Rajesh C. Dash

Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types.

One thousand consecutive cases of surgically proven endometriosis were reviewed to evaluate the frequency and types of pelvic cancers that were associated with ovarian and extraovarian endometriosis. The frequency and types of histologic abnormalities present in the eutopic endometrium when cancers were noted in endometriosis were also evaluated. In the large subset of cases for which the authors were the primary pathologists and all foci of endometriosis were recorded, the frequency of malignancy was 10.8%. In contrast, the frequency was only 3.2% in cases diagnosed by others previously in our institution. Cancers were more commonly found in ovaries when endometriosis was present in that ovary (5%) compared to when endometriosis was present at other sites (1%). Clear cell and endometrioid carcinomas were the malignancies most commonly seen in ovaries containing endometriosis, while clear cell adenocarcinoma and adenosarcoma were most commonly seen in conjunction with extraovarian endometriosis. The association of endometriosis with endometrioid and clear cell carcinoma was much stronger than that of serous and mucinous tumors (p < .01). Concurrent endometrial pathology was commonly seen in cases of malignant transformation of endometriosis (32% of cases).

Fine-needle aspiration cytology of ancient schwannoma

The term “ancient” schwannoma was proposed for a group of neural tumors showing degenerative changes and marked nuclear atypia. Prior to the realization that the observed atypia was a regressive phenomenon, many of these lesions were erroneously diagnosed as sarcomas. Fine‐needle aspiration (FNA) cytologic material from five patients is included in this study. Tissue examined histologically included four resected tumors and 18 gauge core biopsies of one tumor. Aspirates of ancient schwannoma showed many of the same features as FNA of regular schwannoma: aggregates of spindled cells with indistinct cytoplasm and elongate nuclei with blunt point ends. The feature unique to these lesions was nuclear pleomorphism, which was identified in all aspirates. Nuclear inclusions were identified in all but one case. Cystic degeneration, xanthomatous changes, and perivascular sclerosis were identified in excised lesions. Ancient schwannomas show most of the FNA features of benign schwannomas but can demonstrate marked nuclear atypia. The FNA features of ancient schwannoma are important to note because of the potential to confuse this lesion with a more serious one such as sarcoma on FNA. Diagn. Cytopathol. 1999;20:307–311.

Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with productive tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

Malignant Supratentorial Ganglioglioma (Ganglion Cell-Giant Cell Glioblastoma) A Case Report and Review of the Literature

BACKGROUNDnFrom both epidemiologic and pathologic viewpoints, gangliogliomas exhibiting components of giant cell glioblastomas are extraordinary neoplasms. We report herein the case of a 6-year-old girl who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell tumor-giant cell glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period.nnnMETHODSnFormalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 microm for histochemical and immunohistochemical analyses. Hematoxylin-eosin-stained sections and immunohistochemically stained sections from the primary and secondary resections were reviewed. Reactivity for glial fibrillary acidic protein, neurofilament protein, synaptophysin, and Ki67 nuclear antigen was evaluated.nnnRESULTSnHistologically, 2 distinct cell populations were noted on both the primary and secondary resections. The primary resection revealed a neoplasm having a predominant glial component consistent with a glioblastoma. Interspersed were dysmorphic ganglion cells supporting a diagnosis of ganglioglioma. The second resection (following therapy) demonstrated a much more prominent dysmorphic ganglion cell component and a subdued glial component.nnnCONCLUSIONnAlthough immunohistochemical analysis clearly distinguished the 2 tumor cell populations, the identification of Nissl substance in neurons proved to be equally helpful. Although other cases of grade III gangliogliomas and rare cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the only report of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histologic findings in a giant cell glioblastoma and a ganglioglioma and documents the aggressive biologic behavior of this complex neoplasm.

