Correlation between patient weight and defects in DNA mismatch repair: is this the link between an increased risk of previous cancer in thinner women with endometrial cancer?

The objective is to determine the relationship between obesity and defects in DNA mismatch repair (MMR) in women with endometrial cancer and to establish whether our previous finding of a higher rate of previous malignancy in thinner women with endometrial cancer is related to these factors. Specimens from 109 patients with primary uterine cancer were used to create a tissue microarray, which was stained with antibodies against MMR genes MLH1, MSH2, MSH6, and PMS2. Genotyping of normal and tumor tissues for microsatellite instability (MSI) was performed. Patients were stratified by body mass index (BMI) and correlated with a history of previous malignancy and defects in MMR. The average BMI of the overall population was 33 kg/m(2). Defective MMR was seen in 22% of tumors. The mean BMI in patients with tumors with MSI was 30.5, compared with 33.8 in microsatellite stable (MSS) tumors (P= 0.06); MSS tumors were more commonly seen in patients with a BMI more than 40 (25% vs 5% in patients with tumors with MSI, P= 0.07). Prior to their diagnosis of endometrial cancer, 16/109 (15%) patients reported having a prior malignancy, 11 (69%) had breast cancer, and 1 had colorectal cancer. Patients with tumors with MSI had previous cancer in 17% of cases, compared with 14% of patients with MSS tumors (P= 0.75). Our previous finding of an increased rate of prior malignancy in thinner patients with endometrial cancer does not appear to be due to alterations in MMR, and hereditary nonpolyposis colorectal cancer-associated cancers are rarely the prior malignancy.

MSH6 missense mutations are often associated with no or low cancer susceptibility.

Mismatch repair (MMR) deficiency in tumours from patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is mainly caused by mutations in the MLH1, MSH2, and MSH6 genes. A major challenge in the clinical management of patients with suspected HNPCC is the frequent occurrence of missense mutations in MSH6. These can be considered neither deleterious nor clinically innocent a priori. To assess their significance we studied five novel MSH6 missense mutations in six patients derived from a series of consecutive endometrial and colorectal cancer patients selected for study after their tumours were determined to be microsatellite unstable. We tested each mutated protein for heterodimerisation with MSH2 and for in vitro MMR capability. Four mutations (R128L, P623L, K728T, G881K+S) showed no impairment of these functions while the fifth (E1193K) displayed marked impairment of both functions. These results, taken together with our previous similar findings concerning six other missense mutations in MSH6, allow us to conclude that many or most missense changes in MSH6 likely are clinically innocent, whereas some missense changes such as E1193K, which lead to impaired MMR, are likely to be clinically significant, but have low penetrance.

Large colorectal adenomas. An approach to pathologic evaluation.

Adenomatous polyps are common neoplastic lesions of the large intestine. The risk of carcinoma increases with polyp size. Small polyps are typically totally embedded for histologic examination, but no standard method for sampling large, grossly benign polyps has been established. We reviewed grossly noninvasive adenomas 2.5 cm or larger to determine the percentage that contained high-grade dysplasia (HGD) and invasive cancer (IC). Based on these findings, we suggest an approach to evaluating large adenomas. Forty-three colon resections met the inclusion criteria (no previous diagnosis of cancer, no gross evidence of invasion, and totally embedded polyp). Twelve (28%) had HGD with 3% (1 of 33 slides) to 100% (4 of 4 slides) containing HGD. Five (12%) had IC with 4% (3 of 72 slides) to 42% (5 of 12 slides) containing IC. All cases with IC had HGD in other slides. Probability studies showed that in the majority of cases, polyps would need to be entirely embedded to have an estimated probability of 95% or more of detecting either HGD or IC. Therefore, grossly noninvasive adenomas should be routinely entirely embedded.

Major pancreatic resections for chronic pancreatitis.

