CDK8 Expression in Extrauterine Leiomyosarcoma Correlates With Tumor Stage and Progression.

Mediator is a multiprotein complex that acts as a versatile transcription coactivator in eukaryotes. CDK8 kinase complex is a 4-protein subunit of the mediator complex that can act as a transcriptional repressor or coactivator, depending on the specific pathways involved. Although the role of MED12 exon 2 mutations is documented in the pathogenesis of uterine leiomyomas, its role in extrauterine smooth muscle tumorigenesis is less clear. Similarly, there is a paucity of data on the role of CDK8 in extrauterine smooth muscle tumorigenesis and progression. Our study correlates immunohistochemical expression of CDK8 and MED12 with clinical and pathologic parameters in extrauterine leiomyosarcomas. Immunohistochemical expression of CDK8 and MED12 in leiomyosarcomas was correlated with the tumor grade, stage, and the presence of local recurrence or metastasis. MED12 was expressed in the majority of leiomyosarcomas regardless of their stage or grade. CDK8 expression was lost in 1 of 6 pT1 tumors, compared with 9 of 10 pT2 tumors (P=0.0076). When the second group was expanded to include those tumors that did not have a recorded pathologic stage but had local recurrence and distant metastases, the difference in CDK8 expression was also statistically significant. Loss of CDK8 expression by immunohistochemistry is more prevalent in somatic leiomyosarcomas presenting at a higher histopathologic stage, as well as with local and distant recurrence, and can be used to enhance the current predictive parameters.

Correlation of histological grade of dedifferentiation with clinical outcome in 55 patients with dedifferentiated liposarcomas.

In this study the histologic grade of dedifferentiated liposarcomas was correlated with outcome in surgically resected specimens in 55 patients over a 19-year period at the University of Pittsburgh Medical Center. The tumors were located in the retroperitoneum (N=35); the extremities and thigh (N=16), and the remainder involved the spermatic cord and head and neck. Most tumors were large (mean=21 cm.) Follow-up was available in all 55 patients (median=36 months). Forty-one tumors classified as high-grade dedifferentiated liposarcoma (HG-DDLPS) had mitotically active pleomorphic and spindle cells and foci of necrosis. They included tumors with foci of smooth muscle differentiation (N=12), osteosarcoma (N=4), and myxoid areas (N=9). Fourteen tumors classified as low-grade dedifferentiated liposarcoma (LG-DDLPS) displayed a predominantly bland, monomorphic, spindle cell population with few mitoses and scant necrosis. The Kaplan-Meier method and log-rank test were used for statistical analysis. All tumors had unequivocal foci of well-differentiated liposarcoma (WDLPS). Fluorescence in situ hybridization (FISH) detected amplification of MDM2 in 29 cases. Twenty of 41 patients (49%) with HG-DDLPS died of tumor, and two patients died with LG-DDLPS (14%). The overall survival of patients with LG-DDLPS was significantly longer (P=.02). The median survival was 113 months for the LG-DDLPS and 48 months for the HG-DDLPS. Metastases (N=4) occurred only in the high-grade tumors and were independent of the type of heterologous differentiation. Patients with HG-DDLPS were at a greater risk of earlier death. Distinction between the two groups is important for patient selection for possible adjuvant therapy.

GRB7 Expression and Correlation With HER2 Amplification in Invasive Breast Carcinoma.

Growth factor receptor-bound protein 7 (GRB7) gene is located adjacent to the HER2 gene on the 17q12-21 amplicon, is often coamplified with HER2 in a subset of breast cancers, and has been implicated in resistance to anti-HER2 and antiestrogen therapy. This study investigated the correlation of GRB7 expression by immunohistochemistry with HER2 expression, HER2 amplification, increased chromosome 17 copy number, and other prognostic and predictive factors in invasive breast cancer, including histologic grade, pathologic stage, and ER, PR, and p53 status. Paraffin-embedded samples of 188 invasive breast carcinomas with documented HER2, ER, and PR testing were collected and divided into 3 groups: cases positive for HER2 overexpression/gene amplification (n=60), negative for HER2 overexpression (n=97), and cases with increased chromosome 17 copy number without HER2 amplification (n=31). GRB7 expression was evaluated on all 188 cases. In addition, p53 immunohistochemistry was performed on 13 HER2+/GRB7+ cases and 39 HER2+/GRB7- cases. GRB7 expression correlated strongly with HER2 overexpression. GRB7 expression was present in 20/60 (33.33%) of HER2+ cases, compared with 1/97 (1.03%) HER2- cases, and 1/31 (3.22%) increased chromosome 17 copy number cases (P<0.0001). In HER2+ cases, GRB7 expression was found to correlate significantly with a greater degree of HER2 amplification. The mean±SEM HER2 copy number was 21.14±2.59 in GRB7+ cases, compared with 9.8±1.38 in GRB7- cases (P=0.0001). GRB7 expression correlated significantly with ER negativity (P=0.012) and p53 positivity (P=0.03). GRB7 expression did not correlate with histologic grade, pathologic stage, or PR expression. Our data shows that GRB7 expression in invasive breast cancer correlates with markers of a more aggressive phenotype, including HER2 overexpression, a greater degree of HER2 amplification, ER negativity, and p53 positivity.

