Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Shaomin Hu, MD, PhD, gastrointestinal/liver pathology fellow, University of Chicago; and S. Emily Bachert, MD, pathology resident, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington.
Prognostic significance of tumor budding in gastric carcinoma
June 2020—The authors conducted a study in which they independently evaluated the utility and prognostic value of tumor budding according to International Tumour Budding Consensus Conference (ITBCC) criteria in a large well-characterized European gastric cancer cohort. They assessed tumor budding according to the ITBCC criteria for 456 consecutive, surgically treated gastric cancers using the scoring system Bd0 (no buds), Bd1 (one to four buds), Bd2 (five to nine buds), and Bd3 (10 or more buds). Cases with tumor budding were divided into low-budding (Bd1/Bd2) and high-budding (Bd3) groups. The tumor budding score was analyzed in relation to clinicopathological parameters, overall survival, and tumor-specific survival. The authors found that 115 (25.2 percent) cases had no tumor budding, 104 (22.8 percent) had low tumor budding, and 237 (52 percent) had high tumor budding. The tumor budding score correlated significantly with gender; Laurén phenotype; grade; T, N, and M categories; Union for International Cancer Control stage; lymph node ratio; presence of lymphatic and perineural invasion; and R status. The authors reported significant associations between the presence and extent of tumor budding and presence of lymph node metastasis in total and intestinal-type early invasive gastric cancer (n = 57 and n = 41, respectively). Significant differences in overall survival and tumor-specific survival were found between the tumor budding groups. However, tumor budding did not retain significance in multivariate models. These data show that the ITBCC criteria can be applied to gastric cancer. The data correlated significantly with the diverse clinicopathological characteristics, including patient outcomes, and can help standardize diagnostics and research for special histological features of malignant tumors, in general, and gastric cancer in particular.
Ulase D, Heckl S, Behrens HM, et al. Prognostic significance of tumour budding assessed in gastric carcinoma according to the criteria of the International Tumour Budding Consensus Conference. Histopathology. 2020;76(3):433–446.
Correspondence: Dr. Christoph Röcken at christoph.roecken@uksh.de
Myxoid smooth muscle neoplasia of the uterus: analysis by NGS and nucleic acid hybridization
Uterine myxoid smooth muscle tumors, including myxoid leiomyosarcoma, are rare and their genomic profile has not been fully characterized. With the discovery of uterine sarcomas with ZC3H7B-BCOR fusion and BCOR internal tandem duplications, the differential diagnosis of myxoid smooth muscle lesions is expanding to include molecularly defined tumors. Therefore, the authors aimed to explore the genomic landscape of myxoid smooth muscle tumors using comprehensive tools. They performed whole exome next-generation sequencing and a pan-sarcoma RNA fusion assay in tumoral paraffin-embedded tissue from nine well-characterized uterine myxoid smooth muscle tumors—seven myxoid leiomyosarcomas and two myxoid smooth muscle tumors of unknown malignant potential. Using IHC, all tumors were found to be strongly positive for smooth muscle markers and negative for BCOR staining. Four of six tumors expressed PLAG1. None of the tumors harbored known fusions, including ZC3H7B-BCOR, TRPS1-PLAG1, and RAD51B-PLAG1. In addition, none harbored exon 15 BCOR internal tandem duplications. However, four tumors contained BCOR internal tandem duplications of unknown significance (mostly intronic). Mutational burden was low (median, 3.8 mutations per megabase). DNA damage repair pathway gene mutations, including TP53 and BRCA2, were found. Copy number variation load, inferred from sequencing data, was variable, with genomic indices ranging from 2.2 to 74.7 (median, 25.7). Higher indices were found in myxoid leiomyosarcomas than in myxoid smooth muscle tumors of unknown malignant potential. The absence of clear driver mutations suggests that myxoid smooth muscle tumors are a genetically heterogeneous group of tumors and that other genetic or epigenetic events drive the pathogenesis of uterine myxoid smooth muscle neoplasia.
Yoon JY, Mariño-Enriquez A, Stickle N, et al. Myxoid smooth muscle neoplasia of the uterus: comprehensive analysis by next-generation sequencing and nucleic acid hybridization. Mod Pathol. 2019;32:1688–1697.
Correspondence: Dr. Carlos Parra-Herran at carlos.parraherran@utoronto.ca
Adverse histologic features in colorectal nonpedunculated malignant polyps with nodal metastasis
Tumor differentiation, lymphovascular invasion, margin status, and polyp shape and size are some of the pathologic risk factors for malignant polyps (pT1) on which the decision to perform surgical resection is based. However, size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The authors conducted a study to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. They reviewed 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens identified through a 2005 to 2018 pathology database search. Patients with nodal metastasis were more often positive for high-grade tumor budding (70.8 versus 16.7 percent; P = .0005), poorly differentiated clusters (54.2 versus 22.2 percent; P = .0369), and both high-grade tumor budding and poorly differentiated clusters (45.8 versus 11.1 percent; P = .0160) than were controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and high-grade tumor budding and poorly differentiated clusters combined increased the risk of nodal metastasis, with odds ratios of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimens, even in completely excised malignant polyps with adverse histologic features. These findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features for predicting lymph node metastatic potential. These histologic features should be reported and may warrant colectomy when present.