OBJECTIVE: Indications for major pancreatic resections have been expanded to include complicated chronic pancreatitis (CP). We assessed clinical findings and outcomes and evaluated histology in patients who had major pancreatic resections for CP. We also determined if histologic findings were associated with persistent postoperative pain. DESIGN: We reviewed charts and slides from 44 patients who underwent major pancreatic resections for CP between 1989 and 1999. RESULTS: The etiology for disease included alcohol (n = 15), hereditary (n = 5), idiopathic (n = 6), pancreas divisum (n = 3), stricture (n = 2), trauma (n = 2), systemic lupus erythematosus (n = 1), and unknown (n = 10). Patients included 20 men and 24 women; ages ranged from 22 to 76 years. Perioperative mortality and morbidity were 0% and 4.5%, respectively. Persistent pain was present in 25 (57%) of the 44 patients, and pain was encountered more frequently in patients with alcoholic pancreatitis (67%) versus other etiologies (52%), and in those who underwent Whipple/Beger or total resections (68%) versus distal or subtotal pancreatectomy (42%). Metaplastic changes were present in 14 cases, and ductal atypia was seen in 9 cases. No malignancies were found. Acinar necrosis and acute inflammation were seen more often in patients with persistent pain than in those who were pain free (P =.081). CONCLUSION: Major pancreatic resection for CP can be performed with low morbidity and mortality. This procedure relieves pain in nearly half the patients. There is a wide spectrum of histopathologic changes seen in CP, including ductal atypia and metaplastic changes. Acute exacerbations of CP identified histologically at the time of surgery and alcohol as etiology for CP may be associated more frequently with intractable pain.

The value of second opinion in gastrointestinal and liver pathology.

OBJECTIVE: The value of routine second opinion review of liver and gastrointestinal pathologic material was evaluated to determine whether there were discrepancies in diagnoses and if these discrepancies had an impact on treatment or prognosis. MATERIALS AND METHODS: All gastrointestinal and hepatobiliary histopathology referral diagnoses made during a 1-year period for patients being treated at Ohio State University Medical Center were compared with the outside pathologic diagnosis. All major discrepant diagnoses were reviewed by at least 2 pathologists. Diagnoses were classified as no diagnostic disagreement, diagnostic disagreement, or no diagnostic disagreement but pertinent information missing or terminology unclear. Discrepant cases were also classified according to the clinical significance of the discrepancy. RESULTS: Pathology reports from 194 hepatobiliary and gastrointestinal cases were reviewed. Of the hepatobiliary cases, 57 (64.8%) of 88 cases showed no discrepancies. Discrepancies were noted in 31 cases (35.2%), including missing information or unclear terminology in the diagnosis in 23 cases (26.1%) and diagnostic disagreement in 8 cases (9.1%). Of the cases with discrepancies, 6 (6.8%) were of major significance. Of the gastrointestinal cases, 87 (82.1%) of 106 cases showed no discrepancies. Discrepancies were noted in 19 cases (17.9%), including missing or unclear information in 3 cases (2.8%) and diagnostic disagreements in 16 cases (15.1%). The cases with discrepancies included 8 cases (7.5%) for which the change was of major clinical significance. CONCLUSIONS: Routine pathologic review of gastrointestinal and hepatobiliary cases revealed notable discrepancies in diagnoses. In 14 cases (7.2%), the change in diagnosis or additional information had a significant effect on the proper treatment or a significant prognostic implication. Routine review of all pertinent pathologic material should be performed on all patients being transferred to a second institution for treatment or second opinion.

Primary hepatic anaplastic large-cell lymphoma of T-cell phenotype in acquired immunodeficiency syndrome: a report of an autopsy case and review of the literature.