Ossifying fibromyxoid tumor: a study of 6 cases of atypical and malignant variants.

Ossifying fibromyxoid tumors (OFMT) of soft parts are rare, slow-growing tumors that have potential for local recurrence and may metastasize. While OFMT originally was considered benign, several cases of malignant OFMT have been documented. There is no universally accepted risk stratification, although this study emphasizes the importance of utilizing histology, immunohistochemistry and FISH in establishing the diagnosis. Herein, we describe six cases of atypical and malignant OFMT with differences in morphologic features, 5 of which display the proposed morphological criteria for malignancy. The patients were mostly male (M=5, F=1) with an age range of 33-69 years. The tumors arose from the extremities (3 cases), the shoulder (1 case), the head and neck area (1 case), and the paraspinal area (1 case). One tumor had high grade and overtly sarcomatous changes, while another invaded the underlying clavicle. Two cases showed cytological atypia and necrosis. Fluorescence in situ hybridization (FISH) detected rearrangement of the PHF1 gene in 5 cases. All cases were positive for EAAT4 and actin by immunohistochemistry, while negative for desmin. Three tumors were immunoreactive for S100 protein. INI-1 immunohistochemical staining was conserved in all but 2 cases in which a mosaic loss of expression was noted. All but two patients are currently alive and free of disease.

Detection of malignant mesothelioma using nuclear structure of mesothelial cells in effusion cytology specimens.

Mesothelioma is a form of cancer generally caused from previous exposure to asbestos. Although it was considered a rare neoplasm in the past, its incidence is increasing worldwide due to extensive use of asbestos. In the current practice of medicine, the gold standard for diagnosing mesothelioma is through a pleural biopsy with subsequent histologic examination of the tissue. The diagnostic tissue should demonstrate the invasion by the tumor and is obtained through thoracoscopy or open thoracotomy, both being highly invasive surgical operations. On the other hand, thoracocentesis, which is removal of effusion fluid from the pleural space, is a far less invasive procedure that can provide material for cytological examination. In this study, we aim at detecting and classifying malignant mesothelioma based on the nuclear chromatin distribution from digital images of mesothelial cells in effusion cytology specimens. Accordingly, a computerized method is developed to determine whether a set of nuclei belonging to a patient is benign or malignant. The quantification of chromatin distribution is performed by using the optimal transport-based linear embedding for segmented nuclei in combination with the modified Fisher discriminant analysis. Classification is then performed through a k-nearest neighborhood approach and a basic voting strategy. Our experiments on 34 different human cases result in 100% accurate predictions computed with blind cross validation. Experimental comparisons also show that the new method can significantly outperform standard numerical feature-type methods in terms of agreement with the clinical diagnosis gold standard. According to our results, we conclude that nuclear structure of mesothelial cells alone may contain enough information to separate malignant mesothelioma from benign mesothelial proliferations.

Fine-needle aspiration cytology of disseminated Kaposi sarcoma of the bone in an AIDS patient.

BACKGROUND: Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8). Skin and mucous membranes are the most common sites, but other organs may be involved. Skeletal KS is rare and occurs either by direct spread of mucocutaneous lesions or through dissemination. Patients present with bone pain and lytic lesions for which they may undergo fine-needle aspiration (FNA). While there are about 70 published case reports of skeletal KS, there is limited literature specifically describing its cytomorphology. Our literature search yielded only a single prior reported case of FNA biopsy of skeletal KS in a Nigerian AIDS patient. CASE: We present a case of disseminated KS of the axial skeleton in a 45-year-old African-American man with AIDS which was diagnosed on FNA cytologic examination. The patient presented with multiple lytic lesions in the axial skeleton. The aspirate, core-needle biopsy and touch imprint cytology of a bone lesion demonstrated clusters of spindle and epithelioid cells in radial and streaming arrangement with indistinct intercytoplasmic borders, elongated nuclei, fine chromatin and inconspicuous nucleoli. Immunohistochemical studies revealed positivity for HHV-8 and vascular markers. The cytomorphologic and ancillary features of the case are presented and discussed.

Fine needle aspiration cytology of acinar cell cystadenoma of the pancreas.

BACKGROUND: Acinar cell cystadenoma (ACC) is a recently recognized cystic lesion of the pancreas that demonstrates acinar differentiation and is currently believed to behave in a benign fashion. ACC enters the differential diagnosis of pancreatic cystic lesions alongside better recognized entities such as mucinous cystic and intraductal papillary mucinous neoplasms. Although uncommon, patients with ACC can undergo fine needle aspiration (FNA) of the lesion. However, the diagnosis is rarely made on cytologic examination due to sparse cellularity. Furthermore, the eosinophilic amorphous material in the cyst lumen may be mistaken for mucin, resulting in an incorrect diagnosis of a mucinous cyst. To date, there is a paucity of literature on the cytomorphology of ACC, both in peer-reviewed publications and cytopathology texts. CASE: To our knowledge, we present the first detailed case report of FNA of ACC in a 22-year-old asymptomatic female. The FNA cytology specimen was hypocellular, and the presence of amorphous secretions led to the initial diagnosis of a mucinous-type neoplasm. Following surgical resection, the cytology specimen was reviewed. CONCLUSION: We discuss the cytomorphologic features of ACC along with the potential pitfalls and diagnostic implications.