STIL), and 56 STICs. An additional 30 HGSCs were included for comparison. FRα expression was assessed using the percentage score ≥2+ (PS2+) system. Associations with germline BRCA status and age were evaluated. FRα expression was detectable in normal fallopian tube epithelium but usually below the high-expression threshold. In contrast, expression was increased in STIC and HGSC, with high PS2+ scores in 73.2% and 76.7% of cases, respectively. Earlier tubal lesions showed predominantly low or negative/very low expression. No significant difference in FRα expression was observed between STIC and HGSC. BRCA-mutated STIC and HGSC showed higher FRα expression than their BRCA nonmutated counterparts, whereas earlier lesions showed no such association. In normal fallopian tube epithelium, FRα expression decreased with age. These findings demonstrate that FRα upregulation is established at the STIC stage and maintained in invasive HGSC. Diffuse high-level expression is uncommon in STIL and earlier lesions, suggesting that FRα may serve as an adjunct biomarker for distinguishing STIC from morphologically overlapping lesions. When interpreted in conjunction with morphology, p53, and Ki-67, FRα may improve diagnostic confidence along the STIL-to-STIC spectrum. The early and sustained upregulation of FRα in STIC also raises interesting questions regarding the timing of FRα-targeted interventions.
Adenomyoepithelioma (AME) of the breast is a biphasic neoplasm prone to misclassification. To enhance diagnostic awareness, we evaluated 26 AMEs stratified across a spectrum of benign (54%), atypical (27%), special salivary gland-like (12%), and malignant (8%) subtypes. Size and borders stratified the spectrum: benign, atypical, and special subtypes (median: 12 to 18 mm) exhibited lobulated/multilobulated contours, whereas malignant AMEs were larger (median: 27.5 mm) and infiltrative. Cytologic atypia and mitoses were predominant in atypical and malignant subtypes. Overall, 35% of cases were reclassified. Surgical excision corrected 6 core biopsy misinterpretations: 3 benign nodular adenosis-like, 1 unidentified benign AME, 1 benign tubular adenoma-like, and 1 atypical AME mimicking infarcted papilloma. Retrospective review reclassified 3 cases: upgrading 2 benign AMEs to atypical due to cytologic atypia with mitoses, and correcting a metastatic malignant AME misclassified as a papilloma with ductal carcinoma in situ. Aberrant myoepithelium was seen in 19% of cases as loss or heterogeneous p63 and calponin expression. Sequencing of a metastatic malignant AME identified co-occurring AKT1 E17K and GNAS R844C mutations shared between the primary mass and its pulmonary metastasis, confirming clonality. Over a median follow-up of 44 months, the disease-free survival rate was 89%, with one benign local recurrence at 29 months and one malignant pulmonary metastasis at 134 months. Recognizing the histologic spectrum of AMEs allows early detection of these tumors with recurrent or metastatic potential. Given the 35% reclassification rate, excision is recommended for AME-like lesions on core biopsy, particularly those measuring >20 mm.
Herein, we report the results of clinicopathologic and radiographic analyses of 55 patients with primary adenocarcinoma of the urethra. Their ages at diagnosis ranged from 42 to 88 years (mean: 66 y). Twenty-six patients were male and 29 were female (ratio: 1.0:1.1). We noted 2 distinct groups of cases: de novo urethral adenocarcinoma (n=45) and urethral adenocarcinoma in patients after radiation therapy for prostatic adenocarcinoma (n=10), defined as postradiation adenocarcinoma. Postradiation tumors developed 8 to 25 years (mean: 15.6 y) after radiation therapy. Eight patients underwent brachytherapy. Among the 45 patients with de novo adenocarcinoma, 29 were female, for a female-to-male ratio of 1.8 to 1.0. In 17 female patients with de novo urethral adenocarcinoma, tumors developed in a urethral diverticulum. Histologically, urethral adenocarcinomas exhibited adenocarcinoma not otherwise specified or clear cell, mucinous, enteric, and adenoid cystic carcinoma morphology. In 2 cases of de novo adenocarcinoma and 3 cases of postradiation adenocarcinoma, the tumors progressed to sarcomatoid carcinoma. The mean disease-specific survival time for the entire cohort was 100.35 months. As reflected by the Kaplan-Meier curves for these patients, the patterns of disease-specific survival were similar in the de novo and postradiation groups.