Anaplastic large-cell lymphomas (ALCL) were first described by Stein et al. in 1985 as large-cell neoplasms with a pleomorphic appearance, subtotal effacement of the lymph node structure, and expression of the lymphoid activation antigen CD-30 (Ki-l). Since their first description, these tumors have been documented in a variety of extranodal sites. We report a primary hepatic anaplastic large-cell lymphoma in a patient with advanced AIDS, who presented with hepatic failure and multiple nodules in the liver. A complete autopsy showed discrete tumor nodules throughout the entire liver without gross or microscopic involvement of lymph nodes or any other organs by the neoplastic process. The tumor cells showed typical histological and immunohistochemical features of ALCL and were strongly immunoreactive with the T-cell markers CD-3 and UCHL-1. Only one previous case of primary hepatic ALCL has been reported in the literature, and this tumor occurred in an immunocompetent patient and was not immunoreactive for B- or T-cell markers. To our knowledge, this study represents the first reported case of primary hepatic anaplastic large-cell lymphoma of T-cell phenotype. Additionally, this is the first case of primary hepatic ALCL reported in an AIDS patient.

Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat.

This study examined the effects of lyophilized black raspberries (BRB) on azoxymethane (AOM)-induced aberrant crypt foci (ACF), colon tumors, and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in male Fischer 344 rats. AOM was injected (15 mg/kg body wt i.p.) once per week for 2 wk. At 24 h after the final injection, AOM-treated rats began consuming diets containing 0%, 2.5%, 5%, or 10% (wt/wt) BRB. Vehicle controls received 5% BRB or diet only. Rats were sacrificed after 9 and 33 wk of BRB feeding for ACF enumeration and tumor analysis. ACF multiplicity decreased 36%, 24%, and 21% (P < 0.01 for all groups) in the 2.5%, 5%, and 10% BRB groups, respectively, relative to the AOM-only group. Total tumor multiplicity declined 42%, 45%, and 71% (P < 0.05 for all groups). Although not significant, a decrease in tumor burden (28%, 42%, and 75%) was observed in all BRB groups. Adenocarcinoma multiplicity decreased 28%, 35%, and 80% (P < 0.01) in the same treatment groups. Urinary 8-OHdG levels were reduced by 73%, 81%, and 83% (P < 0.01 for all groups). These results indicate that BRB inhibit several measures of AOM-induced colon carcinogenesis and modulate an important marker of oxidative stress in the Fischer 344 rat.

Primary localized extranodal hodgkin disease of the transverse colon.

Extranodal Hodgkin disease presenting as a primary localized neoplasm is uncommon, with rare case reports describing primary sites other than lymph nodes. The gastrointestinal tract is the most frequent site of involvement by extranodal Hodgkin disease, typically involving the stomach or small bowel. To date, we have been able to find only one fully documented case of Hodgkin disease of the sigmoid colon confirmed by immunohistochemical studies. We report a case of extranodal Hodgkin disease involving the transverse colon, presenting as inflammatory bowel disease and documented by light microscopic, immunohistochemical, cytogenetic, and molecular studies.

Diffuse leiomyomatosis of the uterus: a case report with clonality analysis.

Diffuse uterine leiomyomatosis is a rare condition distinguished from the common uterine leiomyomata by involvement of the entire myometrium by innumerable, ill-defined, often small and confluent, histologically benign smooth-muscle nodules. Fourteen cases have been previously described in the literature. We report a case of diffuse leiomyomatosis in a 39-year-old woman. Several microscopic foci of the process were microdissected for clonality analysis. All samples showed a non-random X-chromosome inactivation pattern, and thus were consistent with a monoclonal neoplastic population of cells. However, in different foci of tumor, different X chromosomes were inactivated, supporting the independent origin of neoplastic clones and rejecting the possibility of a single clonal origin of all tumor cells. The results of the molecular analysis suggest that diffuse uterine leiomyomatosis may be an exuberant example of diffuse and uniform involvement of the entire myometrium by multiple leiomyomata. HUM PATHOL 31:1429-1432.

Smooth muscle tumor of the pleura. A case report and review of the literature.

