The NCCN/American Cancer Society partnership.

The National Comprehensive Cancer Network (NCCN) partnered with the American Cancer Society two years ago in an effort to translate the NCCN Practice Guidelines for professionals into guidelines for patients. The response from patients to the first two guidelines was overwhelmingly positive. The following panel discussion provides some background information on this alliance and discusses the development and highlights of their latest collaboration, the Colorectal Cancer Patient Guidelines.

Ras-associated nuclear structural change appears functionally significant and independent of the mitotic signaling pathway.

An altered nuclear morphology has been previously noted in association with Ras activation, but little is known about the structural basis, functional significance, signaling pathway, or reproducibility of any such change. We first tested the reproducibility of Ras-associated nuclear change in a series of rodent fibroblast cell lines. After independently developing criteria for recognizing Ras-associated nuclear change in a Papanicolaou stained test cell line with an inducible H(T24)-Ras oncogene, two cytopathologists blindly and independently assessed 17 other cell lines. If the cell lines showed Ras-associated nuclear change, a rank order of increasing nuclear change was independently scored. Ras-associated nuclear changes were identified in v-Fes, v-Src, v-Mos, v-Raf, and five of five H(T24)-Ras transfectants consisting of a change from a flattened, occasionally undulating nuclear shape to a more rigid spherical shape and a change from a finely textured to a coarse heterochromatic appearance. Absent or minimal changes were scored in six control cell lines. The two cytopathologists' independent morphologic rank orders were similar (P < .0002). The mitogen signaling pathway per se does not appear to transduce the change since no morphologic alterations were identified in cell lines with activations of downstream components of this pathway--MAPKK or c-Myc--and the rank orders did not correlate with markers of mitotic rate (P > .11). The rank order correlated closely with metastatic potential (P < .0014 and P < .0003) but not with histone H1 composition or global nuclease sensitivity. Based on published studies of five of the cell lines, there may be a correlation between increases in certain nuclear matrix proteins and the Ras-associated nuclear change.

Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival.

Certain cancers exhibit derangement of de novo fatty acid biosynthesis, manifested as overexpression and hyperactivity of the lipogenic enzyme fatty acid synthase (FAS). Correlation of elevated FAS with high tumor grade and advanced stage in primary breast, prostate, and colorectal cancers has drawn attention to the enzyme as a possible marker of poor prognosis. To find a similar utility of FAS in ovarian neoplasms, we compared FAS expression in 68 ovarian tumors with their histological features and clinical outcome. Immunohistochemical localization of FAS was observed in 48 (71%) cases in which staining was either focal (defined as positive staining in 1% to 20% of cells) or multifocal/diffuse (positive staining in >20% of cells). Most (83%) of the 48 cases were represented by endometrioid, serous, or mucinous carcinomas and malignant mixed mullerian tumors (MMMTs). In contrast, ovarian adenomas and tumors of low malignant potential (LMPs) contained little or no FAS. Association between FAS expression and histological diagnosis was statistically significant. The extent of FAS immunostaining was also predictive of prognosis. Among all patients with ovarian malignancies (including LMPs), median survival was 64.8 months, when their tumors exhibited no or focal immunostaining for FAS, as opposed to 31.2 months, when staining was multifocal/diffuse (P = .005). Similar median survival values were obtained when cases were limited to endometrioid, serous, and mucinous carcinomas. Short-term survival at 1 and 2 years was significantly higher in patients whose tumors showed no or focal expression of FAS compared with multifocal/diffuse expression. Thus, elevated FAS may serve as an independent marker for predicting poor clinical outcome in patients with ovarian cancer.

Geographic variations in eosinophil concentration in normal colonic mucosa.

We reviewed 256 mucosal biopsy specimens from the descending and sigmoid colon obtained from surgical pathology departments in several areas of the United States. Only specimens of normal colonic mucosa were included, i.e., no specimens with acute or chronic colitis or adenomatous change, or in which eosinophils invaded the crypts or muscularis mucosae. The mean number of eosinophils per intercryptal space was highest in the southern United States, and there was a 35-fold difference between the mean eosinophil concentrations of patients in New Orleans and Boston. The reason for geographic variation is unknown, but it might be related to allergens in the environment or diet. Normal variations in mucosal eosinophil concentrations should be measured within a specific region before evaluating colonic biopsy specimens for eosinophilia.

Differential polymerase chain reaction assay of cyclin D1 gene amplification in esophageal carcinoma.