Male lactotroph pituitary neuroendocrine tumors (PitNETs) are often considered more aggressive than those in women, but surgically treated cohorts are highly selected and may reflect differences in presentation and indication for surgery. We examined whether advanced clinical presentation in surgically treated lactotroph PitNETs is accompanied by distinct pathologic features. We reviewed 43 patients who underwent surgery for lactotroph PitNETs between 2018 and 2023 at a high-volume referral center. Cases were classified by surgical indication as preference for surgery/intolerance to dopamine agonists (P/I, n=26), resistance with hormonal symptoms (R/H, n=10), and resistance with mass effect (R/M, n=7). Clinical, radiologic, and pathologic parameters, including Ki-67, cytokeratin (CAM5.2), estrogen receptor, somatostatin receptor 2/5, and O6-methylguanine-DNA methyltransferase, were compared. Postoperative endocrinological remission was assessed at the last follow-up (median: 34 mo). All tumors were prolactin-immunoreactive, confirming lactotroph differentiation. Patients in the R/M group were older (median: 56 y), predominantly male (71.4%), and had larger tumors (median: 26 mm) with more frequent cavernous sinus invasion (Knosp grade 4, 85.7%) than those in the other groups. Long-term endocrinological remission differed significantly by indication (P/I, 88.5%; R/H, 80.0%; and R/M, 0%). In contrast, Ki-67 labeling index did not differ significantly across groups (P/I, 1.3%; R/H, 1.5%; and R/M, 2.6%; P =0.598), and no clear between-group differences were identified in CAM5.2 pattern, estrogen receptor, somatostatin receptor 2/5, or O6-methylguanine-DNA methyltransferase status. These findings suggest that the clinically most advanced surgical cases are not matched by distinct pathologic differences in the markers assessed and that the apparent aggressiveness of male-predominant mass-effect cases should not be interpreted solely as reflecting intrinsically aggressive tumor biology.
Lipid-rich urothelial carcinoma (LR-UC) is a rare subtype, with ∼65 cases reported in the literature. Here, we report the largest case series of bladder LR-UC, including 40 patients. Clinical follow-up was available for 29 patients. Twenty-seven patients had at least 2-years follow-up, 15 of whom were alive (55.6%) at 2 years. Twenty-six patients had at least 5-years follow-up, 12 of whom were alive (46%) at 5 years. Definitive resection was associated with improved overall survival (OS) (P=0.0188). Neoadjuvant treatment showed a trend towards improved OS compared with resection alone. Patients with a higher percentage of LR-UC (>10%) showed a trend of decreased OS. Positive MDM2 immunostain in both LR-UC and adjacent UC was observed in 6 of 8 tumors, with MDM2 gene amplification confirmed by FISH in one case and MDM2 RNA-ISH overexpression in one additional case. RNA-seq was performed on 9 paired microdissected LR-UC and adjacent UC samples. Principal component analysis demonstrated LR-UC clustered with its paired UC more than with the LR component of other patients. PRSS3P2 was the only component detected to be higher in LR-UC than in UC. GSEA analysis demonstrated that 59.1% of positively enriched genes were metabolism-related, and 57.6% of negatively enriched genes were immune/inflammation-related. In summary, we report the largest LR-UC series to date, highlighting its aggressive clinical behavior, and suggesting a possible benefit of definitive surgical resection and neoadjuvant therapy. MDM2 expression in UC with lipoblast-like cells may pose a diagnostic pitfall and transcriptomic profiling confirm the UC origin lipoblast-like cells.
