American Journal of Surgical Pathology最新文献

TFEB -altered renal cell carcinoma (RCC) included TFEB -rearranged and TFEB -amplified RCC with unclear clinicopathological features and treatment options. Cases of TFEB -altered RCCs were collected. Fourteen cases showed TFEB rearrangement. Five MALAT1::TFEB fusions and one ACTB::TFEB fusion were verified. 8/14 TFEB -rearranged RCCs showed biphasic "pseudorosette" structure. All TFEB -rearranged RCC patients were alive without recurrence or metastasis after 3 to 122 months. Fifteen cases showed TFEB amplification, including 5 high-level amplifications (>10 copies) and ten low-level amplifications (5 to 10 copies), including 3 cases showing concomitant TFEB amplification and rearrangement. TFEB -amplified RCCs were high-grade, showing papillary, solid, nested, or alveolar arrangements of cells. In addition, 8 cases showed 3 to 4 TFEB signals were collected, indicating diverse morphologies. PDL1 membranous staining was observed in 9/10 TFEB -rearranged RCCs, and 11/13 TFEB -amplified RCCs. Copy number variation analysis revealed specific amplification of chromosome 6p21.1, where TFEB, VEGFA6 , and CCND3 were located, in one high- and 2 low-level amplification cases. Four cases with 3 to 4 TFEB signals did not show specific amplification of this region. Within the follow-up periods of 3 to 64 months, 8/13 TFEB -amplified RCC cases presented with metastasis, and 3/13 patients died in the 12th and 24th months. The treatment processes in several cases and the detailed therapeutic course of a TFEB -amplified case were documented, highlighting the efficacy of PD-1 inhibitors. Our research supported a cutoff of ≥5 TFEB copies for the diagnosis of TFEB -amplified RCCs, though further studies were needed regarding the threshold. The expression of PDL1 might indicate a potential benefit of PD-1 inhibitors.

Evaluation of T-cell receptor (TCR) β-chain constant region 1 (TRBC1) expression is an alternative T-cell clonality assessment method. However, evaluation of TRBC1 immunohistochemistry (IHC) for distinguishing mycosis fungoides (MF)/Sezary syndrome (SS) from reactive inflammatory infiltrates in skin is incomplete. We evaluated the utility of a novel dual TRBC1-CD3 IHC stain in skin biopsies with MF/SS (n=40), reactive (n=24), or atypical T-cell infiltrates indeterminant for MF/SS (n=9). Twenty of 24 reactive cases showed clear polytypic TRBC1 expression (median percent TRBC1 positivity among CD3-positive T cells [%TRBC1+] 50% in dermis, 42.5% in epidermis among all cases), while 34/40 MF/SS were clearly monotypic (%TRBC1+ either ≤20% or ≥85%) (sensitivity 85.0%, specificity 91.7%, positive predictive value 94.4%, negative predictive value 78.6%). Discordance between TRBC1 expression and diagnosis was associated with few neoplastic/monotypic T cells and/or lack of physical separation between neoplastic and non-neoplastic populations. Among patch/plaque MF/SS, TRBC1 showed similar diagnostic sensitivity (80.0% vs. 86.7%) and high categorical correlation (monotypic vs. not monotypic, 80%) with TCR gene rearrangement results. TRBC1 interpretation was reproducible, with ≥2/3 and 3/3 pathologists rendering identical interpretations in 100% and 86% of cases, respectively, after independent review and 100% agreement following collective review. Digital image analysis confirmed visual %TRBC1+ accuracy ( r =0.9749, P <0.0001). On the basis of these results, we propose %TRBC1+ cutoffs of <25% or >75% for establishing T-cell monotypia in skin. Considering such thresholds, TRBC1-CD3 evaluation facilitated diagnostic refinement in 7/9 (78%) atypical cases. Overall, TRBC1-CD3 IHC clearly and rapidly aids diagnosis of cutaneous T-cell proliferations.

