A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075.

Primary disseminated central neurocytoma: cytological and MRI evidence of tumor spread prior to surgery.

Since its description in 1982, central neurocytoma (CN) has been a relatively innocuous rare tumor of the central nervous system. Comprising of less than 0.5% of all intracranial tumors, most are reported to be slow growing, with low recurrence rates, and a favorable prognosis. Because of its rarity, its cellular biology, prognosis, and treatment strategies are difficult to ascertain. Its low-grade nature allows for continued growth before signs and symptoms of increase intracranial pressures ensue. Some authors theorize CN may derive from bipotential precursor cells of the periventricular germinal matrix, which are capable of both neuronal and glial differentiation, but maintain a low proliferative potential after birth. Several retrospective studies indicate that a MIB-1 index of greater than 2-3% will show a recurrence rate of 48-63%, respectively. Of hundreds of cases reported, the incidence of recurrence is very low, which makes aggressive forms of this tumor difficult to study. There are only 12 cases of craniospinal dissemination reported since its inception. The diagnoses of dissemination in these cases are made only after surgical intervention. We report the only case of primary disseminated CN, diagnosed on radiographic studies, and confirmed by cytology of the cerebral spinal fluid, prior to any kind of intervention. These cases may represent a subgroup of a more aggressive CN, which requires more assertive surveillance including CSF sampling and routine imaging of the neuroaxis.

Small cell carcinoma: arising in Lynch syndrome: a previously undocumented occurrence.

Lynch syndrome is a genetic cancer predisposition syndrome caused by an inherited defect in 1 of 4 DNA mismatch repair genes (mutL homolog 1, mutS homolog 2, mutS homolog 6, and postmeiotic segregation 2). Despite the theoretically increased risk in all tissues, Lynch syndrome exhibits tissue specificity, with a particular tendency among affected individuals to develop colorectal and endometrial cancer at a young age. A number of other malignancies, including those derived from the ovary, stomach, small bowel, and urothelium, have also been linked to this syndrome. A growing body of evidence exists to support an association between mismatch repair mutations and a growing spectrum of hereditary nonpolyposis colon cancer-associated neoplasms. In this article, a previously undocumented mismatch repair-related malignancy in a patient with Lynch syndrome is reported.

Expression of the p16(INK4a) gene product in premalignant and malignant epithelial lesions of the gallbladder.

The sequence of molecular changes leading to neoplastic transformation in the gallbladder remains elusive. The aim of this study is to characterize the spectrum of nuclear p16 protein product immunohistochemical expression in tissue microarray cores taken from resected gallbladders, comprising histologically normal gallbladder epithelia (n = 29), dyplastic epithelia (n = 19), reactive atypia (n = 7), and gallbladder adenocarcinoma (n = 23). Nuclear staining for p16 was evaluated for intensity (range, 0-3) and distribution (range, 0-3), and a summary staining score (range, 0-6) was obtained. Pairwise comparisons were significant for increased p16 protein expression in dysplastic epithelium (6/19, 31.6%) and invasive carcinoma (9/23, 39.1%) when compared to normal epithelium (0/29, 0%) (P = .003 and P = .0006, respectively). A quantitative increase of nuclear expression of p16 in reactive atypia (1/7, 14%) when compared to normal was also statistically significant (P = .049). Our data demonstrate that nuclear p16 expression is absent in normal gallbladder epithelium and is a frequent event in high-grade dysplasia of the gallbladder and gallbladder adenocarcinoma.

Anaplastic carcinoma of the thyroid with chondroblastoma features mimicking papillary carcinoma: a case report.

BACKGROUND: An unusual case of anaplastic carcinoma of the thyroid arising from a metastatic focus of papillary carcinoma. CASE: The tumor affected a 69-year-old woman with a history of total thyroidectomy for papillary thyroid carcinoma 4 years previously. She presented with a rapidly enlarging neck mass that histologically simulated chondroblastoma. A small, embedded focus of residual follicular variant of papillary carcinoma was present. The patient died of disease 3 months later. CONCLUSION: This "chondroblastoma" variant of anaplastic thyroid carcinoma has not been reported to date.

Reification of abstract concepts to improve comprehension using interactive virtual environments and a knowledge-based design: a renal physiology model.

