J. Kenneth Schoolmeester

Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations.

The Cancer Genome Atlas described four major genomic groups of endometrial carcinomas, including a POLE ultramutated subtype comprising ∼10% of endometrioid adenocarcinoma, characterized by POLE exonuclease domain mutations, ultrahigh somatic mutation rates, and favorable outcome. Our aim was to examine the morphological and clinicopathological features of ultramutated endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Hematoxylin and eosin slides and pathology reports for 8/17 POLE-mutated endometrial carcinomas described in the Cancer Genome Atlas study were studied; for the remaining cases, virtual whole slide images publicly available at cBioPortal (www.cbioportal.org) were examined. A second cohort of eight POLE mutated endometrial carcinomas from University of Calgary was also studied. Median age was 55 years (range 33–87 years). Nineteen patients presented as stage I, 1 stage II, and 5 stage III. The majority of cases (24 of the 25) demonstrated defining morphological features of endometrioid differentiation. The studied cases were frequently high grade (60%) and rich in tumor-infiltrating lymphocytes and/or peri-tumoral lymphocytes (84%); many tumors showed morphological heterogeneity (52%) and ambiguity (16%). Foci demonstrating severe nuclear atypia led to concern for serous carcinoma in 28% of cases. At the molecular level, the majority of the Cancer Genome Atlas POLE-mutated tumors were microsatellite stable (65%), and TP53 mutations were present in 35% of cases. They also harbored mutations in PTEN (94%), FBXW7 (82%), ARID1A (76%), and PIK3CA (71%). All patients from both cohorts were alive without disease, and none of the patients developed recurrence at the time of follow-up (median 33 months; range 2–102 months). In conclusion, the recognition of ultramutated endometrial carcinomas with POLE exonuclease domain mutation is important given their favorable outcome. Our histopathological review revealed that these tumors are commonly high grade, have obvious lymphocytic infiltrates, and can show ambiguous morphology. As they frequently harbor TP53 mutations, it is important not to misclassify them as serous carcinoma.

JAZF1 rearrangement in a mesenchymal tumor of nonendometrial stromal origin: Report of an unusual ossifying sarcoma of the heart demonstrating JAZF1/PHF1 fusion

Rearrangements of JAZF1 are a frequent genetic aberration in endometrial stromal tumors. We report a distinct primary cardiac ossifying sarcoma that harbored a JAZF1/PHF1 fusion. The patient was a 70-year-old man with a history of a 6.8 cm calcific intramural left ventricular mass. Six years after his initial evaluation, the patient developed multiple lung metastases and ultimately died of disease-related complications. Histologically, the cardiac tumor and lung metastases demonstrated an infiltrative, malignant spindle cell neoplasm that grew in short fascicles with areas of bone formation, nuclear palisading, and necrosis. The neoplastic cells were relatively monomorphic in a background of an amorphous collagenous matrix. Immunohistochemical analysis was positive for vimentin and negative for wide-spectrum cytokeratins, S100 protein, desmin, smooth muscle actin, and CD34. Fluorescence in situ hybridization using a dual-color, single-fusion probe set identified the JAZF1/PHF1 fusion. The unique morphology and the presence of a JAZF1/PHF1 rearrangement suggest that this distinctive ossifying sarcoma is not part of a currently established diagnostic entity, representing instead a novel primary cardiac sarcoma. This case also represents the first description of a JAZF1 fusion in a tumor outside the spectrum of endometrial stromal neoplasms.

Analysis of MDM2 Amplification in 43 Endometrial Stromal Tumors: A Potential Diagnostic Pitfall.

MDM2 amplification is known to occur in a variety of neoplasms and its detection by fluorescence in situ hybridization is helpful in distinguishing well-differentiated and dedifferentated liposarcoma from classic lipoma. We recently evaluated a mesenteric mass initially diagnosed as dedifferentiated liposarcoma, largely due to the neoplasm’s myxoid morphology and MDM2 expression by immunohistochemistry, from a 46-yr-old woman with a history of uterine low-grade endometrial stromal sarcoma (LG-ESS) with a JAZF1 rearrangement. Our workup of the mesenteric mass revealed a JAZF1 rearrangement and a revised diagnosis of metastatic LG-ESS with myxoid change was rendered. Retrospective testing of the mesenteric mass was negative for MDM2 amplification, an uncommon, but known diagnostic pitfall in MDM2 expression by immunohistochemistry. As MDM2 amplification is not specific for the diagnosis of liposarcoma, we investigated its occurrence in 43 cases of endometrial stromal tumors: 14 uterine LG-ESS, 11 metastatic or recurrent uterine LG-ESS, 8 undifferentiated uterine sarcomas, 5 endometrial stromal nodules, and 4 high-grade ESS with YHWAE rearrangement. In addition, 40 of the 43 cases had previously undergone fluorescence in situ hybridization analysis of JAZF1, PHF1, and YHWAE. Two of the 43 cases (5%) had MDM2 amplification: one was a uterine LG-ESS (JAZF1 rearrangement) and the other was a undifferentiated uterine sarcoma (polysomy intact JAZF1, PHF1, and YHWAE), both metastatic to the lung. Both cases positive for MDM2 amplification showed MDM2 expression by immunohistochemistry. At last follow-up, both patients had died of disease (19 and 60 mo). Our study is the first to demonstrate MDM2 amplification in endometrial stromal tumor. Awareness of MDM2 amplification in endometrial stromal tumor is critical; particularly in locations more common to liposarcoma, to avoid diagnostic errors.