Smooth muscle tumors of the serosal membranes are extremely rare and have received little attention in the literature. To the best of our knowledge, only 1 published series of 5 pleural smooth muscle neoplasms has been published to date. We describe a primary pleural neoplasm with smooth muscle differentiation documented by light microscopy, immunohistochemistry, and electron microscopy. This tumor originated in the parietal pleura in a 32-year-old white man and was diagnosed incidentally by chest radiography; the diagnosis was confirmed by magnetic resonance imaging and biopsy. Four years later, the tumor was noted to have increased in size and disseminated into the chest wall as a separate circumscribed mass located in the pectoral muscle. Both masses were resected and diagnosed as smooth muscle tumors. We conclude that smooth muscle tumor of the pleura is a well-defined entity with a low, but definite malignant potential; therefore, we recommend complete resection and long-term follow-up for all patients.

Primary anaplastic large cell lymphoma of the adrenal gland.

Primary adrenal lymphomas are rare. Most reported cases are of B-cell phenotype and follow an aggressive clinical course. We report a case of primary anaplastic large cell, CD30+ adrenal lymphoma developing in a 62-year-old woman. The patient presented with fatigue and vague right upper quadrant pressure. Computed tomography revealed bilateral adrenal masses. A right adrenalectomy was performed. Histologic evaluation showed islands of large atypical cells surrounded by eosinophilic acellular material. The tumor cells stained positive for CD45, CD45RO, CD43, and CD30. Epstein-Barr virus genome was identified in tumor cells using in situ hybridization. The patient was treated with chemotherapy and a 23-month follow-up examination showed no change in the size of the opposite adrenal gland and no other evidence of lymphoma.

Immunohistochemical analysis of hepatocellular and adenocarcinoma in the liver: MOC31 compares favorably with other putative markers.

Distinguishing hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) and cholangiocarcinoma (CC) can, at times, be difficult and sometimes requires immunohistochemical analysis. Recently, MOC31, an antibody directed against a cell surface glycoprotein, has been shown to be useful in separating HCC from both MA and CC; however, no study has compared MOC31 and other frequently used immunostains. We compare MOC31 with other commonly used immunostains for HCC, MA, and CC. Formalin-fixed, paraffin-embedded tissue sections from 57 previously characterized hepatic neoplasms (13 HCC, 14 CC, 3 combined HCC-CC, and 27 MA) were immunostained with antibodies directed against MOC31, cytokeratin (CK) 7, CK20, alpha-fetoprotein (AFP), polyclonal carcinoembryonic antigen, Ber-EP4, and Factor XIII-A. Two pathologists reviewed slides, and positivity was defined as more than 1% of cells staining with the appropriate pattern. Positive MOC31 immunostaining was seen in 0 of 13 HCC, 13 of 14 CC, 3 of 3 HCC-CC, and 27 of 27 MA; the staining was strong and diffuse. CK20 reactivity was observed in 0 of 13 HCC, 2 of 14 CC, 0 of 3 HCC-CC, and 12 of 27 MA; CK7 immunostained 4 of 13 HCC, 13 of 14 CC, 3 of 3 HCC-CC, and 15 of 27 MA; AFP was detected in 4 of 13 HCC and 2 of 3 HCC-CC, whereas all CC and MA were negative; polyclonal carcinoembryonic antigen showed immunoreactivity in 12 of 13 HCC and 3 of 3 HCC-CC in a canalicular pattern, whereas diffuse positivity was identified in 13 of 14 CC and 26 of 27 MA; Ber-EP4 immunostained 1 of 13 HCC, 14 of 14 CC, 2 of 3 HCC-CC, and 26 of 27 MA; and Factor XIII-A was negative in all HCC, CC, and MA. MOC31 expression distinguished HCC from adenocarcinoma in 56 of 57 cases. AFP was specific for HCC but was not sensitive. CK7 and CK20 have limited utility in distinguishing HCC from CC or MA, and Factor XIII-A is not useful. Ber-EP4 staining was similar to MOC31, but one HCC did stain with Ber-EP4. Polyclonal CEA yields similar numerical results as MOC31, but the focal nature of the staining and occasional difficulty in evaluating the pattern can make interpretation problematic. We conclude that MOC31 should be a component of the immunohistochemical panel to distinguish HCC from CC and MA.