Most salivary gland tumors are found to have genetic fusions driving their oncogenesis, with an explosion of such findings in recent years. They typically represent previously identified and well-characterized tumors and the fusions are generally not necessary for diagnosis but rather serve as diagnostic arbitrators in challenging cases. That said, occasional unexpected molecular findings are broadening our understanding of these common tumors and have led to the emergence of new entities, some of which were "hiding in plain sight" and are quite common, like secretory carcinoma. In contrast, others are sufficiently rare that molecular testing was required to identify them in small cohorts, combining cases from multiple institutions, such as microcribriform adenocarcinoma. Recently, we identified a rare case of tongue adenocarcinoma with EWSR1::BEND2 fusion with an unusual morphology, and 2 additional cases were subsequently briefly reported in the literature. In this study, we collected and analyzed a total of 7 cases that show variable but consistent morphology, including a fenestrating glandular appearance, occasional squamous or basaloid growth, and focal mucinous cells. The tumors showed a predilection for the pharynx with 4 cases in the base of the tongue, one case in the tonsil/oropharyngeal wall, one case in the nasopharynx, and only one nonpharyngeal case in the trachea. No oral cavity or major salivary gland tumors were found with this set of findings to date. The tumors showed some aggressive tendencies, with 2/4 with follow-up information having adverse outcomes, including lymph node metastases in 2 cases and 1 of these cases also having brain metastases, recurrence, and death from disease. All cases tested showed EWSR1::BEND2 fusion by NGS, as well as CK7/BEND2 positivity, and S100 negativity by immunohistochemistry. The tumors showed variable p63 staining depending on whether squamous or basaloid features were present. A tissue microarray (TMA) stained with an antibody directed against the BEND2 protein showed no significant staining in any other salivary tumor type. The constellation of findings in this cohort is highly suggestive of a specific entity, and we propose the appellation "Fenestrating Adenocarcinoma (FAC)" of the salivary gland.

Brain metastasis (BRM) of pancreatic ductal adenocarcinoma (PDAC) is rare. The clinicopathological characteristics of BRM have not been defined. We reviewed the clinicopathologic and molecular features of 18 PDAC patients who underwent resection of primary tumor (RPT) and developed BRM, along with 2 patients who had BRM resection without RPT and compared with 679 patients without BRM who received neoadjuvant therapy (NAT) and pancreatectomy. There were 11 males and 9 females (median age: 60.7 y). The median intervals to BRM were 47.0, 44.4, and 31.6 months from dates of diagnosis, surgery, and first metastasis to other sites, respectively. Five patients underwent resection for BRM and showed unique cystic papillary growth patterns with detached cell clusters. All BRMs had mutant p53 staining, 4 had retained SMAD4, and 3 were focally positive for CK17. Among 18 patients who underwent RPT, 12 received NAT. Patients with BRMs have lower tumor stage ( P <0.001) and better tumor response ( P =0.01) at RPT. The median overall survival (OS) for 18 patients with BRM after RPT was 62.3 months compared with 42.4 months for those without BRM (n=679, P =0.59). The median survival was 3.3 months from BRM diagnosis for all patients and 6.9 months for 5 patients who underwent brain surgery. In summary, BRM represents a late event in PDAC patients, occurs after patients developed metastasis to other organs, and has distinct cystic papillary growth pattern. The prognosis for patients who underwent RPT and developed BRM is similar to those who underwent RPT without BRM.