The cyclin D1 gene, located on chromosome 11q13, is frequently rearranged in parathyroid neoplasms and amplified in some carcinomas of other organs. Recent studies have detected amplification of cyclin D1 and other markers on chromosome 11q13 (evaluated by Southern or slot blot assays) in approximately 25-50% of squamous cell carcinomas of the esophagus and noted that amplification was associated with lessened survival time. We applied the technique of differential polymerase chain reaction to the evaluation of cyclin D1 gene amplification in squamous cell carcinomas of the esophagus. Cyclin D1 was found to be amplified in 10 of 45 (22%) primary tumors and three of 12 (25%) lymph node metastases. Lymph node metastases tended to be more common in patients with cyclin D1 amplification (70%) than in those without amplification (37%). In 36 patients with follow-up, cyclin D1 amplification was associated with decreased 1 year survival (28% vs. 59%). Cyclin D1 gene amplification in esophageal carcinomas can be evaluated by differential polymerase chain reaction and may provide useful prognostic information.

Characterization of human breast biopsy specimens with near-IR Raman spectroscopy.

Breast biopsy samples were examined with Raman spectroscopy with laser wavelengths ranging from 406 to 830 nm. A combination of a single-stage spectrograph, band reject filter, and CCD detector permitted low laser powers and minimal risk of sample radiation damage. Spectra of formalin-fixed human tissue revealed Raman features for lipids and carotenoids. The best defined lipid features were observed for 782- and 830-nm laser excitation, while carotenoid features were strongest in the 488-515-nm range due to resonance enhancement. Comparison of the spectra with those of fatty acid esters revealed that the major lipid component is a derivative of oleic acid. Lipid and carotenoid Raman bands were superimposed on a luminescent background which was less prominent at longer laser wavelengths. A compact, portable, diode laser spectrometer was tested in a clinical setting with fiber optic sampling. The results indicate that substantial biochemical information is available from near-IR Raman spectroscopy and the technique may have clinical applications.

Aspiration cytologic, ultrastructural, and DNA cytometric findings of solid and papillary tumor of the pancreas.

Solid and papillary epithelial neoplasm of the pancreas (SPENP) is a rare lesion characteristically occurring in young women. By contrast with pancreatic ductal adenocarcinomas, SPENP is a slow-growing tumor that rarely metastasizes or is fatal. The current report describes light and electron microscopic and histochemical findings with DNA flow cytometric analyses of two cases of SPENP. The first patient was a 24-year-old woman; the second, a 72-year-old man. Although SPENP is rare in older men, both patients had characteristic radiographic and light microscopic features of SPENP. Ultrastructural evidence of acinar differentiation was seen in the first patient; the second patient had focal neuroendocrine differentiation. Flow cytometric analysis of the first tumor demonstrated diploid-range DNA content with a 5.8% S-phase fraction (SPF). The DNA cytometric analysis of a biopsy specimen from the second tumor revealed diploid-range DNA content with a 6.1% SPF, although subsequent sampling of the resected tumor showed an aneuploid population with a DNA index of 1.8 and SPF of 2.1%.

Fine needle aspiration and frozen section of salivary gland lesions.

This report examines the role of fine needle aspiration (FNA) and frozen section (FS) examination in the management of salivary gland lesions, and is based on a review of 58 cases. FNA specimens were first classified as nonneoplastic, or as benign or malignant neoplasms. Identification of specific morphologic type of neoplastic lesions was attempted. Overall accuracy for assigning cases was 86%. Specific accuracy (histologic type of neoplasms predicted by FNA) was 72%. No inflammatory lesion was incorrectly diagnosed as neoplasm. Eight patients with histologically documented neoplasm had aspirates classified as nonneoplastic because the sample obtained was not representative. These data indicate that FNA is a highly specific method for identifying benign and malignant neoplasms. Applications of salivary gland FNA include (1) identification of nonneoplastic lesions that may respond to nonsurgical management, (2) identification of neoplasms that represent lymph node metastases rather than primary lesions of the salivary gland, (3) preliminary identification of lymphomas, and (4) preliminary separation of benign and malignant neoplasms.

Superficially invasive carcinoma of the vagina following treatment for cervical cancer: a report of six cases.