Renal cysts in autosomal dominant polycystic kidney disease (ADPKD) frequently harbor small intracystic epithelial proliferations that arise in continuity with the cyst lining and are distinct from other recognized proliferative lesions or well-defined renal tumors and lack a formal designation. We aim to provide the histomorphologic, immunohistochemical (IHC), and molecular characteristics of these lesions, determine their incidence, and employ the term papillary hyperplasia (PH), consistent with the recent International Society of Urological Pathology (ISUP) consensus meeting report on precursor lesions of the kidney. A multi-institutional retrospective study of nephrectomies affected by ADPKD was reviewed for PH, histomorphologic features, and clinicopathologic data. PH was defined by intracystic tufted or papillary epithelial proliferations composed of a single layer of bland cuboidal epithelial cells with minimal amphophilic to eosinophilic cytoplasm. IHC stains and molecular analysis using whole-genome sequencing were performed on a subset of cases. Eighty-five nephrectomies from 48 patients demonstrated PH in 88% (75/85) of kidneys. Predominant architectural patterns were tufting (97%), papillary (72%), hobnail (72%), and micropapillary (51%). All PH exhibited low-grade nuclei without atypia, with amphophilic (95%) and/or eosinophilic cytoplasm (63%). The most well-developed PH per case measured 0.3 by 3.1 mm (mean height by width) and occurred within small cysts with an average diameter of 3 mm. PH were positive for KRT7, GATA3, L1CAM, variably positive for AMACR, and negative for CA9 and showed no definitive molecular alterations. PH are common microscopic findings in kidneys affected by ADPKD. PH show a distinct combined histomorphologic, IHC, and molecular profile.
Renal cysts in autosomal dominant polycystic kidney disease (ADPKD) frequently harbor small intracystic epithelial proliferations that arise in continuity with the cyst lining and are distinct from other recognized proliferative lesions or well-defined renal tumors and lack a formal designation. We aim to provide the histomorphologic, immunohistochemical (IHC), and molecular characteristics of these lesions, determine their incidence, and employ the term papillary hyperplasia (PH), consistent with the recent International Society of Urological Pathology (ISUP) consensus meeting report on precursor lesions of the kidney. A multi-institutional retrospective study of nephrectomies affected by ADPKD was reviewed for PH, histomorphologic features, and clinicopathologic data. PH was defined by intracystic tufted or papillary epithelial proliferations composed of a single layer of bland cuboidal epithelial cells with minimal amphophilic to eosinophilic cytoplasm. IHC stains and molecular analysis using whole-genome sequencing were performed on a subset of cases. Eighty-five nephrectomies from 48 patients demonstrated PH in 88% (75/85) of kidneys. Predominant architectural patterns were tufting (97%), papillary (72%), hobnail (72%), and micropapillary (51%). All PH exhibited low-grade nuclei without atypia, with amphophilic (95%) and/or eosinophilic cytoplasm (63%). The most well-developed PH per case measured 0.3 by 3.1 mm (mean height by width) and occurred within small cysts with an average diameter of 3 mm. PH were positive for KRT7, GATA3, L1CAM, variably positive for AMACR, and negative for CA9 and showed no definitive molecular alterations. PH are common microscopic findings in kidneys affected by ADPKD. PH show a distinct combined histomorphologic, IHC, and molecular profile.
Segmental atrophy of the liver (SAL) is a recently described vascular-related pseudotumor. We report a series of 26 SAL cases in cancer patients, highlighting clinical, pathologic, and imaging features, with insights into pathogenesis. Cases were prospectively collected between 2017 and 2023 at the Montpellier Cancer Institute. Lesion staging, vascular lesions, and extralesional changes were systematically assessed, with immunohistochemical analysis. All patients (mean age 68 y; female-to-male ratio 1.7) were under oncologic follow-up; 46% had cardiovascular disease and/or diabetes. The median lesion size was 14 mm. Obliterative thrombosis was identified in 14 of 16 evaluable surgical specimens (88%), involving arteries, veins, or both, with intralesional and/or perilesional distribution. Arteriolar hyperplasia was present in 50% of cases, predominantly in advanced lesions, and showed a nonsignificant trend toward higher prevalence in bevacizumab-treated patients. Sinusoidal obstruction syndrome was observed in 31% of cases. Local contributing factors included prior liver-directed therapy (12% of patients) and concurrent tumor involvement (37% of patients), occasionally suggesting tumor-related vascular compression. We identified SMA-positive stromal cells clustered around small- and medium-sized vessels, supporting a perivascular origin and implicating thrombotic vascular injury in fibroelastotic remodeling. These findings highlight the contribution of both local and systemic factors to vascular injury underlying SAL. Recognition of this pseudotumor is essential to avoid misinterpretation and inappropriate clinical management.
