Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas.

Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium.

FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary.

Sex cord-stromal tumors (SCSTs) of the ovary are relatively uncommon tumors. Diagnosis of SCST rests primarily on the histomorphology of these tumors, and tumors with an atypical or unconventional appearance can pose diagnostic challenges. Previously, we had identified FOXL2 (402C→G) mutation as being characteristic of adult granulosa cell tumors (aGCTs). However, molecular screening for this mutation is not always possible and adds time and cost to the diagnostic process. In this study, we investigated the potential diagnostic use of immunostaining for FOXL2 on formalin-fixed paraffin-embedded tissue sections. Using a commercially available polyclonal antiserum against FOXL2 protein, immunoexpression of FOXL2 was tested in 501 ovarian tumor samples, including 119 SCSTs, using whole tissue sections and tissue microarrays. Staining was correlated with FOXL2 mutation status. In addition, we compared FOXL2 immunoexpression with that of α-inhibin and calretinin, the 2 traditional immunomarkers of SCST, in a subset of 89 SCSTs. FOXL2 immunostaining was present in 95 of 119 (80%) SCSTs, including >95% of aGCTs, juvenile granulosa cell tumors, fibromas, and sclerosing stromal tumors. Only 50% of Sertoli-Leydig cell tumors (N=40) expressed FOXL2. One of 11 steroid cell tumors and 3 of 3 female adnexal tumors of probable Wolffian origin showed FOXL2 immunoreactivity, whereas all other non-SCSTs tested (N=368) were negative for FOXL2 expression. Thus, the sensitivity and specificity of FOXL2 immunoreactivity for SCST are 80% and 99%, respectively. The FOXL2 (402C→G) mutation was confirmed to be both a sensitive and relatively specific indicator of aGCT. Forty-five of 119 SCSTs were mutation positive. These cases were 39 of 42 (93%) aGCTs, 3 of 40 Sertoli-Leydig cell tumors, 2 of 5 thecomas, and 1 of 4 (25%) SCSTs of unclassified type. SCSTs harboring a FOXL2 mutation consistently immunoexpressed FOXL2 (44 of 45, 98%), but FOXL2 immunostaining was also seen in many SCSTs that lacked a mutation (49 of 73, 67%). FOXL2 immunostaining showed higher sensitivity for the diagnosis of SCST, compared with α-inhibin and calretinin, and FOXL2 staining was typically more intense in positive cases compared with either α-inhibin or calretinin. In the SCSTs that were negative for FOXL2 expression, α-inhibin and/or calretinin immunostaining yielded positive results. In conclusion, FOXL2 is a relatively sensitive and highly specific marker for SCST. FOXL2 staining is present in almost all SCSTs with a FOXL2 mutation, and also in a majority of SCSTs without a mutation. FOXL2, together with α-inhibin and calretinin, forms an immunomarker panel that will result in positive staining with 1 or more markers in essentially all cases of SCST.

High-Grade Serous Carcinoma Involving Fallopian Tube, Ovary and Peritoneum.

The focus of this review is high-grade serous carcinoma (HGSC); for the purposes of this review, the term "pelvic SC" is used for HGSC that could be considered, based on historical definitions, to have arisen from ovary, fallopian tube, or peritoneum. These assignments of primary site are arbitrary and there is evidence that the distal fallopian tube is the site of origin of many pelvic HGSCs. The diagnosis of HGSC can be made readily based on routine histomorphologic examination in most cases; however, a variety of neoplasms can resemble HGSC. Thus, we review the key features of pelvic SC, current concepts of its pathogenesis, histopathological diagnostic criteria, discuss differential diagnosis, and review diagnostic ancillary studies that can be used in practice.

ARID1A mutations in endometriosis-associated ovarian carcinomas.

BACKGROUND: Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. METHODS: We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI­SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. RESULTS: ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. CONCLUSIONS: These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital­University of British Columbia Hospital Foundation.).

CD138 (Syndecan-1) in thymic tumors: correlation with various World Health Organization types and clinical outcome.

We intended to explore the relationship of CD138 with thymic tumors. A series of 64 thymic tumors were studied. Positive staining was seen in 7 of 8 (87.5%) type A, 7 of 16 (43.7%) type AB, 1 of 8 (12.5%) type B1, 1 of 5 (20%) type B2, 10 of 17 (58.8%) type B3, and 3 of 10 (30%) type C (p=0.04), respectively. In terms of subcellular location of CD138 expression, 9 of 10 (90%) CD138 positive type B3 had membranous expression, while cytoplasmic expression was identified in 7 of 7 (100%) type A, and 6 of 7 (86%) type AB (p<0.0001). Positive CD138 was noted in 20 of 31 (64.5%) cases with Masaoka stage I (p= 0.01); while negative CD138 was seen in 24 of 33 (72.7%) cases with Masaoka stages (II-IV). Tumor recurred in 4 cases (7%), all of which had negative CD138 (p=0.008). Our study suggests that CD138 could be used as an ancillary study to differentiate between WHO types. Furthermore, our findings demonstrate that advanced stage-thymic tumors as well as those with high recurrence rate tend to display a reduced expression of CD138. However, more studies with larger cohort and longer follow-up are warranted to validate the clinical utility of CD138 to assess clinical behavior and prognosis of thymic tumors.