The Value of Fluorescence In Situ Hybridization and Polymerase Chain Reaction in the Diagnosis of B-Cell Non-Hodgkin Lymphoma by Fine-Needle Aspiration

CONTEXTnMolecular genetic analyses have been predicted to improve the diagnostic accuracy of fine-needle aspiration of B-cell non-Hodgkin lymphoma.nnnOBJECTIVEnTo determine the value of routine molecular genetic assays, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), in the diagnosis of B-cell non-Hodgkin lymphoma by fine-needle aspiration (FNA).nnnDESIGNnA multiparametric method, including cytology, flow cytometry, PCR, and FISH, was prospectively evaluated in the diagnosis of B-cell non-Hodgkin lymphoma by FNA. Aspirates from 30 consecutive patients with suspected hematolymphoid malignancies were collected. All aspirates were triaged through a uniform program including cell-size analysis, B- and T-cell clonality studies, flow cytometric immunophenotyping, and bcl-1 and bcl-2 gene rearrangements by PCR and FISH. After completion of FNA evaluations, FNA results were compared with diagnoses from prior or subsequent surgical biopsies.nnnRESULTSnMonoclonal B-cell populations were detected in 18 of 20 B-cell non-Hodgkin lymphomas by flow cytometry and PCR. bcl-1 gene rearrangement was detected in 2 of 2 cases of mantle cell lymphoma. bcl-2 rearrangement was detected in 5 cases including 4 of 4 low-grade follicular lymphomas and 1 transformed follicular lymphoma. By incorporating the results of molecular genetic and ancillary diagnostics, a definitive classification was reached in 12 cases of B-cell non-Hodgkin lymphoma by FNA, including all cases of low-grade follicular lymphoma (4/4) and mantle cell lymphoma (2/2) and approximately 50% of small lymphocytic lymphoma (2/4) and large B-cell lymphoma (4/8). Ten of the 12 cases with a final classification reached by FNA had either prior or follow-up surgical biopsies, and all 10 cases showed agreement between the diagnoses rendered on FNA and surgical biopsies.nnnCONCLUSIONSnWith proper handling and management of specimens, FNA can routinely provide samples adequate for molecular genetic studies, in addition to cytomorphology and flow cytometry, making it possible to consistently render accurate and definitive diagnoses in a subset of B-cell non-Hodgkin lymphomas. By incorporating FISH and PCR methods, FNA may assume an expanded role for the primary diagnosis of B-cell non-Hodgkin lymphoma.

Modulation of Circulating Angiogenic Factors and Tumor Biology by Aerobic Training in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin–cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow (15O–water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). 15O–water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined. Cancer Prev Res; 6(9); 925–37. ©2013 AACR.

The cancer translational research informatics platform

BackgroundDespite the pressing need for the creation of applications that facilitate the aggregation of clinical and molecular data, most current applications are proprietary and lack the necessary compliance with standards that would allow for cross-institutional data exchange. In line with its mission of accelerating research discoveries and improving patient outcomes by linking networks of researchers, physicians, and patients focused on cancer research, caBIG (cancer Biomedical Informatics Grid™) has sponsored the creation of the caTRIP (Cancer Translational Research Informatics Platform) tool, with the purpose of aggregating clinical and molecular data in a repository that is user-friendly, easily accessible, as well as compliant with regulatory requirements of privacy and security.ResultscaTRIP has been developed as an N-tier architecture, with three primary tiers: domain services, the distributed query engine, and the graphical user interface, primarily making use of the caGrid infrastructure to ensure compatibility with other tools currently developed by caBIG. The application interface was designed so that users can construct queries using either the Simple Interface via drop-down menus or the Advanced Interface for more sophisticated searching strategies to using drag-and-drop. Furthermore, the application addresses the security concerns of authentication, authorization, and delegation, as well as an automated honest broker service for deidentifying data.ConclusionCurrently being deployed at Duke University and a few other centers, we expect that caTRIP will make a significant contribution to further the development of translational research through the facilitation of its data exchange and storage processes.

