"Ask The Pathologist": An Internet Forum Facilitating Communication Between Cancer Registrars and Pathologists.

CONTEXT.­: Cancer registrars should work closely with pathologists to ensure compliance with reporting standards. Many registrars, however, have little contact with pathologists, resulting in a lack of "real-time" interaction that is essential for their professional activities and development. OBJECTIVE.­: To facilitate registrars' case management, as cancer biology becomes more complex, we developed the ATP (Ask the Pathologist) forum as a place to ask pathology-related questions about neoplasms, such as terminology, biology, histologic classification, extent of disease, molecular markers, and prognostic factors. DESIGN.­: Questions posted are reviewed by the ATP multidisciplinary oversight committee, which consists of 3 pathologists, 4 cancer registrars, 1 internal medicine physician, the pathology resident member of the College of American Pathologists Cancer Committee, and 2 medical technologists. The oversight committee may answer the question. Alternatively, the committee may forward the question to a content expert pathologist, determine that the question is better suited for another reference Web site, or both. RESULTS.­: Since September 2013, when the ATP forum became available, users have posted 284 questions, of which 48 (17%) related to gastrointestinal tumors, 43 (15%) to breast tumors, and 37 (13%) to general pathology. The average turnaround time, from question posted to response, is 11.1 days. CONCLUSIONS.­: The ATP forum has had a positive impact in the daily activities of cancer registrars. Of 440 registrars surveyed, more than 90% considered that questions were answered satisfactorily, and one-third reported that ATP answers affected how they managed a given case.

College of American Pathologists Cancer Protocols: Optimizing Format for Accuracy and Efficiency.

CONTEXT: -The data in College of American Pathologists cancer protocols have to be presented effectively to health care providers. There is no consensus on the format of those protocols, resulting in various designs among pathologists. Cancer protocols are independently created by site-specific experts, so there is inconsistent wording and repetition of data. This lack of standardization can be confusing and may lead to interpretation errors. OBJECTIVE: -To define a synopsis format that is effective in delivering essential pathologic information and to evaluate the aesthetic appeal and the impact of varying format styles on the speed and accuracy of data extraction. DESIGN: -We queried individuals from several health care backgrounds using varying formats of the fallopian tube protocol of the College of American Pathologists without content modification to investigate their aesthetic appeal, accuracy, efficiency, and readability/complexity. Descriptive statistics, an item difficulty index, and 3 tests of readability were used. RESULTS: -Columned formats were aesthetically more appealing than justified formats (P < .001) and were associated with greater accuracy and efficiency. Incorrect assumptions were made about items not included in the protocol. Uniform wording and short sentences were associated with better performance by participants. CONCLUSIONS: -Based on these data, we propose standardized protocol formats for cancer resections of the fallopian tube and the more-familiar colon, employing headers, short phrases, and uniform terminology. This template can be easily and minimally modified for other sites, standardizing format and verbiage and increasing user accuracy and efficiency. Principles of human factors engineering should be considered in the display of patient data.

Adenoid cystic carcinoma of the base of the tongue metastasizing to the scalp.

Adenoid cystic carcinoma is a rare neoplasm that originates from secretory glands, most commonly from the salivary glands. We present a 76 year-old white man with a history of adenoid cystic carcinoma from the base of the tongue diagnosed 15 years prior to the development of the metastatic lesion on his mid-posterior scalp. The present case represents the second reported instance of an extracutaneous adenoid cystic carcinoma metastasizing to the scalp. Differentiating between a primary cutaneous adenoid cystic carcinoma and an extracutaneous adenoid cystic carcinoma metastasizing to cutaneous structures is crucial in determining prognosis and management.

Mesothelioma: a soon to be forgotten disease in the United States?

Malignant pleural mesothelioma is an uncommon cancer that commonly presents with a large unilateral bloody pleural effusion long after asbestos exposure. Its prevalence is decreasing with the decreasing exposure to asbestos in the United States. We present a patient with malignant pleural mesothelioma who underwent evaluation and treatment during medical thoracoscopy. The thoracoscopic evaluation revealed multiple, varied, and severe but characteristic findings of malignant pleural mesothelioma. Medical thoracoscopy is the procedure of choice for the diagnosis of pleural mesothelioma.

Hepatoprotective effects of select water-soluble PARP inhibitors in a carbon tetrachloride model.