Six patients with superficially invasive squamous carcinoma of the vagina are described. All patients meet recently proposed criteria for the diagnosis of microinvasive vaginal carcinoma. The depth of invasion measured from the surface was less than 2.5 mm. There was no lymph-vascular space involvement. The invasive foci arose within a field of carcinoma in situ. Five of these six patients had previously been treated for invasive cervical cancer with pelvic radiation from 82 to 246 months before the diagnosis of vaginal carcinoma. All but one patient had the carcinoma confined to the upper one-third of the vagina. All patients were treated with a single vaginal radium application following vaginectomy. One of these six patients expired from recurrent vaginal cancer 35 months following diagnosis. During the same 17-year period, 17 other cases of Stage I epidermoid cancer of the vagina were treated which did not meet the above criteria for microinvasion. There were no statistically significant differences between these two groups with regard to age at diagnosis, history of cervical cancer, hysterectomy, or pelvic radiation or in survival. Additional experience with early vaginal carcinoma is needed before microinvasive carcinoma of the vagina should be accepted as a distinct clinical entity.

Diagnosis of pancreatic carcinoma by fine needle aspiration cytology and computerized cytomorphometry.

Eighty-one fine needle aspirations (FNAs) of pancreatic masses were performed between 1980 and 1988. Histologic or clinical follow-up was available for correlation with 78 aspirates. The FNA cytologic diagnosis of pancreatic carcinoma had a sensitivity of 79% and a specificity of 91%. Fifteen of the FNA specimens were examined with the Zeiss IBAS image analysis system to determine nuclear area, form (shape), diameter, density and integrated optical density (IOD). Nuclear area and IOD correlated most highly with the final diagnoses. Negative aspirates from benign cases and "false negatives" from malignant cases had similar morphometric values. Cells from adenocarcinoma had greater nuclear area and IOD values in cases cytologically labeled positive than in cytologically suspicious cases. Diagnoses based upon IOD values had a sensitivity and a specificity of 100% and 86%, respectively, while the use of nuclear area measurements produced values of 100% and 100%, respectively. These data indicate that nuclear area and IOD measurements can be valuable adjuncts to qualitative cytology for the diagnosis of pancreatic fine needle aspirates.

Testicular plasmacytoma.

The case of a sixty-five-year-old man with multiple myeloma and a testicular plasmacytoma is described. This represents the thirty fourth reported case of testicular plasmacytoma and the first in which immunoperoxidase histochemistry has been used to demonstrate that the testicular plasma cells contain immunoglobulin of the same isotype as the patient's paraprotein. The clinical and morphologic features of previously reported testicular plasmacytoma are reviewed.

White sponge nevus. Diagnosis by light microscopic and ultrastructural cytology.

The lesions of white sponge nevus, an autosomal dominant abnormality of squamous epithelial differentiation that primarily affects the oral cavity, may be grossly similar to those of other hereditary mucosal syndromes, infections or preneoplastic/neoplastic processes. This differential diagnosis is best resolved in many cases by exfoliative cytology, interpreted in the context of clinical history and physical findings. The following report describes a case of white sponge nevus with typical clinical and cytologic findings, in which the diagnosis was confirmed by ultrastructural cytology. Light microscopic cytology revealed parakeratotic cells and many cells containing dense eosinophilic intracytoplasmic inclusions. Electron micrographs of exfoliated cells demonstrated that these inclusions are composed of disordered aggregates of tonofilaments.

The fibrolamellar variant of hepatocellular carcinoma. Its association with focal nodular hyperplasia.

A case of fibrolamellar hepatocellular carcinoma (FL-HCC) associated with adjacent focal nodular hyperplasia (FNH) is described. These two regions were adjacent but distinct, both on gross and microscopic examination. Currently, it is unclear whether FL-HCC rarely arises in preexisting FNH, or whether FNH is a typical response to this vascular variant of hepatocellular carcinoma (HCC). The FNH region, which is peripheral, may be biopsied to exclude the underlying carcinoma, and thus lead to inadequate therapy. Previous reports of this association are reviewed.

Heterogeneous effects of inhibitors of receptor processing on insulin binding and intracellular accumulation in various cell types.

This study utilized uniform incubation conditions and demonstrated heterogeneity in the effects of various agents on 125-insulin binding and intracellular accumulation in five cell types. The cells used in this study included rat adipocytes, H4IIEC3 cultured hepatoma cells, normal human fibroblasts, and 3T3-L1 preadipocytes and adipocytes. Bacitracin increased insulin binding to rat adipocytes but inhibited binding to all other cells. Chloroquine increased total cell-associated insulin in all cells except H4IIEC3 hepatoma cells. Methylamine and dansylcadaverine increased or decreased binding depending on cell type. Similar heterogeneity was found in the intracellular accumulation of insulin. Under control conditions, intracellular insulin at steady state varied from 16 to 52% of the total cell-associated insulin. Bacitracin decreased intracellular accumulation of insulin in 3T3-L1 adipocytes, preadipocytes, and human fibroblasts but increased accumulation in rat adipocytes. Chloroquine increased insulin accumulation in all cell types except H411EC3 hepatoma cells. Both methylamine and dansylcadaverine increased intracellular insulin in rat adipocytes and decreased accumulation in human fibroblasts. These results provide additional evidence of heterogeneity in insulin and/or insulin receptor processing among different cell types.