Patel N, Vyas M, Celli R, et al. Adverse histologic features in colorectal nonpedunculated malignant polyps with nodal metastasis. Am J Surg Pathol. 2020;44(2):241–246.
Correspondence: Dr. Xuchen Zhang at xuchen.zhang@yale.edu
Mesothelioma in situ: morphologic features and clinical outcome
The existence of an in situ phase of malignant mesothelioma has long been postulated but, until recently, has been impossible to prove. The authors conducted a study in which they described 10 patients with mesothelioma in situ, defined by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining; no evidence of tumor using imaging or direct examination of the pleura/peritoneum, or both; and no invasive mesothelioma developing for at least one year. Nine of the cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology. In two patients, mesothelioma in situ was found incidentally in lung cancer resections. In addition to having surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Using IHC, methylthioadenosine phosphorylase showed partial loss in the surface mesothelium in three cases. Invasive malignant mesothelioma developed in seven patients, with time between biopsy and invasive disease ranging from 12 to 92 (median, 60) months. Invasive mesothelioma had not developed in the other three patients at 12, 57, and 120 months. However, the latter patient, who had pleural plaques, continued to have repeated pleural effusions, probably representing a so-called benign asbestos effusion. The authors concluded that mesothelioma in situ, as diagnosed using the criteria outlined herein, is associated with a high risk of developing invasive mesothelioma, typically over a relatively protracted time, allowing for the possibility of curable interventions.
Churg A, Galateau-Salle F, Roden AC, et al. Malignant mesothelioma in situ: morphologic features and clinical outcome. Mod Pathol. 2020;33(2):297–302.
Correspondence: Dr. A. Churg at achurg@mail.ubc.ca
SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas
A rare subset of aggressive SMARCA4-deficient uterine sarcomas was recently proposed. The authors conducted a study in which they identified 16 additional cases of SMARCA4-deficient uterine sarcoma from the database of a large CLIA-certified and CAP-accredited reference molecular laboratory and expanded on the spectrum of their clinicopathological, morphological, and genomic features. The patients were a median age of 49 years (range, 32–70 years). Most of the tumors were aggressive and had distant metastasis. The SMARCA4-deficient uterine sarcomas demonstrated predominantly rhabdoid or large epithelioid cells with abundant cytoplasm, but they also had varying degrees of small cell and spindle cell morphology. The tumors were microsatellite stable and exhibited few or no other co-occurring genomic alterations by comprehensive genomic profiling. The authors identified one patient who developed SMARCA4-deficient uterine sarcoma at the age of 55, had a germline SMARCA4 mutation, and whose daughter had died of small cell carcinoma of the ovary, hypercalcemic type, at the age of 32. These data support the assertion that SMARCA4 inactivation is the driver oncogenic event of a morphologically and molecularly distinct form of uterine sarcoma. Therefore, it may be important to identify SMARCA4-deficient uterine sarcomas due to their aggressive behavior and germline association and because of the emergence of targeted therapies.
Lin DI, Allen JM, Hecht JL, et al. SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. Mod Pathol. 2019;32:1675–1687.
Correspondence: Dr. Douglas I. Lin at dlin@foundationmedicine.com
Pathological risk factors for metastatic disease at presentation in testicular seminomas
Management of clinical stage I testicular seminoma is controversial, and treatment choice is based on a number of pathological risk factors. Furthermore, testicular seminomas have been inconsistently associated with risk of metastatic disease. The eighth edition of the American Joint Committee on Cancer AJCC Cancer Staging Manual has separated pT1a and pT1b tumors according to a 3-cm size cutoff and upstaged invasion of hilar soft tissue and epididymis as pT2. The authors investigated pathologic predictors of metastatic disease at presentation in 332 testicular seminomas. Age, tumor size, invasion of vessels, hilar soft tissue, rete testis, epididymis, spermatic cord, tunica vaginalis, and tumor at spermatic cord margin were assessed and correlated with clinical stage at presentation. Of the 332 seminomas, 290 (87 percent) were clinical stage I and 42 (13 percent) were clinical stage II/III. Median patient age for those who were clinical stage I was 36 years (20–81 years) and for those who were clinical stage II/III was also 36 years (26–63 years). Mean tumor size for clinical stage I was 38 mm (5–95 mm) and for clinical stage II/III was 54 mm (8–95 mm). On univariate analysis, lymphovascular invasion (P = .044), epididymal invasion (P = .009), and tumor size (P = .0001) were associated with higher clinical stage. On multivariate analysis, tumor size (P = .0001) and epididymal invasion (P = .023) remained significant. Optimal tumor size cutoff was 4.25 cm. The authors concluded that tumor size and epididymal invasion are the strongest predictors of metastatic disease at presentation. The study results validate the changes in the eighth edition of the AJCC Cancer Staging Manual but suggest a tumor size of 4 cm as a better cutoff value.
Scandura G, Wagner T, Beltran L, et al. Pathological risk factors for metastatic disease at presentation in testicular seminomas with focus on the recent pT changes in AJCC TNM eighth edition. Hum Pathol. 2019;94:16–22.
Correspondence: Dr. Glenda Scandura at g.scandura@qmul.ac.uk