In soft tissue pathology, MUC4 is considered a sensitive and specific immunohistochemical marker for low-grade fibromyxoid sarcoma (LGFMS) and sclerosing epithelioid fibrosarcoma (SEF), which are characterized by FUS/EWSR1::CREB3L2/1 fusions. Recently, MUC4-positive fibroblastoma has been proposed as a novel entity, and we herein describe 7 cases that align with this disease concept. These tumors occurred in 7 female patients aged 14 to 60 years, and they were located in the neck (2 cases), temple, arm, chest wall, pharynx, and thigh, with 5 being deep-seated. All tumors were surgically removed. No patients experienced recurrence during follow-up periods of 2 to 113 months. The well-circumscribed tumors comprised hypocellular fibrous tissue, populated by nonatypical spindle cells. Myxoid stroma was absent. Common features included thin-walled patent vessels, extremely long vessels, and mast cells. In some cases, fat entrapment/overgrowth was conspicuous. All tumors tested positive for MUC4 and nuclear beta-catenin expression. The tumors were molecularly investigated with fluorescence in situ hybridization, RNA sequencing, DNA panel sequencing, DNA methylation analysis, and/or nanopore sequencing. Genetic analysis showed the absence of FUS/EWSR1 fusions in all 7 cases. All 5 tested tumors harbored APC alterations, with 3 having inactivating mutations and 2 showing copy number loss. DNA methylation profiles of 2 tumors did not match those of any references, including LGFMS or SEF, as indicated by t-SNE. Overall, our study supports the recent proposal of MUC4-positive fibroblastoma as a distinct entity and further delineates its phenotypic and molecular characteristics. These tumors should be distinguished from LGFMS, SEF, desmoid fibromatosis, and other fibrous or fibroadipose tumors.
Leiomyomas (LMs) represent the most frequent mesenchymal tumors of the urinary bladder. Despite their relative frequency, large clinicopathological studies are scarce, and their pathogenesis remains poorly understood. In this study, we performed a clinicopathological analysis of 35 bladder LMs and explored whether they share pathogenic mechanisms previously documented in uterine LMs. The tumors occurred in 18 women and 17 men, with a median age of 55 years (range: 20 to 78 y). Clinical data were available for 30 cases (85%). Most tumors were incidentally discovered (16/30, 53%), while the remaining patients presented predominantly with lower urinary tract symptoms. Ten patients had a prior history of cancer, and 3 women had a history of uterine LM. Tumor size, available in 12 cases, ranged from 6 to 66 mm (mean, 31 mm). Histologically, most tumors showed a uniform morphology, consisting of well-circumscribed nodules composed of bland smooth muscle cells without mitotic activity. Rare findings included extensive necrosis (3/35, 8%) and a pseudohyperplastic appearance (1/20, 5%). On immunohistochemistry, a subset of tumors, predominantly in females, expressed estrogen receptors (7/28, 25%), progesterone receptors (5/24, 21%), and androgen receptors (10/23, 43%). HMGA2 expression was observed in one case (1/27, 4%). Fumarate hydratase (FH) expression was retained in all tested tumors (n=31); 2SC expression was detected in 4 tumors (4/32; 12%), all with preserved FH and lacking distinctive histomorphological features of FH-deficient LMs. DNA sequencing of 2SC-positive tumors identified a pathogenic FH variant in one of the 4 analyzed cases at a low variant allele frequency. No other known pathogenic variants, including MED12 commonly seen in uterine LMs, were detected. Altogether, this study characterizes the clinicopathological features of large cohort of bladder LMs, highlighting unrecognized morphologic features, including cases with massive necrosis. Our findings suggest that bladder LMs differ pathogenetically from their uterine counterparts, with a more limited role for hormone receptor signaling and distinct genetic alterations.
