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This study evaluated the expression patterns of claudins 1, 3, 4, 7, and 8 in human renal cell carcinomas and oncocytomas and correlated expression with patient prognosis. Tissue microarrays were created from paraffin-embedded tissue samples from 141 patients with renal cell carcinomas or oncocytoma (90 clear cell, 22 papillary, 17 chromophobe renal cell carcinomas, and 12 oncocytomas). The staining pattern for claudins 3, 4, 7, and 8 was membranous and/or cytoplasmic, whereas claudin 1 was predominantly membranous in both nonneoplastic renal tissue and tumors. Negative to weak claudin 3 staining was predominantly detected in Fuhrman's grade 1 and 2 clear cell renal cell carcinomas (78%; P=0.016), suggesting that upregulation of claudin 3 potentially occurs concomitantly with increasing grade of clear cell renal cell carcinomas. In addition, Kaplan–Meier univariate analysis showed a significant inverse correlation between moderate to strong claudin 3 and 4 expression with overall survival in clear cell renal cell carcinomas (P=0.038 and P=0.031). Moderate to strong claudin 7 expression was significantly more common in chromophobe renal cell carcinomas (94%) than in oncocytomas (55%; P=0.041). Claudin 8 staining was moderate to strong in 92% of oncocytomas, which differentiated them from papillary and clear cell renal cell carcinomas (14 and 12%; both P<0.0001). Only negative to weak claudin 8 staining was detected in all chromophobe renal cell carcinomas, whereas there were no claudin 8 negative oncocytomas and 8% exhibited a weak staining pattern (P<0.0001). Due to their distinctive expression patterns, claudins 7 and 8 can be used as useful immunohistochemical markers for the separation of chromophobe renal cell carcinomas from oncocytomas, whereas claudins 3 and 4 may serve as indicators of prognosis in clear cell renal cell carcinomas.

Identification of clonal lymphocytic populations by polymerase chain reaction may be difficult in cases with scant cellular infiltrates or those with a heterogeneous population of cells. Here, we assessed the diagnostic utility of laser capture microdissection (LCM) and high-resolution microcapillary electrophoresis in the analysis of clonality of small biopsy specimens. Clonality was determined in 24 cases: five reactive tonsils, five reactive lymph nodes, six inflammatory skin lesions, and eight T-cell lymphomas. CD3-positive T lymphocytes were captured by LCM from paraffinized immunohistochemically stained sections. Genomic DNA was analyzed for T-cell receptor-γ gene rearrangement by polymerase chain reaction followed by high-resolution microcapillary electrophoresis with the DNA 500 LabChip and the Agilent Bioanalyzer. In the reactive specimens, T-cell receptor-γ polymerase chain reaction revealed monoclonal bands when 10 to 1000 cells were captured. This pattern changed to polyclonal when higher numbers of cells were microdissected (2000 to 10,000 cells). In contrast, lymphoma cells were consistently monoclonal whether low or high numbers were microdissected. Microcapillary electrophoresis coupled with LCM facilitated clonality analysis in equivocal cases. In two of eight lymphoma cases, LCM revealed diagnostic monoclonal bands, whereas routine T-cell receptor-γ assessment of whole tissue sections with 10% polyacrylamide gel electrophoresis demonstrated only minor clonal bands. We conclude that clonality determined by LCM is cell number-dependent. Biopsy specimens containing low numbers of reactive polyclonal T cells may produce pseudomonoclonal bands and therefore should be interpreted with great caution.

Neuroendocrine (NE) carcinomas may originate in a wide variety of tissues and organs, including those that do not normally contain NE cells. These tumors may occur in pure forms or in association with conventional adenocarcinomas or squamous cell carcinomas, and they may also be associated with the paraneoplastic production of adrenocorticotropin, antidiuretic hormone, or other hormones. The 6 cases presented in this paper highlight the morphologic and functional characteristics of well- and poorly differentiated NE carcinomas arising in the kidney, thymus, prostate, esophagus, cervix, and skin. Recognition of NE carcinomas in these sites is critical both for therapeutic and for prognostic purposes.

Medullary thyroid carcinomas (MTCs) are currently defined as malignant tumors with evidence of C-cell differentiation. They comprise 5%-10% of all thyroid malignancies and occur sporadically (75%) or as a manifestation of the type 2 multiple endocrine neoplasia syndromes (25%). Results of calcitonin screening in patients with nodules thyroid disease have revealed a mean prevalence of tumors of 0.61% (range, 0.24% to 2.85%), most of which represent microscopic or incidental MTCs measuring less than 1 cm. While heritable and sporadic tumors contain amyloid and have a lobular to solid growth pattern and polyhedral- to spindle-shaped cells, numerous variants of these tumors also occur. C-cell hyperplasia (CCH) has been regarded as the precursor of heritable MTCs, although recent studies suggest that CCH is a clonal process and should be considered a form of intraepithelial C-cell neoplasia. Activating germline mutations of RET, primarily affecting exons 10 and 11, with less frequent involvement of exons 13, 14, 15, and 16, represent the molecular basis for the development of heritable MTCs. Somatic RET mutations, primarily affecting codon 918, occur in a substantial proportion of sporadic MTCs. Five-year and 10-year survivals for sporadic MTCs are 65% and 50%, respectively, with major risk factors for unfavorable outcome including tumor stage, male sex, and age greater than 60 years. With the development of molecular testing for RET mutations, the prognosis for patients with heritable MTCs is generally excellent.

