Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.

BACKGROUND: Corticotropin-releasing factor (CRF) mediates our body's overall responses to stress. The role of central CRF in stress-stimulated colonic motility is well characterized. We hypothesized that transient perturbation in expression of enteric CRF is sufficient to change stress-induced colonic motor and secretory responses. METHODS: Sprague-Dawley rats (adult, male) were subjected to 1-h partial restraint stress (PRS) and euthanized at 0, 4, 8, and 24 h. CRF mRNA and peptide levels in the colon were quantified by real-time RT-PCR, enzyme immuno-assay and immunohistochemistry. Double-stranded RNA (dsRNA) designed to target CRF (dsCRF) was injected into the colonic wall to attain RNA interference-mediated inhibition of CRF mRNA expression. DsRNA for ß-globin was used as a control (dsControl). Four days after dsRNA injection, rats were subjected to 1-h PRS. Fecal output was measured. Ussing chamber techniques were used to assess colonic mucosal ion secretion and transepithelial tissue conductance. KEY RESULTS: Exposure to PRS elevated CRF expression and increased CRF release in the rat colon. Injection of dsCRF inhibited basal CRF expression and prevented the PRS-induced increase in CRF expression, whereas CRF expression in dsControl-injected colons remained high after PRS. In rats treated with dsControl, PRS caused a significant increase in fecal pellet output, colonic baseline ion secretion, and transepithelial tissue conductance. Inhibition of CRF expression in the colon prevented PRS-induced increase in fecal output, baseline ion secretion, and transepithelial tissue conductance. CONCLUSIONS & INFERENCES: These results provide direct evidence that transient perturbation in peripherally expressed CRF prevents colonic responses to stress.

Idiopathic hypereosinophilic syndrome with skull base involvement.

Idiopathic hypereosinophilic syndrome (HES) is a heterogeneous disorder characterized by prolonged eosinophilia without an identifiable cause, ultimately resulting in organ dysfunction. Three major types of neurologic involvement have been well defined in HES; however, to our knowledge, inflammatory pseudotumor (IPT) in association with HES has not been reported. We present a case of IPT of the skull base in a patient with HES that suggests that HES may result in an exaggerated immunologic or inflammatory response leading to the formation of IPT.

Vascular endothelial growth factor and soft tissue sarcomas: tumor expression correlates with grade.

INTRODUCTION: Vascular endothelial growth factor (VEGF), an endothelial-specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor. METHODS: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 microg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers' exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier. RESULTS: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining. CONCLUSIONS: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

A novel t(1;8)(p13;p11) in a thymic carcinoma with unusual giant cell features and renal metastasis.

Cytogenetic analysis of a thymic carcinoma metastatic to the left kidney revealed the presence of a t(1;8)(p13;p11). In addition to a previously undescribed translocation, this tumor histologically showed unusual giant cell features.

Alveolar soft part sarcoma metastatic to small bowel mucosa causing polyposis and intussuseption.

A report of alveolar soft part sarcoma metastatic to the small bowel is presented. Hematogenous metastases to the small bowel from primary tumors outside the abdominal cavity are uncommon, and most remain asymptomatic and are not discovered until autopsy. However, small bowel metastases can lead to intestinal obstruction, intussuseption or even perforation. While metastases to the small bowel have been described for other tumor types, including melanoma and lung cancer, this is extremely uncommon for sarcoma, especially alveolar soft part sarcoma. We describe a 42-year-old male with a long history of alveolar soft part sarcoma, metastatic to the lung and brain, who developed an intussuseption from metastases to the small bowel.

Massive localized lymphedema: additional locations and association with hypothyroidism.

