Laura W. Lamps

Elevated cyclooxygenase-2 levels in Min mouse adenomas

BACKGROUND & AIMS Mutations in the APC gene result in an increased propensity to develop intestinal neoplasia; however, a complete understanding of the mechanisms resulting in tumor formation has remained elusive. Min mice possess a mutation in the APC gene and display a neoplastic phenotype similar to that observed in familial adenomatous polyposis coli in humans. Cyclooxygenase (COX) inhibitors decrease tumor multiplicity in the Min mouse intestine. The present study was designed to determine if there was an increase in COX-2 in adenomas harvested from Min mouse intestine. METHODS COX-2 messenger RNA levels were determined by Northern blots and reverse-transcription polymerase chain reactions of B6Min x 129 mouse-derived tumors. Protein levels and localization were determined by Western blots and immunohistochemical staining. RESULTS The Northern blots revealed an approximately threefold increase in the level of COX-2 messenger RNA in Min mouse adenoma compared with normal mucosa. COX-2 protein levels in adenomatous tissues were also approximately threefold higher compared with normal mucosa from the same mouse. Immunohistochemical staining with a monospecific COX-2 antibody confirmed that increases in COX-2 immunoreactivity were restricted to dysplastic and neoplastic foci within intestinal mucosa. CONCLUSIONS These data show that COX-2 levels may be increased at an early stage in colorectal neoplasia during polyp formation and before invasion.

Thyroid Transcription Factor-1 Is Expressed in Extrapulmonary Small Cell Carcinomas but Not in Other Extrapulmonary Neuroendocrine Tumors

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non–small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non–small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TTF-1 expression. We examined TTF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma. No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TTF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.

Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn's disease

Previously, we detected pathogenic (invasive) Yersinia DNA in the appendices of two patients who later developed Crohns disease (CD). This subsequent investigation is the first to evaluate a series of specimens from CD patients for the presence of pathogenic Yersinia DNA. A total of 54 intestinal resection specimens from 52 patients with confirmed CD were evaluated. Lesional tissue was tested by polymerase chain reaction analysis for the presence of genes occurring only in pathogenic Yersinia. Primer pairs are specific for each species, with no known cross reactions with other bacteria. Forty normal bowel specimens, 30 cases of acute appendicitis, and 50 cases of various active colitides served as disease controls. Medical records were reviewed following polymerase chain reaction and histologic evaluation. A total of 17 of 54 resections (31%) contained Yersinia DNA by polymerase chain reaction. Mesenteric lymph nodes were also positive in eight of these cases. All controls were negative. Yersinia-positive patients had carried the diagnosis of CD for a median of 10 years before resection (range 1 month to 40 years). We report the first documentation of Yersinia DNA in a series of CD cases. Further studies are needed, including serial study, over time, of Yersinia-positive CD patients, as well as prospective studies of newly diagnosed CD patients for evidence of Yersinia infection. Like previous studies associating infectious organisms with CD, much work remains to elucidate whether the presence of Yersinia DNA is an epiphenomenon or actually a factor in the pathogenesis of CD.

The pathologic spectrum of gastrointestinal and hepatic histoplasmosis

We characterized the pathologic spectrum of lesions in gastrointestinal and hepatic histoplasmosis by studying cases of disseminated disease in immunocompromised and immunocompetent patients from endemic and nonendemic areas. We evaluated 56 specimens from 52 patients with H&E and silver stains. Of these patients, 43% presented with gastrointestinal rather than pulmonary symptoms. Thirty-one percent had gastrointestinal lesions, 10% had liver lesions, and 43% had both. Gross gastrointestinal features included ulcers (49% of patients), nodules (21%), hemorrhage (13%), obstructive masses (6%) and normal mucosa (23%). Microscopic gastrointestinal findings included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%), or minimal inflammatory reaction (15%) but only rare well-formed granulomas (8.5%). The most common hepatic finding was portal lymphohistiocytic inflammation; discrete hepatic granulomas were seen in less than 20% of involved livers. The pathologist must be aware of the broad range of gastrointestinal and hepatic lesions produced by histoplasmosis and, in particular, that well-formed granulomas are rare. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in nonendemic as well as endemic areas.

Long-term survival after resection for primary hepatic carcinoid tumor.