Increased immunoglobulin G4-positive plasma cells in collagenous sprue.

Collagenous sprue is a rare enteropathy whose etiology is unknown, but immune-mediated mechanisms are one of several possibilities. However, the role of immunoglobulin G4 (IgG4)-positive plasma cells has not been studied in collagenous sprue. Endoscopic biopsies from the duodenum with a histologic diagnosis of collagenous sprue (n = 40 from 35 patients), celiac disease (n = 25), peptic duodenitis (n = 15) and normal duodenum (n = 25) were immunohistochemically stained with IgG4 and CD138 antibodies. For each case, the quantities of IgG4- and CD138-positive plasma cells in the lamina propria were estimated by averaging the number in 3 high-power fields (hpf) that showed the highest concentration. Nine of forty collagenous sprue samples showed a mean of 10 or more IgG4 plasma cells per hpf, whereas none of the duodenal control biopsies showed 10 or more IgG4 plasma cells per hpf: celiac disease (P = .01), peptic duodenitis (P = .05), and normal duodenum (P = .01). Our study demonstrates that increased IgG4-positive plasma cells are present in a subset (23%) of collagenous sprue and may play a role in its pathogenesis.

Granular cell tumors overexpress TFE3 without corollary gene rearrangement.

We read with interest the report by Chamberlain and investigators [1] on their immunophenotypic comparison of alveolar soft part sarcoma and granular cell tumor (GCT), particularly their finding of diffuse,marked positivity for TFE3 in 91% of GCTs. TFE3 is a ubiquitous transcription factor whose overexpression is useful to detect neoplasms of the TFE3 family with an underlying Xp11.2 translocation [2]. The observation of strong TFE3 immunolabeling in GCT by Chamberlain et al prompted us to examine GCT for TFE3 rearrangement to determine whether GCT may be included as a new member of the TFE3 family. Six cases of GCT were retrieved from our institutions archive for diagnosis verification, immunostaining for TFE3 (clone MRQ-37, prediluted, Ventana, Tucson, AZ; Ventana OptiView DAB Platform), and fluorescence in situ hybridization (FISH) using a validated TFE3 break-apart probe protocol [3]. Our case cohort comprised 5 women and 1 man ranging in age from 7 to 56 years with tumors involving the tongue, esophagus, breast, trachea, vulva, and skin. Intense and diffuse TFE3 positivity was seen in the nuclei of all 6 cases of GCT (Fig. A and B). FISH was negative for TFE3 rearrangement in every case. Our findings indicate that TFE3 is overexpressed in most GCTs, but there is no corollary gene rearrangement detectable by FISH. Although low-level TFE3 positivity can be seen in other neoplasms, reflecting the presence of native TFE3 protein and is not indicative of TFE3 rearrangement, the finding of intense and widespread nuclear TFE3 positivity is considered sensitive and specific for tumors with TFE3 fusion [2]. GCT is an exception in that overexpression of TFE3 protein does not appear to be linked to separation of the TFE3 gene. In the TFE3 tumor family, the mechanism for overexpression of TFE3 protein is not known. Some authors have proposed an error in native TFE3 degradation or promoter enhancement resulting in protein overproduction [2]. It is likely that GCTs harbor some kind of recurrent genetic alteration other than translocation of TFE3 to account for their increased levels of nuclear TFE3 protein.

Collision Tumor of the Ovary: Adult Granulosa Cell Tumor and Endometrioid Carcinoma

We report the first case of a combined adult granulosa cell tumor and endometrioid carcinoma collision tumor occurring in an ovary.

Incidental Nodal Lymphangioleiomyomatosis Is Not a Harbinger of Pulmonary Lymphangioleiomyomatosis: A Study of 19 Cases With Evaluation of Diagnostic Immunohistochemistry.