We report the second series of a new entity called "massive localized lymphedema in morbidly obese patients" (MLL), recently described in medical literature. Our 6 cases present additional locations as well as an association with hypothyroidism. Huge masses, of longstanding duration ranging from 9 months to 8 years, afflicted the thigh, popliteal fossa, scrotum, suprapubic and inguinal region, and abdomen of morbidly obese adults. Although clinical impressions were generally of a benign process, including lipoma and recurrent cellulitis, the possibility of a malignant neoplasm could not be eliminated. Poorly defined and non-encapsulated, these skin and subcutaneous lesions were most remarkable for their sheer size, measuring 50.6 cm in mean diameter (range, 38-75 cm) and weighing a mean of 6764.5 g (range, 2,060-12,000 g) The overlying skin exhibited the induration and peau d'orange characteristic of chronic lymphedema. Grossly and histologically, a prominent marbled appearance, rendered by fibrous bands intersecting lobules of adipose tissue, simulated sclerosing well differentiated liposarcoma. However, the absence of atypical stromal cells, atypical adipocytes, and lipoblasts precluded the diagnosis of well differentiated liposarcoma. Instead, reactive features, encompassing lymphatic vascular ectasia, mononuclear cell infiltrates, fibrosis, and edema between the collagen fibers, as well as ischemic changes including infarction and fat necrosis, established the diagnosis of MLL. Although the pathogenesis of MLL may be as simple as obstruction of efferent lymphatic flow by a massive abdominal pannus and/or prior surgery, the presence of hypothyroidism in 2 of our patients suggests an alternative pathogenesis. Recognition of this entity by both clinicians and pathologists should avert a misdiagnosis as a low-grade liposarcoma.

Immunoreactivity of MIC2 (CD99) in acute myelogenous leukemia and related diseases.

MIC2 is characteristically expressed in lymphoblastic lesions and Ewing's/primitive neuroectodermal tumor sarcomas. Although MIC2 has recently been reported in chloroma and rare terminal deoxynucleotidyl transferase-positive acute myelogenous leukemia (AML), the incidence and the significance of MIC2 (CD99) immunoreactivity in myeloid lesions is not clear. In this study, we evaluated MIC2 positivity in a variety of myeloid diseases and normal marrow to determine its incidence and distribution in myeloid diseases; its correlation with flow cytometric and cytogenetic data in AML; and its association with leukemic transformation, relapse, and chloroma formation. Paraffin sections of 11 chloromas and 94 bone marrow core biopsies from 66 patients were stained with CD99 monoclonal antibody 12E7. Of 94 bone marrow core biopsies, there were 30 AML (fragment antigen binding M0 to M6), 23 remissions, 5 relapses, 12 myeloproliferative disorders, 13 myelodysplastic syndromes, and 11 normal marrows from patients who did not have leukemia. CD99 immunoreactivity was evaluated with light microscopy. MIC2 expression was seen in leukemic blasts in 6 of 11 chloromas (55%) and 13 of 30 AML (43%) but rarely in myeloproliferative disorders, myelodysplastic syndromes, remission, and normal marrow. CD99 tended to be positive in M1-, M3-, and HLA-Dr-negative AML and negative in AML with relapse. MIC2 expression did not correlate with the karyotype independent of French-American-British Cooperative Group classification and the disease remission or occurrence of chloroma in AML. We concluded that MIC2 is commonly expressed in leukemic blasts of AML and is not predictive of leukemic transformation from myeloproliferative disorders and myelodysplastic syndromes or chloroma formation. Caution should be taken when using MIC2 as a marker for Ewing's sarcoma/ primitive neuroectodermal tumor or lymphoblastic lymphoma on paraffin sections of either soft tissue or bone marrow specimens.

Malignant epithelioid vascular tumors of the pleura: report of a series and literature review.

Primary malignant vascular tumors of the pleura are rare. The significance and difficulty of distinction between pleural epithelioid hemangioendothelioma (EHE) and angiosarcoma have not yet been addressed. A new series of pleural angiosarcoma is reported, and the relevant literature is reviewed. Five cases were identified from files of the authors' institutions and personal consultation cases (J.J.B.). Twenty-six cases of primary malignant vascular tumors of the pleura were identified in the literature. In a total of 31 cases, 22 were from the West and 9 from Japan. Patients were 22 to 79 years old (average, 57), and the male/female ratio was 9:1. Prior chronic pyothorax was identified only in cases reported from Japan. History of exposure to radiation or asbestos was noted in a few Western cases. The most common presentation was pleural thickening and effusion. Almost all of the patients died of disease shortly after diagnosis. A spectrum of histology ranging from characteristic high-grade epithelioid to relatively low-grade EHE-like features was observed in our cases and can be found in previous reports. Most cases showed variable spotty cytokeratin immunoreactivity. Endothelial markers (factor 8, CD34, or CD31) were invariably positive. Pleural angiosarcomas are often epithelioid and can be easily mistaken for mesothelioma or carcinoma clinically and histologically. Awareness of this rare tumor should prompt the use of endothelial markers when faced with a questionable mesothelioma. When cytokeratin is negative, or focal with strong vimentin reactivity, a vascular tumor should be suspected and confirmed with vascular markers. Because of their invariably aggressive behavior, all epithelioid vascular tumors of the pleura should be considered highly malignant regardless of the presence of EHE-like histological features.