Background:Primary hepatic carcinoid tumors (PHCTs) are extremely rare, and fewer than 50 cases have been reported in the English-language literature. We report a patient with a PHCT and review the cases in the literature.Methods:Our patient presented with symptoms and underwent liver resection for PHCT and regional lymph node metastasis. He underwent two more liver resections over the following 7 years for recurrent PHCT. Cases reported in the English-language literature were reviewed and survival analysis was performed with the Kaplan-Meier method. The survival impacts of age, gender, tumor foci, extrahepatic metastasis, unilobar versus bilobar disease, and type of preoperative treatment were determined by means of log-rank test.Results:Our patient has been free of symptoms for 14 years of follow-up and free of disease for 8 years of follow-up. Forty-eight cases of PHCT were found in the literature, and 92% of these patients underwent resection. Actuarial 5- and 10-year survival for all patients was 78% and 59%, respectively, whereas for resected patients, 10-year survival was 68%. The administration of preoperative chemotherapy, radiation therapy, or chemoembolization did not impact survival, nor did age, gender, presence of extrahepatic metastasis, number of tumors, or distribution of the tumor within the liver.Conclusions:Resection is the treatment of choice for PHCT and has provided favorable outcomes. Resection for PHCT can be performed in most patients and offers long-term survival.

Protein gene product 9.5 (PGP 9.5) is not a specific marker of neural and nerve sheath tumors: an immunohistochemical study of 95 mesenchymal neoplasms.

In non-neoplastic tissues, the expression of protein gene product 9.5 (PGP 9.5), a member of the ubiquitin hydrolase family of proteins, is confined to neural and neuroendocrine cells. Although it has been claimed that PGP 9.5 is a specific marker of neural and/or nerve sheath differentiation in human tumors, careful review of the literature suggests that relatively few nonneural or nerve sheath tumors have been studied. Prompted by our recent observation of a PGP 9.5–positive malignant fibrous histiocytoma, we undertook a study of PGP 9.5 expression in a large group of well-characterized mesenchymal neoplasms. Sections from 95 mesenchymal tumors were retrieved from our archives and immunostained for PGP 9.5 using standard avidin-biotin complex technique and heat-induced epitope retrieval. Scoring was as follows: negative, 1+ (<10–25% of cells), 2+ (25–50% of cells), and 3+ (>50% of cells). Normal nerves and fibrous tissue were internal positive and negative controls, respectively. Positive immunostaining was seen in 80/95 (84%) of cases. Positive results by tumor subtype were as follows: (1) nerve sheath tumors: malignant peripheral nerve sheath tumor (7/10), neurofibromas (10/10), and perineuriomas (3/3); (2) (Myo) fibroblastic tumors: malignant fibrous histiocytoma (18/20), low-grade fibromyxoid sarcomas (8/9), fibromatoses (7/7), and desmoplastic fibroblastomas (2/2); (3) vascular tumors: angiosarcomas (4/4), hemangioendotheliomas (3/5), and hemangiomas (3/4); and (4) other non-nerve sheath tumors: pleomorphic liposarcoma (4/4), dermatofibrosarcoma protuberans (2/5), rhabdomyosarcomas (2/2), synovial sarcomas (8/8), melanomas (1/2). All positive cases were 2–3+ except 6 malignant peripheral nerve sheath tumor, 1 neurofibroma, 3 malignant fibrous histiocytoma, 2 low-grade fibromyxoid sarcoma, and 1 dermatofibrosarcoma protuberans. Positive staining was seen in normal smooth muscle and germinal centers in addition to nerves. We conclude that in this, the largest study to date of PGP 9.5 expression in mesenchymal neoplasms, we have found strong (2–3+) expression in the vast majority of nonneural or nerve sheath neoplasms studied. Although PGP 9.5 is a sensitive neural/nerve sheath marker, it is essentially totally nonspecific for diagnostic purposes. It is possible that our findings reflect cross-reactivity of the 13C4 clone with epitopes present on other ubiquitin hydrolases. Alternatively, PGP 9.5 expression may be aberrantly up-regulated in a variety of mesenchymal neoplasms.

Cat-scratch disease: historic, clinical, and pathologic perspectives.