Several abstract concepts in medical education are difficult to teach and comprehend. In order to address this challenge, we have been applying the approach of reification of abstract concepts using interactive virtual environments and a knowledge-based design. Reification is the process of making abstract concepts and events, beyond the realm of direct human experience, concrete and accessible to teachers and learners. Entering virtual worlds and simulations not otherwise easily accessible provides an opportunity to create, study, and evaluate the emergence of knowledge and comprehension from the direct interaction of learners with otherwise complex abstract ideas and principles by bringing them to life. Using a knowledge-based design process and appropriate subject matter experts, knowledge structure methods are applied in order to prioritize, characterize important relationships, and create a concept map that can be integrated into the reified models that are subsequently developed. Applying these principles, our interdisciplinary team has been developing a reified model of the nephron into which important physiologic functions can be integrated and rendered into a three dimensional virtual environment called Flatland, a virtual environments development software tool, within which a learners can interact using off-the-shelf hardware. The nephron model can be driven dynamically by a rules-based artificial intelligence engine, applying the rules and concepts developed in conjunction with the subject matter experts. In the future, the nephron model can be used to interactively demonstrate a number of physiologic principles or a variety of pathological processes that may be difficult to teach and understand. In addition, this approach to reification can be applied to a host of other physiologic and pathological concepts in other systems. These methods will require further evaluation to determine their impact and role in learning.

Magnetic resonance imaging identifies the fibrous cap in atherosclerotic abdominal aortic aneurysm.

BACKGROUND: MRI can distinguish components of atherosclerotic plaque. We hypothesized that contrast enhancement with gadolinium-DTPA (Gd-DTPA) could aid in the differentiation of plaque components in abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Twenty-three patients (19 males, age 70+/-8 years) with AAA underwent MRI on a 1.5-T clinical scanner 3+/-3 days before surgical grafting. T1- and T2-weighted (W) black blood spin echo imaging was performed in 1 axial slice, and the T1-W imaging was repeated after a Gd-DTPA-enhanced 3D magnetic resonance angiogram. A section of the aorta at the site of imaging was resected at surgery for histopathologic examination of tissue components and inflammatory cells. Signal-to-noise and contrast-to-noise ratios (CNR) were measured in visualized plaque components from multispectral MRI, and percent enhancement after contrast on T1-W imaging was calculated. The kappa value for agreement between pathology and MRI for the number of tissue components was 0.785. T2-W imaging identified thrombus as regions of high signal and lipid core as low signal, with a CNR of 6.43+/-3.41. Nine patients had a fibrous cap pathologically, which was visualized as a discrete area of uniform increased signal on T2-W imaging with a CNR of 4.52+/-1.93 compared with lipid core. Within the cap, the percent enhancement after Gd-DTPA on T1-W imaging was 91+/-63%. CONCLUSIONS: Higher signal on T2-W MRI identifies the fibrous cap and thrombus within AAA. Contrast enhancement improves delineation of the fibrous cap. The addition of contrast to MRI plaque imaging may enhance identification of vulnerable plaque.

Glandular inclusions in inguinal hernia sacs: morphologic and immunohistochemical distinction from epididymis and vas deferens.

Glandular inclusions in inguinal hernia sacs may bear a striking resemblance to the epididymis or vas deferens. Misinterpretation as a transected functional structure may raise significant concerns regarding reproductive capability, even if encountered unilaterally. In a child, resolution of these concerns may be years away with the onset of puberty and documentation of normal sperm counts. CD10 has been shown to be present in Wolffian-type epithelium and to be absent in Mullerian-type epithelium. We hypothesized that an antibody to CD10 would react with vas deferens and epididymis and fail to react with hernia sac inclusions, most of which we thought were Mullerian duct-derived structures. Glandular inclusions in 29 hernia sacs from prepubertal males were classified histologically according to their resemblance to normal structures and analyzed for CD10 by immunohistochemistry. Inclusions resembling vas deferens had their external diameters measured and were also stained for smooth muscle actin. Thirty-one examples of normal vas deferens and 13 examples of normal epididymis were included for comparison. The inclusions were classified as vas deferens-like (9), epididymis-like (13), and Mullerian-like (7). CD10 reactivity was lacking in all vas deferens-like inclusions; their median external diameter was 0.6 mm. Of the epididymis-like inclusions, 7 of 13 were CD10 positive. The CD10-negative cases consisted of glands with well-defined stromal coats distinct from adjacent stromal coats. CD10-positive cases were more numerous, more tightly aggregated, and surrounded by less well-developed stromal coats that blended with adjacent coats. All seven Mullerian-like remnants were CD10 negative. All normal vas deferens and epididymis showed at least focal CD10 reactivity. CD10 positivity in all cases had a luminal membranous staining pattern. Both the vas deferens-like inclusions and the normal vas deferens showed strong smooth muscle actin positivity in their stromal coats. CD10 negativity and external diameter <1 mm are highly useful to distinguish vas deferens-like inclusions from true vas deferens. Epididymis-like inclusions are more problematic. Some react for CD10 and may represent aberrant Wolffian ductules. Others are CD10 negative, distinct from true epididymis, and may be of Mullerian differentiation. Mullerian-like remnants can be diagnosed on the basis of their limited number and scattered distribution. Lack of CD10 immunostaining corroborates this interpretation.

Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas.

The 40-kilodalton processed glycoprotein, mesothelin, is highly expressed in epithelial mesotheliomas and adenocarcinomas of the ovary (serous papillary) and pancreas, but its expression in a large series of other common carcinomas has not been completely explored. In the present study, we used oligonucleotide and tissue microarrays to profile the expression of the mesothelin gene (MSLN) and encoded protein, respectively. Among 150 carcinomas of multiple anatomic sites, we found the highest average expression of MSLN in serous carcinomas of the ovary and adenocarcinomas of the pancreas, consistent with previous reports, as well as measurable but less-striking expression in pulmonary, gastric/esophageal, and colorectal adenocarcinomas. On tissue microarrays containing 621 carcinomas derived from the same and additional sites as those profiled by gene expression, mesothelin immunoreactivity was highest in cancers of the ovary (serous papillary, endometrioid, and undifferentiated) and pancreas, with less frequent staining seen in adenocarcinomas of the endometrium, lung, and stomach/esophagus. Some immunopositivity was observed in 42% of pulmonary adenocarcinomas, including 18% that had >50% of tumor cells that were immunoreactive. Some 14% of breast and 30% of colorectal adenocarcinomas showed immunopositivity, but no case contained >50% tumor cells that were immunoreactive. Mesothelin was either entirely absent or present in <5% of carcinomas of the prostate, bladder/ureter, liver, kidney, and thyroid. Overall, we observed good concordance between the results obtained by oligonucleotide and tissue microarrays. This large study of the MSLN gene and protein expression in common carcinomas provides data for future investigations that evaluate the utility of mesothelin/megakaryocyte potentiating factor as a potential serum tumor marker or target of immunotoxin-based therapy in human cancers.

Interpretation of RET immunostaining in follicular lesions of the thyroid.

We applied monoclonal antibodies against RET and cytokeratin 19 (CK19) to the following tumor sections: classic papillary carcinoma (PC), 16; Hürthle-type PC (HPC), 1; sclerosing PC with nodular fasciitis-like stroma (SPC), 1; PC, follicular variant (FVPC), 12; follicular adenoma (FA), 9; Hürthle cell adenoma (HA), 4; Hürthle cell carcinoma (HC), 3; and follicular carcinoma (FC), 7. CK19+ tumors included 16 PCs, 1HPC, 1SPC, 11 FVPCs, 7 FAs, 4 FCs, and 1HC. RET+ tumors included 4 HAs, 3 HCs, 1HPC, 12 PCs, 7 FVPCs, and 2 FAs. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a RET transcript in 6 Hürthle cell lesions. RET immunoreactivity is less sensitive and specific for PC than CK19. CK19 is useful for identifying PC, although only lesions with diffuse, intense staining should be considered positive. The detection of RET protein by immunohistochemical analysis was corroborated by the presence of the RET transcript by RT-PCR. Further study is warranted to determine whether this represents activation by gene fusion or some other mechanism in this subset of thyroid neoplasms.

The differential diagnosis of colitis in endoscopic biopsy specimens: a review article.

CONTEXT: A variety of inflammatory disorders may affect the colon, with widely differing clinical outcomes and management. These conditions encompass a spectrum of acute and chronic conditions. OBJECTIVE: Review the pathology of the major colitides and highlight the most diagnostically useful features. DATA SOURCES: Review of recent literature supplemented with personal experience in the field of gastrointestinal pathology. CONCLUSIONS: The etiologies associated with the various types of colitis are diverse and the range of histologic changes is somewhat limited. Nevertheless, the combination of clinical and endoscopic data coupled with histopathology allows for accurate classification in the majority of cases.

CD10 immunoreactivity in sarcomatoid carcinomas: comparison with true sarcomas.

CD10 is a cell surface-related neutral endopeptidase that is involved in cleaving cytokine peptides; it may also play a role in the proliferation of tumor cells and their acquisition of invasiveness. On account of its association with other overtly epithelial neoplasms, we hypothesized that CD10 might be preferentially expressed in the sarcoma-like components of sarcomatoid carcinomas as compared with true sarcomas. Immunohistochemical labeling for CD10 was assessed in various sarcomas and sarcomatoid carcinomas. An aggregate score was generated using both the intensity and extent of staining throughout the neoplasms. Overall, CD10 was expressed more often in true sarcomas (27 of 33 cases) as contrasted with sarcomatoid carcinomas (22 of 34 cases), but with no statistically significant difference between the 2 groups. Uterine "carcinosarcomas" expressed CD10 with accentuation in periglandular tumor cells. The sarcoma-like components in squamous cell carcinoma of the respiratory tract (larynx and lung), tongue, bladder, skin, and penis also expressed CD10 consistently. In the final analysis, there was no difference in CD10 expression between sarcomatoid carcinomas and true sarcomas. This marker seems to have little, if any, differential diagnostic value in the specified histopathologic context.