Cirrhosis occurs in 20-50% of patients with hepatitis C and is thought to be irreversible. We describe two patients with cirrhosis secondary to hepatitis C in whom the extensive fibrosis and cirrhosis appeared to regress in response to treatment with interferon-α (IFN-α). Both patients were in the early stages of cirrhosis, class A in the Child-Pugh classification, total score 5 for each patient. Both responded fully to IFN-α and had normalization of all liver function tests and disappearance of hepatitis C viral RNA. Liver biopsies, performed before and after treatment, were coded unpaired by patient, combined with 21 liver biopsies from eight other patients with chronic hepatitis, and read independently by two pathologists using the Knodell scoring system. Knodell scores decreased from 14 to 3.5 and from 13.5 to 4 in these two patients. Cirrhosis and extensive fibrosis, present at baseline, were not present on follow-up liver biopsies, which were of sufficient size to reduce the likelihood of sampling error. We conclude that hepatic fibrosis and clinically early cirrhosis may be reversible in some patients with hepatitis C who respond to treatment with IFN-α.

This case report describes a patient with pancreatic cholera caused by a vasoactive intestinal polypeptide-producing pancreatic tumor. The case presents several unusual characteristics of this disease. The primary tumor was a mucinous adenocarcinoma of the pancreas. The serum vasoactive intestinal polypeptide level of 2400 pmol/L is the highest reported. At this vasoactive intestinal polypeptide level, the somatostatin analogue SMS 201-995 at doses up to 2 mg/24 h did not control the 21 L/24 h stool output. Fecal incontinence due to a manometrically documented hypotonic internal anal sphincter occurred. Using surgically created stomas, the segmental gastrointestinal fluid and sodium losses were shown to be greatest from the jejunum, whereas potassium losses from the colon and small intestine were equal. The cellular mechanism for the small intestinal potassium secretion is not known.

We have examined an unselected series of 72 lymphomas of diverse histologies with a panel of mouse monoclonal antibodies specific for human B-lymphoma-derived Ig idiotypes (anti-ids) to determine the nature and extent of id/anti-id crossreactivity. The anti-id antibodies were prepared from Ig isolated from seven follicular center cell lymphomas by heterohybridoma technique. Thirty-six of 75 individual anti-ids obtained in this manner were further selected based on their reactivity with highly restricted or private idiotypic determinants. Twelve of the 72 (17%) lymphoma biopsies reacted with one or more of the 36 anti-ids that detect private determinants. A pool consisting of five individual antibodies would have detected 11 of the 12 crossreacting tumors. Staining of tumor cell populations was homogeneous in the positive cases, suggesting uniform idiotype expression. If there was a segregated staining pattern, it was generally related to the presence of CD3+ T cells in the section. These follicular center cell-derived anti-ids crossre-acted with follicular center cell tumors of all histologic grades with frequencies ranging from 13% to 50%. The structural basis for the crossreactivity of our lymphoma-derived private anti-ids is as yet not known. However, the reactivity of certain anti-ids with both kappa- and lambda-expressing tumors suggests a biased use of V gene segments in these crossreactive clones that is probably related to the VH gene. These data suggest the possibility that lymphoma may develop in a highly restricted pool of normal differentiated B cells or in B-cell subsets that express a limited repertoire of unmutated VH gene segments.© 1992 by The American Society of Hematology.0006–4971.92/8004-0030$3.00/0

A patient with watery diarrhea, hypokalemia, hypochlorhydria, and a non-beta islet cell carcinoma of the pancreas (Verner-Morrison syndrome) was found to have an elevated vasoactive intestinal peptide (VIP) concentration in the plasma as well as in the tumor. Treatment with streptozocin resulted in a dramatic subjective and objective tumor response in this patient. Plasma VIP concentration fell into the normal range after four courses of treatment, diarrhea ceased after the third course of therapy, and measurable tumor mass markedly decreased during that same period of time. The patient remains in clinical remission with no evidence of tumor regrowth 18 months after the beginning of treatment. In this patient, plasma VIP measurements were an excellent marker of tumor activity and correlated well with objective disease measurements and clinical response.(Arch Intern Med 136:1429-1435, 1976)