POLE-mutated endometrial carcinomas (POLEmut EC) have the most favorable prognosis among all TCGA molecular subgroups. Though the consequent "ultramutated" phenotype is recognized as a trademark feature, hypermutated tumors (10-100 mutations/megabase), as well as those that are histologically low-grade, have been described. Herein, we investigate 19 POLEmut ECs from a single institution to determine whether morphologic and genomic differences exist between tumors with high tumor mutational burden (TMB-H: 10-100 mutations/megabase) and ultra-high TMB (TMB-UH: >100 mutations/megabase). All tumors were FIGO stage I, of endometrioid histotype, and no patients recurred (median follow-up of 90 mo). Six previously described POLE exonuclease domain mutations were detected, with the 2 most common being P286R (n=7) and V411L (n=6). Seven ECs were TMB-H (median 76 mutations/megabase), and 12 TMB-UH (median 187 mutations/megabase). TMB-UH tumors were more frequently high-grade, with intratumoral heterogeneity, serous-like nuclei, and bizarre nuclei. Using an integrated approach, multiple classifiers were observed in both cohorts (53% of all tumors); however, those associated with MMRd were exclusive to TMB-UH ECs. All TMB-H ECs had a dominant (>50%) POLE mutational signature, in contrast to only 5 TMB-UH tumors. The remaining TMB-UH ECs demonstrated mixed signatures associated with mismatch repair deficiency (MMRd, n=4) or nonspecific signatures (n=3). All POLEmut tumors were enriched in single-nucleotide variants, while insertions-deletions were rare (maximum of 1.7%). In both groups, all harbored PTEN mutations, with other commonly recurring mutations including PIK3CA, ATRX, BRCA2, FBXW7, and NF1. ARID1A mutations were not identified in any TMB-H ECs. Although our cohort is small, the morphology of POLEmut ECs appears to be influenced by TMB, a phenomenon not yet described in the evolving landscape of these tumors. Taken in combination with differences in underlying genomic signatures, these findings provide an interesting springboard for better understanding POLEmut EC pathobiology.

Patients undergoing periods of starvation or malnutrition may develop degenerative and/or atrophic changes of various organs. These findings may manifest histologically and may cause confusion when first encountered, raising a differential that includes benign and malignant tumor entities. Herein, we report 16 cases of incidentally identified degenerative changes within abdominal-site fatty tissues that caused diagnostic difficulties. The patients were 11 males and 5 females, aged from 1 day to 82 years (mean: 58 years). The degenerative changes were all incidentally identified within adipose tissue of the abdominal cavity or adjacent to organs contained within the abdominal cavity in procedures done for unrelated reasons such as cancer, infection, or perforation. Cases were identified in the colon (n=6), small intestine (n=4), omentum (n=3), inguinal hernia sac (n=1), peritoneum (n=1), and retroperitoneal soft tissue (n=1). Patients had variable past medical histories with multiple comorbidities. Ten patients presented with some form of malnutrition and/or cachexia. Histologically, the lesions demonstrated lobules of atrophic-appearing fat with small signet-ring-like adipocytes that were sometimes bilobed. The nodules varied in size and were characterized in some cases by a variably myxoid stromal background, often with a prominent delicate capillary network. Immunohistochemistry was performed and was uniformly positive for S100 protein and negative for cytokeratins. The lesions were generally recognized as degenerative, but various differential diagnoses proposed at the time of sign-out included signet-ring cell carcinoma, liposarcoma, and vascular lesions, among others. Nomenclature to describe this phenomenon has been inconsistent in the literature, and thus, we suggest the term "pseudoneoplastic fat atrophy."

Silicone granulomas can have histologic features that mimic xanthogranulomatous inflammation, particularly in small samples or when the diagnosis is unsuspected. Histochemical stains for microorganisms may be performed to assess for infection in such cases. After observing diffuse Fite staining in a specimen exhibiting histologic features of silicone granuloma, the frequency of Fite staining in a series of confirmed silicone granulomas was assessed. Modified acid-fast (Fite) staining was performed in 20 silicone granuloma cases. In a subset (n=5), Ziehl-Neelsen (Z-N), Grocott's methenamine silver (GMS), and Brown & Brenn (B&B) stains, as well as mycobacterial immunohistochemistry were also performed. All 20 cases (100%) demonstrated Fite staining, ranging from patchy (45%) to diffuse (55%). Finely vacuolated histiocytes exhibited reticular to granular Fite staining, some morphologically resembling bacteria, whereas larger vacuolar spaces showed globular to crescent-like staining at their peripheral edges. Focal Z-N staining in a pattern similar to Fite staining was observed in 4 of the 5 cases examined. GMS, B&B, and mycobacterial IHC were negative. Silicone granulomas consistently show Fite staining. While the reason for this is uncertain, it is postulated that the hydrophobicity of silicone polymers may simulate the hydrophobic barrier of mycolic acids, preventing entry of decolorizer and removal of the primary stain. Recognition of this phenomenon is important to avoid misinterpretation of silicone granulomas as infectious. Fite staining may also serve as a potential diagnostic aid in cases with histologic features of silicone granuloma in which a history of silicone injection or silicone implant use is not established.