BACKGROUND: Inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP-1) have been demonstrated to attenuate pathophysiologic conditions associated with oxidative stress, specifically with carbon tetrachloride (CT)-induced hepatotoxicity. SETTINGS AND DESIGN: In this investigation, we evaluated 3 previously untested water-soluble PARP-1 inhibitors, namely, 3-aminobenzamide (ABA), 5-aminoisoquinolinone (AIQ), and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide HCl (PJ-34) to determine their efficacy in blocking or attenuating CT-induced hepatotoxicity in male imprinting control region (ICR) mice. STATISTICAL ANALYSIS: Indicators of hepatotoxicity were compared with F-tests among groups to determine statistically significant effects. Pearson's correlation coefficients were used to evaluate the correlation between PARP inhibition and the attenuation of hepatotoxicity. RESULTS AND CONCLUSIONS: CT treatment resulted in hepatic cytotoxicity, increased serum transaminase (ALT), lipid peroxidation (MDA), intracellular glutathione (GSH) depletion, increased carbonyl content, and substantially increased PARP-1 activity. CT treatment also produced profound observable hemorrhagic necrosis in the hepatic centrilobular region of ICR mice. Pretreatment with PJ-34, ABA, and AIQ before CT treatment significantly decreased PARP-1 activity in hepatocytes after CT treatment by 3.4, 2.0, and 1.9 times, respectively. Corresponding to this reduction in PARP-1 activity, a significant reduction in the ALT levels and MDA and a reduction in the GSH depletion were observed. Also, there were no visible tissue defects in the liver samples from animals pretreated with individual PARP-1 inhibitors before CT administration. These results demonstrate the efficacy of the 3 previously untested water-soluble PARP-1 inhibitors in attenuating CT-induced hepatocellular toxicity and further characterize the role of PARP-1 activation and oxidative stress among the cascade of events in hepatocellular necrosis induced by CT treatment.

Extraskeletal para-articular osteochondroma of the posterior knee.

Extraskeletal para-articular osteochondromas are unusual osteocartilaginous lesions that arise in the soft tissues adjacent to the joint with no bone or joint continuity. This diagnosis should be considered in patients with a well-circumscribed, extraskeletal, mineralized mass without any direct continuity with adjacent bone or joint. Although the knee is a common location for extraskeletal para-articular osteochondroma, it has not been described arising in the posterior aspect of the knee. This article presents a case of extraskeletal paraarticular osteochondroma posterior to the knee joint. Differentiation from other extraskeletal mineralized lesions, particularly extraskeletal sarcomas and synovial osteochondromatosis, is essential to avoid unnecessary aggressive surgical procedures as marginal excision is adequate for these lesions. Correlation of clinical and radiographic features with pathology is essential for diagnosis. The lesion in our patient was marginally excised, and the postoperative course was uneventful with no recurrence at 2-year follow-up.

Soft-tissue amyloidoma of the extremities: a case report and review of literature.

Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of unique protein fibrils. Amyloidosis may be hereditary or acquired, and the deposits may be focal, localized, or systemic in distribution. The least common presentation of an amyloid deposition is as a discrete mass called amyloidoma or amyloid tumor. Although described at various body sites, soft-tissue amyloidoma in an extremity is exceedingly rare. We report such a case of a large amyloidoma in the thigh, which simulated a soft-tissue sarcoma. In spite of attaining a very large size over a course of more than 20 years, the clinical course and the histology of this lesion were benign. Awareness of this entity will allow this rare diagnosis to be considered, prevent confusion with malignant disease, and allow appropriate management and patient reassurance. A review of literature on soft-tissue amyloidomas of extremities is also being presented.

Aberrant methylation inactivates transforming growth factor Beta receptor I in head and neck squamous cell carcinoma.

Background. Alterations in TGF-beta signaling are common in head and neck cancer (HNSCC). Mutations in TGF-beta type II receptor (TbetaR-II) occur frequently in HNSCC while TGF-beta type I receptor (TbetaR-I) mutations are rare, suggesting that other molecular alterations in the TGF-beta pathway are likely. To identify abnormalities in TbetaR-I expression we analyzed 50 HNSCCs and correlated the results with clinical-pathologic features. Methods. Hypermethylation of TbetaR-I was evaluated via methylation-specific PCR (MSP) and restriction enzyme-mediated PCR (MSRE). Mutations in exons 1 and 7, mRNA and protein expression were analyzed by direct sequencing, semiquantitative RT-PCR and immunohistochemistry, respectively. Results. TbetaR-I expression was lost in 83% HNSCCs and was linked to DNA hypermethylation of the CpG-rich promoter region in 62% of the tumors. The variants 9A/6A and Int7G24A were found in two patients. Conclusions. This study shows that suppression of TbetaR-I expression in HNSCC is associated with DNA hypermethylation.