Mesothelin and GPR30 staining among a spectrum of pancreatic epithelial neoplasms.

INTRODUCTION: Our study attempts to characterize mesothelin and GPR30 / estrogen receptor (ER) staining in pancreatic pathology. MATERIALS AND METHODS: Immunohistochemical staining for mesothelin, GPR30, and ER was performed on a variety of pancreatic lesions. RESULTS: 24 of 42 (57%) adenocarcinomas stained for mesothelin, while 0 of 16 non-carcinomas (0%) stained (p = 0.0000784). 35 of 39 (90%) adenocarcinomas stained for GPR30, while only 4 of 15 (27%) non-carcinomas stained (p = 0.0000036). Apart from stromal staining in one case of mucinous cystic neoplasm, no cases stained for ER. 27 of 37 (73%) adenocarcinoma fine needle aspirates were positive for mesothelin. DISCUSSION: GPR30 is more sensitive, but less specific than mesothelin for pancreatic adenocarcinoma. Mesothelin is detected in most adenocarcinoma fine needle aspirates. ER is rarely detected in pancreatic lesions.

A practical approach to testicular biopsy interpretation for male infertility.

CONTEXT: The combination of testicular biopsy and clinical evaluation for male infertility is becoming progressively more important because new technologies allow men previously considered infertile to father children. Although most general pathologists are experienced with normal, neoplastic, and cryptorchid testicular specimens, the testicular biopsy for infertility requires understanding of a different set of diagnostic categories not otherwise commonly encountered. OBJECTIVE: To highlight a standardized nomenclature for germ cell abnormalities allowing for effective communication with the urologist and maximal clinical benefit from the biopsy. DATA SOURCES: Previously published consensus statements, review articles, peer-reviewed research publications, and abstracts. CONCLUSIONS: A practical approach to evaluating testicular biopsies for fertility and the clinical implications for each abnormality are herein outlined.

C-kit-positive gastric metastasis of lobular carcinoma of the breast masquerading as gastrointestinal stromal tumor.

A 61-year-old woman with no significant past history underwent gastric biopsies demonstrating a strongly c-kit-positive epithelioid malignancy, initially thought to represent gastrointestinal stromal tumor (GIST). Subsequent clinical and immunohistochemical evaluation proved the neoplasm to represent metastatic lobular carcinoma. This case illustrates that although c-kit is highly specific and sensitive for GIST, its expression may occur in a variety of other neoplasms, some of which morphologically resemble GIST and may present in the gastrointestinal tract as metastases. Therefore, a review of other c-kit-positive lesions is also highlighted.

Metastatic epithelioid trophoblastic tumor involving the spine.

STUDY DESIGN: This is a single case-based report. OBJECTIVE: We report the first case of epithelioid trophoblastic tumor (ETT) presenting as primary metastasis to the spine. SUMMARY OF BACKGROUND DATA: ETT is an extremely rare form of gestational trophoblastic neoplasm with less than 100 cases reported in the literature. A 36-year-old, postpartum woman presented with severe low back pain and was found to have a contrast-enhancing lesion in lower thoracic spine subsequently confirmed as ETT. METHODS: The patient data, history, clinical examination findings, laboratory, and histopathology data and imaging studies were retrospectively reviewed and findings reported. A literature search using Pubmed and Cochrane database was conducted. RESULT: We described the first case of an ETT to present as a primary metastasis to the spine. CONCLUSION: This first report of metastasis of ETT to the spine adds significant new information to the growing literature of this rare and newly identified tumor. It also alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation. As more number of cases of nervous system involvement with this tumor are reported, crucial information on prognostic factors and treatment regimens will emerge.

Desmoplastic fibroma of bone with extensive cartilaginous metaplasia.

Desmoplastic fibroma of bone is a rare tumor demonstrating the same histologic and biologic features of its soft tissue counterpart, aggressive fibromatosis. We report the second case of desmoplastic fibroma of bone with extensive chondroid metaplasia. The tumor arose in the left ischium of a 51-year-old male, with extension into adjacent musculature as a pseudoencapsulated mass. The infiltrating growth and quality of the fibrous component are characteristic of desmoplastic fibroma, and in addition, abrupt transitions into bland hyalin cartilage were frequent. Discriminating features of this lesion from other bone tumors capable of biphasic expression of fibrous and chondroid elements are discussed.