Malignant fibrous histiocytoma: between the past and the present.

The precise nature and diagnostic concept of malignant fibrous histiocytoma (MFH) has been debated for years. Currently, a histiocytic lineage of the tumor cells is no longer favored. The nomenclature and classification of MFH and its subtypes have also been changed. The MFH pattern, especially that of storiform-pleomorphic variant, is viewed as a morphologic pattern shared by a number of sarcomas as well as by other nonsarcomas. Therefore, a diagnosis of MFH based solely on morphology is no longer acceptable and identification of a line of differentiation should be sought. A diagnosis of MFH should be made only for pleomorphic sarcomas in which no specific line of differentiation is discerned. Precise categorization of MFH-like tumors may require thorough sampling of the tumor and judicious use of immunohistochemistry and/or electron microscopy. Familiarity with the current terminology and classification of MFH and its subtypes is of paramount significance in the modern practice of pathology.

Fine needle aspiration of urethral recurrence of urothelial carcinoma after radical cystectomy presenting as a perineal mass: a case report.

BACKGROUND: Recurrence of urothelial (transitional cell) carcinoma in the urethra after cystectomy for invasive urothelial carcinoma is relatively uncommon. It is also uncommon for the recurring urethral tumor to present as a painful perineal mass. Fine needle aspiration (FNA) can be used to evaluate such perineal lesions and confirm tumor recurrence. CASE: A 5-cm-diameter mass was found in the perineum of a 63-year-old man 1 year after radical cystoprostatectomy for invasive urothelial carcinoma of the urinary bladder. The mass was detected on pelvic computed tomographic scanning. FNA cytology showed numerous urothelial carcinoma cells of high grade displaying squamous cell differentiation mimicking the histopathologic findings of the primary tumor found on cystectomy. Diagnosis of recurrent urothelial carcinoma was rendered. The FNA in this case spared the patient an open biopsy. CONCLUSION: Mass lesions arising in the perineum of patients who underwent cystectomy for urothelial carcinoma should raise the suspicion of urothelial carcinoma recurrence. Evaluation of perineal masses for recurrence of urothelial carcinoma can be made on FNA without the need for open biopsy.

An in-depth look at Leydig cell tumor of the testis.

Leydig cell tumor (LCT) is a rare tumor of the male testicular interstitium. This article provides an overview of the major pathologic manifestations of LCT of the testis; patient characteristics; clinical, radiologic, and laboratory features; prognosis; and management. LCTs of the testis are frequently hormonally active, leading to either feminizing or virilizing syndromes. The tumor is usually benign, but malignant variants can occur. The pathologic diagnosis of LCT is usually made based on morphologic characteristics of the tumor cells. The significance of Reinke crystals in the diagnosis of LCT both cytologically and histologically is underscored. Pathologists have to be familiar with the diagnostic histopathologic features, immunohistochemical panel of this tumor, and its principal differential diagnoses to prevent tumor misdiagnosis.

An in-depth look at Krukenberg tumor: an overview.

Krukenberg tumor is an uncommon metastatic tumor of the ovary. This article provides an overview of the major pathologic manifestations of Krukenberg tumor, patient characteristics, clinical and laboratory features of the disease, prognostic factors, and current knowledge about its pathogenesis. Pathologists have to be familiar with the diagnostic histopathologic features of the tumor and its principal differential diagnoses. Awareness of the diagnostic manifestations of the tumor leads to the correct diagnosis and prevents tumor misclassification, thus avoiding improper clinical management. The article also addresses the potential clinical utility of serum CA 125 in patients with Krukenberg tumors. Prognosis of Krukenberg tumor is still very poor but our review of the literature reveals several factors that appear to have an impact on survival. There is no established treatment for Krukenberg tumors. A national registry and prospective studies are needed to set a therapeutic approach for Krukenberg tumors in the hope of improving the survival rate.

Teratoma of the penis in a child.

Teratomas are tumors of germ-cell origin, composed of tissues derived from all three germinal layers: ectoderm, endoderm, and mesoderm. Most teratomas have been reported to arise at sites that are midline or paraxial, with the penis being an unusual location for this tumor. The treatment for most pure teratomas is surgical resection. We report a case of primary teratoma of the penis in a 3-month-old child. This is the second reported case of a primary teratoma of the penis and the first in a child.