Deep penetrating nevus (DPN)-like melanomas are believed to arise through sequential activation of the mitogen-activated protein kinase (MAPK) and Wnt/beta-catenin signaling pathways, followed by additional mutations. Due to their rarity and lack of standardized diagnostic criteria, their molecular landscape and clinical behavior remain still poorly understood. Here, we report the largest cohort to date of 14 DPN-like melanomas. These tumors predominantly affected middle-aged adults (median, 46 y), with the head and neck skin as the most common site. One rare case involved a mucosal site (epiglottis). DPN-like melanomas exhibited infiltrative growth, prominent vertical growth phase, severe nuclear atypia with occasional multinucleation, and increased mitotic activity (median, 3.5/mm2). The median Breslow thickness was 3.3 mm (range: 1.2 to 9.2 mm), with all cases showing microscopic satellitosis, sentinel lymph node positivity, or synchronous metastasis. Most cases (93%) harbored MAPK pathway-activating mutations, predominantly in BRAF (77%), followed by NRAS and EGFR (an upstream regulator of the MAPK pathway). In addition, 79% of cases had mutations activating the canonical Wnt/beta-catenin signaling pathway, mainly in CTNNB1 and APC. Two CTNNB1/APC wild-type cases exhibited alternative mutations in genes indirectly modulating this pathway, such as ARID1A, EZH2, FAT1, and SETD2, along with other mutations, including TERT promoter mutations (TPMs). TPMs were present in 56%, and the median tumor mutational burden was 30 mutations/Mb. After a median follow-up of 33.5 months, 36% of patients developed distant metastases, and 2 patients died of disease 8 and 32 months, respectively, after initial diagnosis. These findings expand the molecular diversity of DPN-like melanomas and provide valuable insights into their clinical outcomes.
The coexistence of benign mesonephric-like proliferation (MLP), mesonephric-like hyperplasia (MLH), and mesonephric-like adenocarcinoma (MLA) with ovarian mucinous cystadenoma or mucinous borderline tumor (MBT) has been previously reported; however, this phenomenon is exceedingly rare, and understanding of the pathology and biology remains limited. Here we report additional cases, with an emphasis on expanded observations and novel pathologic features. This series included 9 cases: (1) 2 cases of mixed MLA and endometrioid adenocarcinoma associated with cystic mucinous neoplasm of lower gastrointestinal (GI) type (case 1) or mucinous cystadenoma (case 2); (2) 1 case of MLA associated with MBT and mucinous adenocarcinoma (case 3); (3) 4 cases of MLA associated with MBT (cases 4 and 5) or mucinous cystadenoma (cases 6 and 7); and (4) 2 cases of MLP/MLH associated with MBT (cases 8 and 9). All mesonephric-like lesions were diffusely positive for PAX8 and either diffusely (7 cases) or focally (2 cases) positive for GATA3. Focal TTF-1 expression was observed in 4 cases (4/9, 44.4%). All mucinous tumors, except for case 1, showed either focal (4 cases) or diffuse (4 cases) PAX8 positivity. Molecular analysis in case 1 revealed a common KRAS p.G12A driver mutation in all 3 tumor components (MLA, endometrioid adenocarcinoma, and mucinous tumor), indicating clonal relatedness. In contrast, pathogenic somatic mutations in ARID1A , DNMT3A , PIK3CA , and TET2 were detected only in the MLA and endometrioid adenocarcinoma, but not in the mucinous tumor component, suggesting lineage-specific differentiation. Notably, case 1 represents the first reported example of a mesonephric-like lesion associated with a mucinous tumor exhibiting lower GI morphology and immunophenotype. Case 3 represents the first case with mucinous adenocarcinoma in this scenario. Case 9 represents the first reported instance in which both ovaries were independently involved by MLP/MLH and MBT. The presence of benign MLP/MLH alongside MLA suggests that the former may represent noncancerous precursor lesions with the potential to develop into MLA; they may represent benign (MLP) or borderline (MLH) mesonephric-like lesions. Whether mesonephric-like lesions serve as precursors of ovarian mucinous tumors remains debated, but their coexistence in the ovary, as documented in 20 cases to date (including previously published cases and the current series), may represent a unique biological process and provide an ideal model for investigating mechanisms of transdifferentiation and tumorigenesis.