Attenuation of bromobenzene-induced hepatotoxicity by poly(ADP-ribose) polymerase inhibitors.

Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant-induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non-specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5-fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice.

Attenuation of bromobenzene-induced hepatotoxicity by poly(ADP-ribose) polymerase inhibitors.

Inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) have been demonstrated to attenuate pathophysiological conditions associated with toxicant-induced oxidative stress. This investigation evaluates Nicotinamide (NIC), a non-specific PARP inhibitor, and 6(5)-Phenanthridinone (Phen), a specific PARP-1 inhibitor, for their efficacy in blocking or attenuating bromobenzene (BB) induced hepatocellular toxicity. Male ICR mice were treated with an intraperitoneal injection of bromobenzene, followed by concomitant treatment with NIC or with NIC at 0.5, 1 and 2 hours after BB treatment, or with concomitant treatment of Phen at 10 mg/ml, 20 mg/ml, or 40 mg/ml solution concentration. Mice with only BB treatment displayed substantial hepatotoxicity as evidenced by a 3.5-fold increase in serum alanine transferase (ALT) compared to controls. Mice treated with 3 injections of NIC (at 0.5, 1 and 2 hours) after BB treatment demonstrated a 90% reduction in serum ALT at 24 hours after BB treatment (p < 0.05). Mice with concomitant BB and Phen treatment demonstrated a 75% reduction in ALT at 24 hours after treatment (p < 0.05). Histological evaluations of centrilobular hepatic tissue from treated animals confirm findings of reduced hepatotoxicity as indicated by the ALT results in the NIC and Phen treatment groups. Mortality after 7 days was reduced to levels near controls in the NIC and Phen treatment groups. The PARP-1 inhibitors evaluated in this investigation produce clinically significant attenuation of BB-induced liver injury in male ICR mice.

Aggressive proximal tibio-fibular joint ganglion cyst after a total knee arthroplasty--a case report.

Although the knee is a common location, a ganglion cyst arising from the proximal tibio-fibular joint (PTFJ) is relatively rarer. Unique diagnostic and management difficulties are encountered as these can extend into subcutaneous tissue, or spread along peroneal muscles and nerve, or erode adjacent bone. We report here a PTFJ ganglion cyst which was indolent for at least 12 years and then caused destructive and expansile changes in the fibula over a period of 6 years after a total knee arthroplasty (TKA), simulating a malignancy. Although no wear or foreign body reaction could be shown, this alarming progression of a PTFJ ganglion cyst in the fibula after the TKA is a noteworthy association, and has not been recognized and reported before. Awareness of such a lesion can aid in the diagnosis and prevent unnecessary aggressive management.

Signal transduction proteins in tumors from Puerto Rican and Caucasian gastric adenocarcinoma patients: expression differences with potential for specific targeted therapies.

Overexpression of the HER2/NEU gene is associated with aggressive behavior and poor prognosis in breast cancer, making the Her2/neu protein a directed-therapy target. Tumors of two Puerto Rican (PR) patients overexpressed Her2/neu and resulting partial clinical responses motivated us to compare Her2/neu expression in PR (n = 101) and Caucasian non-Hispanic (n = 95) patients. Immunohistochemistry of tumors showed overexpression of p-Stat3, Cyclin D1, and Her2/neu, compared to non-neoplastic mucosa. Her2/neu and EGF-R protein levels were statistically significantly different with higher levels of both proteins in the PR group. Importantly, Her2/neu expression was strong and diffuse in tumors with signet-ring morphology, while other histo-pathological subtypes showed higher intra-tumoral Her2/neu heterogeneity than typically observed in breast cancer. Targeted therapies in gastric cancer directed at EGF-R and Hers-2/neu pathways warrant further investigation. These therapies may be especially effective in PR patients and in patients with signet-ring cell morphologies with a dismal prognosis.

Pigmented villonodular bursitis/diffuse giant cell tumor of the pes anserine bursa: a report of two cases and review of literature.

Pigmented villonodular synovitis (PVNS) is a benign but potentially aggressive lesion, characterized by synovial villonodular proliferation with hemosiderin pigmentation and stromal infiltration of histiocytes and giant cells. This consists of a common family of lesions, including localized and diffuse forms of pigmented villonodular synovitis, giant cell tumor of the tendon sheath (nodular tenosynovitis) and the very rare cases of extra-articular pigmented villonodular synovitis arising from the bursa (pigmented villonodular bursitis or diffuse giant cell tumor of the tendon sheath). The purpose of this paper is to present two rare cases of pigmented villonodular bursitis arising from the pes anserinus bursa. The various differentials along with a review of literature of similar lesions are also being discussed. However, as with other lesions, clinicoradiographic features along with close histological correlation is essential for diagnosis.