Cell type-specific variability of bacitracin's effects on insulin binding and intracellular accumulation.

Bacitracin is known to inhibit proteolytic degradation of insulin and several other peptide hormones. Previous work with isolated rat adipocytes showed that bacitracin blocked insulin degradation by the plasma membrane and, even in the absence of detectable insulin degradation, bacitracin increased insulin binding by decreasing the rate of insulin dissociation. The present study examined the effects of bacitracin on insulin binding and degradation and on levels of intracellular insulin in a variety of cell types. Bacitracin inhibited insulin degradation in all cell types. Maximal inhibition varied from 70% (H4IIEC3 hepatoma cells) to 95% (rat adipocytes); concentrations giving half-maximal inhibition varied from 25 microM (3T3-A31 fibroblasts) to 250 microM (H4IIEC3). Dose-response curves showed three distinctive effects on insulin binding: dose-dependent stimulation (rat adipocytes), a biphasic curve with slight stimulation at low doses and inhibition at concentrations greater than 50 microM (human fibroblasts, H4IIEC3, and 3T3-L1 adipocytes), or dose-dependent inhibition of binding (3T3-L1 preadipocytes and 3T3-A31 fibroblasts). The intracellular accumulation of insulin rat adipocytes was not affected by bacitracin but was decreased in all other cell types. These data illustrated type-specific variability in the effects of bacitracin on insulin processing resulting from cellular heterogeneity either in processing insulin or in response to bacitracin, or both, and suggest that insulin binding studies performed in the presence of bacitracin can be biased.

Chronic administration of dehydroepiandrosterone reduces pancreatic beta-cell hyperplasia and hyperinsulinemia in genetically obese Zucker rats.

The Zucker obese (fa/fa) rat is a model of hypertrophic/hyperplastic obesity. These rats develop marked hyperinsulinemia, insulin resistance, and pancreatic beta-cell hyperplasia. In the present study, chronic (22 weeks) administration of the 17-ketosteroid, dehydroepiandrosterone (DHEA), to obese Zucker rats significantly decreased body weight, and retroperitoneal and parametrial fat pad weights. In addition, beta-cell hyperplasia was reduced as well as pancreatic insulin content. DHEA treatment of lean Zucker rats also reduced body weight, fat depot weight, pancreatic islet diameter, and pancreatic insulin content. These data indicate that DHEA treatment appears to inhibit insulin synthesis and beta-cell proliferation. Whether this is due to a direct effect on the pancreas or due to improvement of peripheral insulin sensitivity remains to be elucidated.

Mammary sarcoidosis. Two cases and literature review.

A patient with sarcoidosis had a biopsy of a firm nontender breast nodule that at analysis disclosed multiple noncaseating granulomas. In another patient with sarcoidosis, noncaseating granulomas were an incidental finding in a mastectomy specimen containing medullary carcinoma and in two subsequent biopsy specimens of the contralateral benign breast. Tests for acid-fast bacteria and fungi using special stains were negative in both cases. There are nine other histologically documented cases of mammary involvement with sarcoidosis. Since the lesions of mammary sarcoidosis often cannot be distinguished from those of carcinoma by physical examination, we suggest that clinically suspicious lesions undergo biopsy whether or not disseminated sarcoidosis is present.

Amiodarone pulmonary toxicity.

Pulmonary toxicity may occur in association with amiodarone hydrochloride therapy. The clinical features of the pulmonary involvement are mild dyspnea, leukocytosis, hypoxemia, elevation in the erythrocyte sedimentation rate, and restrictive changes on pulmonary function testing. Diffuse interstitial and patchy peripheral alveolar infiltrates, which may frequently involve the upper lobes, characterize the radiologic findings. Accumulation of foamy macrophages in alveolar spaces, hyperplasia of type II pneumocytes, and widening of alveolar septae are noted histologically. Ultrastructural examination shows granular and lamellar membranous structures within distended lysosomes. With cessation of amiodarone therapy and treatment with corticosteroids, clinical symptoms and radiographic abnormalities resolve. The time interval for resolution of radiographic changes appears to be greater than 2 months. The precise role of corticosteroid therapy remains unknown in light of pathologic findings suggesting a metabolic rather than immunologic basis for the toxicity.