A Call to Standardize Preanalytic Data Elements for Biospecimens

CONTEXTnBiospecimens must have appropriate clinical annotation (data) to ensure optimal quality for both patient care and research. Clinical preanalytic variables are the focus of this study.nnnOBJECTIVEnTo define the essential preanalytic variables (data fields) that should be attached to every collected biospecimen and to provide a complete list of such variables, along with their relative importance, which can vary, depending on downstream use, institutional needs, and information technology capabilities.nnnDESIGNnThe College of American Pathologists Diagnostic Intelligence and Health Information Technology Committee sponsored a Biorepository Working Group to develop a ranked list of the preanalytic variables for annotating biospecimens. Members of the working group were experts in anatomic, clinical, and molecular pathology; biobanking; medical informatics; and accreditation. Several members had experience with federal government programs, such as the National Cancer Institutes Biospecimens and Biorepository Branch and the National Cancer Institutes Community Cancer Center Program. Potential preanalytic variables were identified and ranked along with available supporting evidence, definitions, and potential negative effects if the variable was not attached to the biospecimen. Additional national and international stakeholders reviewed the draft manuscript.nnnRESULTSnThe ranked listing of 170 preanalytic variables produced can be used as a guide for site-specific implementation into patient care and/or research biorepository processes. Conclusions.-In our collective experience, it is often difficult to choose which of the many preanalytic variables to attach to any specific set of biospecimens used for patient care and/or research. The provided ranked list should aid in the selection of preanalytic variables for a given biospecimen collection.

Biospecimens and Biorepositories for the Community Pathologist

Pathologists have long served as custodians of human biospecimens collected for diagnostic purposes. Rapid advancements in diagnostic technologies require that pathologists change their practices to optimize patient care. The proper handling of biospecimens creates opportunities for pathologists to improve their diagnoses while assessing prognosis and treatment. In addition, the growing need for high-quality biorepositories represents an opportunity for community pathologists to strengthen their role within the health care team, ensuring that clinical care is not compromised while facilitating research. This article provides a resource to community pathologists learning how to create high-quality biorepositories and participating in emerging opportunities in the biorepository field. While a variety of topics are covered to provide breadth of information, the intent is to facilitate a level of understanding that permits community pathologists to make more informed choices in identifying how best their skills and practice may be augmented to address developments in this field.

Recurrence Risk and Margin Status in Granular Cell Tumors of the Breast: A Clinicopathologic Study of 13 Patients

CONTEXTnGranular cell tumors (GCTs) of the breast are rare neoplasms that mimic epithelial malignancy clinically and rarely occur in association with it. Granular cell tumors of the breast are not infrequently excised with positive margins. Reports describing risk of recurrence including data on margin status and follow-up are lacking.nnnOBJECTIVEnTo review our series of GCTs of the breast to determine the risk of recurrence if excised with positive or close margins.nnnDESIGNnCases of GCT of the breast were reviewed. Margin status of specimens was recorded as positive, close (<1 mm), and negative.nnnRESULTSnThirteen female patients with GCT of the breast were identified. Mean patient age at presentation was 45 years. Seventy-seven percent of patients were African American and 23% were white. African American patients presented on average 13 years earlier than white patients. Average tumor size was 1.22 cm. Fifteen percent of lesions had positive margins on excisional biopsy or lumpectomy and 31% had tumor cells within 1 mm of the margin. One of 13 patients (8%) had coexistent invasive ductal carcinoma. Average follow-up for the entire group was 77 months. Patients with positive margins remained free of tumor progression or recurrence for 89 months and patients with close margins also remained disease free during a 64-month follow-up period. No tumors recurred out of the entire group.nnnCONCLUSIONnGranular cell tumors of the breast have little long-term risk for recurrence, even when excised with positive margins. Surgical evaluation after nonexcisional biopsy may still be indicated to assess for the possible association of colocalized carcinoma.