Expression of TGFbeta type-II receptor in association with markers of proliferation and apoptosis in premalignant lung lesions.

BACKGROUND: Analysis of the early molecular abnormalities that play an oncogenic role in the progression of pulmonary neoplasia may lead to the identification of useful markers for early detection and prognosis. In normal squamous epithelium, transforming growth factor beta (TGFbeta) regulates cell growth and differentiation via specific membranous receptors and intracellular signaling molecules (Smads). The authors previously observed that, in head and neck squamous cell carcinoma, the expression of the TGFbeta type II receptor (TbetaR-II) decreases as tumors become less differentiated and more biologically aggressive. METHODS: In this pilot study of 48 premalignant bronchoepithelial lesions, the authors evaluated the expression of TbetaR-II and 2 proliferation markers (Ki-67 and MCM2), and the amount of early DNA fragmentation as evidence of apoptosis. RESULTS: The authors observed that the progression of premalignant lesions toward carcinoma in situ is accompanied by a decrease in TBR II expression and apoptosis and an increase in the expression of Ki-67 and MCM2. CONCLUSIONS: These results suggested that the TGFbeta pathway may be impaired early in the neoplastic process and that a combination of selected markers can provide a useful profile to detect preneoplastic changes in individuals at high risk for developing pulmonary carcinoma.

Framework analysis for the carcinogenic mode of action of nitrobenzene.

Nitrobenzene (CASRN: 98-95-3) has been shown to induce cancers in many tissues including kidney, liver, and thyroid, following chronic inhalation in animals. However, with a few exceptions, genotoxicity assays using nitrobenzene have given negative results. Some DNA binding/adduct studies have brought forth questionable results and, considering the available weight of evidence, it does not appear that nitrobenzene causes cancer via a genotoxic mode of action. Nitrobenzene produces a number of free radicals during its reductive metabolism, in the gut as well as at the cellular level, and generates superoxide anion as a by-product during oxidative melabolism. The reactive species generated during nitrobenzene metabolism are considered candidates for carcinogenicity. Furthermore, several lines of evidence suggest that nitrobenzene exerts its carcinogenicity through a non-DNA reactive (epigenetic) fashion, such as a strong temporal relationship between non-, pre-, and neoplastic lesions leading to carcinogenesis. In this report, we first describe the absorption, distribution, metabolism, and excretion of nitrobenzene followed by a summary of the available genotoxicity studies and the only available cancer bioassay. We subsequently refer to the mode of action framework of the U.S. Environmental Protection Agency's 2005 Guidelines for Carcinogen Risk Assessment as a basis for presenting possible modes of action for nitrobenzene-induced cancers of the liver, thyroid, and kidney, as supported by the available experimental data. The rationale(s) regarding human relevance of each mode of action is also presented. Finally, we hypothesize that the carcinogenic mode of action for nitrobenzene is multifactorial in nature and reflective of free radicals, inflammation, and/or altered methylation.

Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors.

Survivin is a good candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses can be generated in mice and cancer patients. These responses resulted in a substantial antitumor effect. However, the fact that survivin is expressed in normal hematopoietic progenitor cells and endothelial cells may potentially limit the use of vaccination against survivin in the clinic due to possible toxicity. In this study, we have evaluated this risk by using dendritic cells (DC) transduced with an adenovirus encoding mutant human survivin (Ad-surv DCs). Immunization of mice with Ad-surv DCs resulted in generation of CD8 T cells recognizing multiple epitopes from mouse survivin. These responses provided significant antitumor effect against 3 different tumors EL-4 lymphoma, MC-38 carcinoma, and MethA sarcoma. Survivin-specific T-cells did not affect bone marrow hematopoietic progenitor cells and no autoimmune abnormalities were observed. However, as was the case with other tumor vaccines it provided only partial antitumor effect against established tumors. The existing paradigm suggests that generation of immune response against multiple tumor-associated antigens may provide a better antitumor effect. Here, we directly tested this hypothesis by combining vaccines targeting different tumor-associated proteins: survivin and p53. Despite the fact that combination of 2 vaccines generated potent antigen specific T-cell responses against both molecules they did not result in the improvement of antitumor effect in any of the tested experimental tumor models.