Cat-scratch disease (CSD) initially was described in 1931, but the etiologic agent (Bartonella henselae) was not elucidated until decades later. This disease is the most common cause of chronic lymphadenopathy among children and adolescents, characteristically manifesting as subacute regional lymphadenitis with an associated inoculation site due to a cat scratch or bite, often accompanied by fever. The hallmark histologic lesion is granulomatous inflammation with a central stellate microabscess. Numerous atypical manifestations of CSD have been described, and these often lack the characteristic superficial lymphadenopathy and inoculation site papule. These atypical forms may be misdiagnosed initially as other infectious processes or neoplasms. We present a review of the history and epidemiologic features of CSD, describe common and unusual clinicopathologic manifestations, and discuss current diagnostic modalities.

Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America.

Francisella tularensis (FT), a zoonotic bacterium that causes tularemia, has received attention as a possible bioterrorism threat. We developed a PCR assay for use in fixed, processed tissues, which are safer to handle and allow archival testing. PCR analysis for a 211-bp fragment of the FT lipoprotein gene was performed on tissues from 16 cases of tularemia. In all, 14/15 cases with intact DNA (93%) were positive for FT by PCR. Frequent histologic findings in PCR-positive tissues included irregular microabscesses and granulomas in liver, spleen, kidney, and lymph nodes, and necrotizing pneumonia. Unusual cases featuring suppurative leptomeningitis and gastrointestinal ulcers were also seen. As this disease is endemic in North America, and has been identified as a potential bioterroristic threat, awareness of the clinicopathologic spectrum of disease and available detection methods is increasingly important. This PCR assay, the first designed for use in processed tissues, is an excellent method for diagnosis of tularemia.

Infectious Causes of Appendicitis

The pathologic spectrum of the inflamed appendix encompasses a wide range of infectious entities, some with specific histologic findings, and others with nonspecific findings that may require an extensive diagnostic evaluation. The appendix is exclusively involved in some of these disorders, and in others may be involved through extension from other areas of the gastrointestinal tract. This review discusses the pathologic features of bacterial, viral, fungal, and parasitic infections affecting the appendix, including adenovirus; cytomegalovirus; Yersinia, Actinomyces, Mycobacterium, or Histoplasma species; Enterobius vermicularis; schistosomiasis; and Strongyloides stercoralis. Pertinent ancillary diagnostic techniques and the clinical context and significance of the various infections are also discussed.

The coexistence of low-grade mucinous neoplasms of the appendix and appendiceal diverticula: a possible role in the pathogenesis of pseudomyxoma peritonei.

We examined 38 appendectomies with diagnoses of mucocele, diverticulum, or adenoma to study the coincidence of appendiceal diverticula and appendiceal low-grade mucinous neoplasms and to examine the possible role of diverticula in the pathogenesis of pseudomyxoma peritonei. Invasive adenocarcinomas and retention cysts were excluded (six cases). Cases were classified as adenomas or mucinous tumors of unknown malignant potential, with or without diverticula. Medical records were reviewed for multiple parameters, including presenting symptoms, presence of pseudomyxoma peritonei, and presence of associated malignancies. Binomial statistics were used to calculate the probability that the observed prevalence of low-grade mucinous neoplasms and diverticula together was significantly different from the expected prevalence of diverticula or low-grade mucinous neoplasms alone, using historical controls from the literature.Twenty-five percent of the total cases (8 of 32) contained both a low-grade mucinous neoplasm (7 cystadenomas and 1 mucinous tumor of unknown malignant potential) and a diverticulum. Thus, 8 of 19 low-grade mucinous neoplasms (42%) were associated with diverticula. Of the appendices with both low-grade mucinous neoplasms and diverticula, three contained dissecting acellular mucin within the appendiceal wall, four showed diverticular perforation, and one had pseudomyxoma peritonei associated with the ruptured diverticulum.A significant percentage (P <.001) of cases contained low-grade mucinous neoplasms and diverticula together. The case of coexistent low-grade mucinous neoplasm, diverticulum, and pseudo-myxoma peritonei suggests that diverticula could play a role in the pathogenesis of pseudomyxoma peritonei. This could occur either by involvement of preexisting diverticula by the neoplasm or by distention of the appendiceal lumen by mucin, leading to increased intraluminal pressure and subsequent diverticulum formation at a weak area in the wall. Either mechanism might allow low-grade mucinous neoplasms to penetrate the appendiceal wall more easily.