Immunoexpression of villin in neuroendocrine tumors and its diagnostic implications.

BACKGROUND: Villin, a 95-kd cytoskeletal protein associated with axial microfilament bundles of brush border microvilli, is mostly restricted to intestinal glandular tumors. Villin immunoexpression was recently observed in a small number of carcinoids of the intestinal tract and lung, but its significance in a broad category of neuroendocrine tumors has not been evaluated. DESIGN: A total of 114 neuroendocrine tumors of different origins were tested for villin expression. They included gastrointestinal carcinoids (n = 30), lung carcinoids (n = 15), small cell carcinomas of the lung (n = 24), small cell carcinomas of other sites (n = 15), islet cell tumors (n = 8), Merkel cell carcinomas (n = 6), paragangliomas (n = 6), and others (n = 10). Nine round cell sarcomas were tested as well. RESULTS: Villin immunoreactivity was present in 85% of gastrointestinal carcinoids and small cell carcinomas, but was found in only 40% of lung carcinoids. Other tumors tested were virtually negative for villin. In general, while cytoplasmic reactivity was most common, a characteristic apical membranous pattern simulating brush border was seen in 76% of the gastrointestinal carcinoids and in 50% of the lung carcinoids. CONCLUSIONS: We found that villin was predominantly restricted to gastrointestinal neuroendocrine tumors (excluding islet cell tumors), although a small number of bronchial carcinoids may be positive as well. These results suggest a role for villin in the differential diagnosis of neuroendocrine tumors.

Effectiveness of multiple-level sectioning in detecting axillary nodal micrometastasis in breast cancer: a retrospective study with immunohistochemical analysis.

OBJECTIVE: To evaluate the effectiveness of original multiple-level sectioning in detecting axillary nodal micrometastasis in breast carcinoma. DESIGN: Retrospective analysis of 707 axillary nodes from 34 consecutive node-negative invasive breast cancers from the years 1989 and 1990. All but 2 cases were originally examined by multiple-level sectioning. The original histologic sections were reviewed. Additional sections were cut for hematoxylin-eosin staining and cytokeratin immunohistochemistry. RESULTS: A micrometastasis was found in only 1 case (1 node) on the original histologic section, which was 1 of the 2 cases not originally processed by multiple-level sectioning. Additional sections and cytokeratin immunostains were negative on all cases, including the false-negative case identified on original section. CONCLUSIONS: The finding of a micrometastasis in 1 case on the original, but not on any additional recuts or cytokeratin immunostains, indicates that the original multiple-level sectioning was very effective (0% false negatives). Immunohistochemistry provided no additional benefit in detecting micrometastases in cases already examined by multiple-level sectioning. Thorough histologic examination on properly prepared sections is probably the most efficient and cost-effective way to detect the vast majority of axillary nodal micrometastases.

Malignant granular cell tumors: report of a case and review of the literature.

BACKGROUND: Granular cell tumors are uncommon soft tissue tumors and are more commonly benign. Malignant granular cell tumors are extremely rare, may be confused with other soft tissue sarcomas, and can be diagnosed only when metastatic disease that has the same histologic features as the primary tumor has been identified. Metastases are more commonly seen in lymph nodes and lungs; however, often the metastatic disease is not identified at the time of initial diagnosis and presents anywhere from 3 to 37 months after initial treatment. Certain findings, such as histologic appearance and size, may suggest that a granular cell tumor has uncertain malignant potential. METHODS: We evaluated a patient with a granular cell tumor of uncertain malignant potential of the left chest wall and no evidence of metastatic disease on physical examination with a preoperative work-up to identify sites of occult disease. RESULTS: The patient was found to have suspicious ipsilateral axillary adenopathy on magnetic resonance imaging and computed tomography scan. No other regional or distant disease was identified. The patient underwent an en bloc wide excision and axillary lymph node dissection. Metastatic disease was identified in nine of 23 lymph nodes. CONCLUSIONS: Patients who are diagnosed with a granular cell tumor of uncertain malignant potential may benefit from preoperative radiologic evaluation because occult metastatic disease may be identified, alter the surgical approach, and possibly affect the long-term outcome.