Clear cell adenocarcinoma of the urinary tract (CCA-UT) is a rare, potentially aggressive tumor with very limited information regarding its clinicopathologic characteristics and molecular alterations. This study aimed to elucidate the clinicopathologic features and molecular landscape of one of the largest cohorts (35 cases) of this tumor, to identify genomic alterations and potential therapeutic targets. Seventy-nine percent of the patients were women, with a median age of 61 years. The urethra was the most common site (18; 51%), and all cases were ≥pT2 (pT2:15; pT3:11; pT4:8). Twenty-nine percent of the patients died of their disease on follow-up. On whole-exome sequencing, pathogenic/oncogenic alterations were identified in 91% (32/35) cases. These alterations, most frequently involved chromatin modifiers (66% cases), including ATRX , KMT2C , ARID1A , and ARID1B . Other frequently mutated genes included ATM , NF1 , and ERBB2 . Ninety-seven percent (34/35) of cases were microsatellite stable, and tumor mutational burden (TMB) was >10 mut/Mb in 9% (3/35) of cases. Five cases were homologous recombinant-deficient on ScarHRD analysis, and 3 cases showed BRCA mutations. Recurrent copy number loss events in Chr 1(p36.33-p35.3) were the most common copy number alterations (80%; n=28 cases). RNA-sequencing data analysis revealed numerous differentially expressed genes and enrichment of the epithelial-to-mesenchymal transition gene signature in individual samples. However, there was no statistical significance in the progression-free survival between cases with epithelial and mesenchymal phenotypes. CCA-UT are aggressive tumors with a heterogeneous molecular profile, underscoring the role of molecular analysis in identifying potential therapeutic options for the treatment of this pernicious tumor.
Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment for refractory hematologic malignancies; however, gastrointestinal adverse events (GI-AEs) are increasingly recognized as its use expands. We identified 6 patients with GI-AEs following CAR-T therapy over a 5-year period at our institution and conducted a comprehensive PubMed literature review to characterize histopathologic patterns and highlight differential diagnostic considerations. In the institutional cohort, the colon was most frequently involved (83%), followed by the small bowel (67%) and stomach (33%). Most patients developed watery diarrhea (83%) with negative infectious studies. Symptom onset occurred at a median of 107 days after infusion (range, 19 to 236 d). Twenty-one gastrointestinal biopsies were evaluated; 15 (71%) showed histologic abnormalities. Four histologic patterns were identified: active inflammation (33%), chronic active inflammation (27%), apoptosis-predominant injury (27%), and chronic inflammation (13%). Crypt epithelial apoptosis or intraepithelial apoptotic bodies were present in 67% of biopsies. Site-specific patterns included active colitis in the colon, chronic or chronic active duodenitis in the duodenum, apoptosis-predominant ileal injury, and active gastritis in the stomach. The literature review identified 22 additional patients, with histopathologic data available in 21 cases. Findings overlapped substantially with the institutional cohort and most commonly involved the colon and small intestine, with heterogeneous clinical outcomes. Overall, CAR-T-associated GI-AEs demonstrate reproducible yet nonspecific clinicopathologic features that overlap with immune-mediated, drug-related, infectious, and inflammatory conditions, necessitating careful clinicopathologic correlation and exclusion of alternative etiologies.