Proteus syndrome is a rare mosaic overgrowth disorder caused by somatic activating variants in AKT1, most commonly the c.49G>A p.(Glu17Lys) variant. It predisposes individuals to asymmetric tissue proliferation and an elevated risk for both benign and malignant neoplasms. Among 64 males with genetically confirmed Proteus syndrome enrolled in a longitudinal natural history study, 12 (19%) underwent surgery for paratesticular masses. The average age at surgery was 9 years, most tumors were unilateral, small (median 1.6 cm), and slow growing, but 50% showed recurrence or metachronous tumor development, occasionally with progression to more atypical histology. Histologically, these tumors demonstrated a broad spectrum of differentiation. Eight reviewed cases included Müllerian-type papillary cystadenomas and low-grade papillary adenocarcinomas, a Brenner tumor, and one case of a papillary adenocarcinoma with spindle cell transformation. The epithelial components were typically arranged in papillary and glandular architectures, with variable degrees of cytologic atypia. Psammomatous calcifications were common. Immunohistochemistry showed consistent expression of PAX8(7/7), WT1(7/7), estrogen receptor (ER)(7/7), and progesterone receptor (PR)(6/7), supporting Müllerian lineage, while negative staining for germ cell and mesothelial markers excluded common paratesticular differential diagnoses. Four of the 7 tumors were positive for SF-1. All 7/7 sequenced tumors harbored the AKT1 c.49G>A variant with no additional oncogenic alterations identified by exome sequencing. This series is the largest series to date documenting the clinicopathologic features of paratesticular tumors, a poorly understood component of the Proteus syndrome phenotype.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting for B-cell maturation antigen (BCMA) is used to treat patients with multiple myeloma (MM). To investigate gastrointestinal changes associated with CAR-T therapy, we performed a retrospective study. A total of 10 patients with 26 gastrointestinal biopsy specimens who underwent CAR-T therapy for MM were identified. Except for one patient with residual multiple myeloma, all specimens demonstrated markedly reduced or absent plasma cells. The most prominent biopsy findings occurred in the small intestine, primarily the duodenum, and included lamina propria lymphocytic infiltration, villous atrophy, foveolar metaplasia, an absence of plasma cells, and an increase in intraepithelial lymphocytes. There was an average of 7 apoptotic bodies per 10 high-power fields (hpf). The terminal ileum was also notable for increase in apoptotic bodies (average of 9.5 apoptotic bodies/10 hpf), villous atrophy, and lamina propria lymphocytic infiltration. The stomach biopsies overall typically showed mild inflammation with no increase in apoptotic bodies. A few colonic specimens demonstrated active colitis and prominent apoptotic bodies, while the majority of the colonic biopsies did not have significant findings other than melanosis coli, and an absence or reduction of plasma cells. The disproportionately greater injury in the duodenum versus the colon highlights the importance of upper endoscopic evaluation in symptomatic patients after CAR-T therapy. The mechanisms for these patterns of injury and differential anatomic findings are unknown; however, an immune-mediated injury associated with CAR-T therapy is suspected. Our study identifies a unique pattern of intestinal injury in patients with MM who received BCMA-targeted CAR-T therapy; this encompasses histologic findings more profound in the small intestine, which include absence of plasma cells, an increase in apoptotic bodies, lymphocytic infiltration, and villous atrophy.