Enteroenteric intussusception due to a metastatic malignant fibrous histiocytoma.

Intussusception secondary to metastatic sarcoma is an unusual cause of small bowel obstruction. When a patient who has no history of a previous laparotomy, and has a known malignancy which metastasized hematogenously, presents with small bowel obstruction, the diagnosis of intussusception should be considered. The patient should be evaluated and treated accordingly.

The detection of acquired immunodeficiency syndrome-associated Kaposi sarcoma cells in pleural effusion by CD34 immunostain.

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) cells have not been reported in pleural effusions. This study identifies the effusional form of AIDS-KS cells with the CD34 antibody, a newly recognized marker for vascular neoplasia. METHODS: In the pleural effusion of a patient with AIDS and biopsy proven pulmonary KS, the authors found bizarre amoeboid cells. Parallel sections from the cell blocks of the pleural effusions from the index patient and six other patients with AIDS were immunostained for cytokeratin, CD68, leukocyte common antigen (LCA), Factor VII:R, and CD34. RESULTS: The atypical cells were not observed in the pleural effusions of the other six patients with AIDS. The atypical cells were positive for CD34 (4+) and Factor VIII:R (1+) but were negative for cytokeratin, CD68, or LCA, which were expressed by mesothelial cells, macrophages, and lymphocytes, respectively. The expression for CD34 and Factor VIII:R was limited to a sharply delineated perinuclear region in the cytoplasm, corresponding to the erythrocyte-containing intracytoplasmic space of the atypical cells on the filter. CONCLUSION: In conclusion, the erythrocyte-containing intracytoplasmic space within the atypical cells most likely represents the intracytoplasmic lumina of the AIDS-KS endothelial cells and the CD-34-positive atypical cells represent the effusional form of the AIDS-KS cells.

Trends in the incidence of soft tissue sarcomas in the United States from 1973 through 1987.

BACKGROUND: Soft tissue sarcomas (STS) comprise a relatively rare group of malignant tumors of the connective tissues. It is estimated that approximately 6000 cases of STS will occur in the United States in 1993. Concerns have been raised in the clinical community that the incidence of STS may be increasing. METHODS: Incidence rates of STS were obtained from the Surveillance, Epidemiology, and End Results program. Cases were restricted by histologic classification to malignant tumors determined a priori to be STS by a pathologist specializing in diseases of soft tissue. Age-, sex- and race-specific rates also were examined. RESULTS: A total of 18,525 newly diagnosed cases of STS were identified for the period 1973 through 1987 in the United States. There was a marked increase in the age-adjusted incidence rate during the interval from 1981 to 1987, with rates increasing from 4.4 x 10(-6) in 1981 to 7.1 x 10(-6) in 1987. However, when patients with Kaposi sarcoma (KS) (International Classification of Diseases for Oncology [ICD-O] code 9140) were eliminated from this analysis, the rates remained relatively unchanged throughout the time period. Additional stratification by age, gender, and race revealed no important differences in this observed lack of a time trend. Gastrointestinal tract cases were examined separately, and no significant changes in incidence rates were observed. CONCLUSIONS: It appears as though the increase in STS during this time period is accounted for primarily by KS, perhaps because of the acquired immune deficiency syndrome epidemic (since single men between the ages of 20 and 59 years accounted for almost 69% of all cases of KS). Additional studies that examine other populations or time periods after 1987 might be useful.

Translocation (11;22)(p13;q12): primary change in intra-abdominal desmoplastic small round cell tumor.

We present the cytogenetic findings in a case of a newly described tumor of childhood, intra-abdominal desmoplastic small round cell tumor (IADSRCT). The karyotype demonstrated a single chromosomal translocation, (11;22)(p13;q12).

Signet cell melanocytic lesions.

Malignant melanoma can produce diagnostic problems for the histopathologist because of its protean histologic patterns. The recently recognized signet cell pattern can be particularly confusing and must be distinguished from adenocarcinoma, tumors of vascular endothelium or adipose tissue, lymphoma, and epithelioid smooth muscle lesions. We report four new cases of signet cell melanoma and illustrate this pattern in primary as well as metastatic sites. In addition, we document the signet cell pattern in benign nevi for the first time, expanding the concept of this pattern to melanocytic cells in general. The differential diagnosis of signet cell melanoma and its mimics is discussed and the utility of immunohistochemical stains in this diagnosis is stressed.