Lymphangioleiomyomatosis (LAM) is a proliferation of perivascular epithelioid cells typically affecting the lung as a low-grade, destructive and progressive disease but may also be found in lymph nodes and other organs. LAM is sometimes seen as an incidental finding in lymph node dissections performed for staging of gynecologic tumors. To our knowledge, no study has investigated the clinical significance of incidental nodal LAM in relation to subsequent development of pulmonary LAM. We identified 19 patients from our institution with LAM in lymph nodes. Follow-up was available for 100% of patients and ranged from 3 to 123 months (mean 33.8 mo). All were women, ranging in age from 35 to 71 years (mean 56.3 y). None had a history of tuberous sclerosis, renal angiomyolipoma, or pulmonary LAM. LAM involvement spanned 1 to 6 nodes (mean 2), ranging from 1% to 100% of the total excised lymph nodes. The single largest focus of nodal LAM ranged from 1 to 9 mm (mean 4.3 mm) in 18 patients without evidence of persistent or recurrent nodal LAM. In the 1 patient with persistent local nodal LAM, the greatest diameter was 25 mm. Affected lymph node sites were regional pelvic and retroperitoneal chains routinely sampled in staging operations. An immunohistochemical panel of HMB45, A103, and &bgr;-catenin was evaluated in 18 cases. HMB45 showed strong but usually focal staining in every case compared with A103, which was very focally expressed (39%) or negative. &bgr;-catenin showed strong, diffuse cytoplasmic and membranous (non-nuclear) reactivity in 100% of cases. At the last clinic visit, all 19 patients had no manifestations of pulmonary LAM. In an absence of signs of symptoms of extranodal LAM, patients with incidentally discovered nodal LAM smaller than 10 mm are not at risk of developing pulmonary LAM.

Criteria for Risk Stratification of Vulvar and Vaginal Smooth Muscle Tumors: An Evaluation of 71 Cases Comparing Proposed Classification Systems

Accurate risk stratification of smooth muscle tumors (SMTs) is essential for appropriate patient management. Yet, the rarity of SMTs of the vagina and vulva makes development of a prognostically meaningful classification system challenging. While 2 classification methods for vulvar SMTs and 1 for vaginal SMTs have been proposed, it is our experience that many pathologists tend to apply criteria for uterine SMTs when evaluating vulvovaginal tumors. We retrospectively reviewed a large cohort of vulvovaginal SMTs with clinical follow-up and evaluated which method most accurately classified tumors according to patient outcome. A total of 71 tumors, 53 vaginal (75%) and 18 vulvar (25%), from 71 patients were identified. All tumors were centrally examined for degree of cytologic atypia, morphology (spindled, epithelioid, myxoid), mitotic index per 10 high power fields, atypical mitotic figures, tumor cell necrosis, ischemic necrosis, tumor interface (circumscribed or infiltrative) and margin status. Clinical features were recorded for each patient. Follow-up was available for 63 patients (89%), and ranged from 1 to 234 months (median: 64 mo). While site-specific and uterine criteria showed equally excellent sensitivity in classifying smooth muscle neoplasms as leiomyosarcoma according to patient outcome, uterine criteria showed improved specificity relatively to site-specific methods in classifying tumors as nonsarcoma according to patient outcome. We recommend that uterine SMT criteria and nomenclature be adopted for evaluation and classification of vulvovaginal SMTs.

Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2

Germline BRCA mutations account for a significant proportion of genetic/familial risk of breast and ovarian cancer (GBOC) susceptibility, but a broader spectrum of GBOC susceptibility genes has emerged in recent years. Genotype-to-phenotype correlations are known for some established forms of GBOC; however, whether such correlations exist for less common GBOC variants is unclear. We reviewed our institutions experience with non-BRCA GBOC, looking specifically for trends in pathologic and clinical features. Eighteen women with deleterious germline mutations in RAD51C (5 patients), BARD1 (1 patient), BRIP1 (2 patients), PALB2 (3 patients), MUTYH (2 patients), or CHEK2 (5 patients) were identified between January 2011 and December 2016. Thirteen (72%) of 18 patients developed carcinoma of the breast, fallopian tube, or ovary, with 1 patient developing 2 separate primary neoplasms. Twelve (86%) of 14 tumors occurred in the breast. One (7%) arose in the fallopian tube and another (7%) arose in the ovary. Evidence of genotype-phenotype correlation was not identified. However, some data suggest that the type of alteration in select genes may influence tumor behavior and patient outcome. In our PALB2 mutation cohort, 2 patients with frameshift mutations led to early onset and rapid progression to stage IV breast cancer in contrast to stage IA breast cancer in 1 patient with a nonsense mutation. Despite no apparent genotype-phenotype trends, our data indicate that some loss-of-function variants in PALB2 may lead to differences in tumor behavior and patient outcome.

Cervical mesonephric hyperplasia lacks KRAS/NRAS mutations

Mesonephric carcinoma, a rare malignant tumor thought to be derived from mesonephric remnants and/or hyperplasia, has recently been characterized by recurrent KRAS/NRAS mutations (1). The molecular features of mesonephric hyperplasia and whether it truly represents a precursor lesion to mesonephric carcinoma are unknown. This article is protected by copyright. All rights reserved.