Laparoscopic postmortem examination: a minimally invasive approach to the autopsy.

Laparoscopic and thoracoscopic autopsies have previously only been performed on an experimental basis to determine their potential usefulness as a substitute for a conventional postmortem examination. We present the case of a patient with an unusual variant of malignant melanoma (diffuse melanosis) in whom the immediate cause of death clinically was thought to be fulminant hepatic failure, the etiology of which was unknown. The family was unwilling to consent to a conventional autopsy, but would permit a postmortem examination limited to a 2-cm abdominal incision and removal of a sample of liver. In view of the unanswered clinical questions regarding the cause of the acute hepatic failure and its possible relationship to the diagnosis of diffuse melanosis, we decided that more extensive examination of the abdominal cavity, specifically the liver, was required and that the only way that this could be accomplished was by laparoscopic techniques. Laparoscopic examination of the abdominal cavity revealed multiple melanotic nodules on the surface of the liver and studding the omentum. Multiple liver samples were easily obtained; these revealed massive diffuse necrosis of the liver parenchyma with scattered nodular deposits of dark pigment consistent with melanin. We report the first known case in which a laparoscopic autopsy was used to obtain valuable information that answered clinically relevant questions. Laparoscopic autopsy can offer the a family that is unwilling to consent to a conventional postmortem examination an alternative that can potentially provide answers to clinical questions that otherwise would have been unresolved.

Recurrent type I membranoproliferative glomerulonephritis in a renal allograft: successful treatment with plasmapheresis.

Recurrent disease is increasingly recognized as a cause of renal allograft dysfunction and failure. We describe a patient with type I membranoproliferative glomerulonephritis not associated with hepatitis C. The glomerular disease recurred in the renal allograft within 1 month of transplantation, leading to acute allograft dysfunction and nephrotic syndrome. Aggressive treatment with prednisone and plasmapheresis resulted in improvement in kidney function, improvement of the light microscopic picture, and removal of immune complexes from the glomerular subendothelial space.

Renal cell carcinoma with massive osseous metaplasia and bone marrow elements.

Focal calcifications are frequently seen in renal masses and may be present in renal cell carcinomas. Metaplastic bone formation, on the other hand, is a rare event. We report a unique case of a large calcified renal cell carcinoma with massive osseous metaplasia and bone marrow elements. The clinical and pathologic differential diagnosis for this tumor is discussed along with a review of the literature on this unusual phenomenon.

Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival.

De novo focal segmental glomerulosclerosis (FSGS) in renal allografts most often is diagnosed in association with chronic allograft nephropathy (CN). In this study, we assessed the clinical and pathological variables that correlate with the presence of de novo FSGS and the implications of FSGS for the survival of grafts with CN. The study population included 293 renal allograft recipients (52 living related donor, 241 cadaveric donor) diagnosed with CN by biopsy more than 6 months after transplantation. Patients with recurrent FSGS or FSGS associated with other glomerulopathies were excluded. FSGS was present in 87 patients with CN (30%). FSGS was diagnosed more commonly in the following groups of patients: young (P = 0.04), black (P = 0.02), and those with elevated serum cholesterol levels (P = 0.002) and/or high-grade proteinuria (P < 0. 0001, all univariate analysis). FSGS was diagnosed later after transplantation than CN without FSGS (P < 0.0001), and FSGS correlated with the presence of arteriolar hyalinosis in the biopsy specimen (P = 0.04). Compared with CN without FSGS, FSGS was associated with significantly worse death-censored graft survival (P = 0.008, univariate Cox). In addition, when we analyzed all patients with CN, graft survival correlated by multivariate analysis with the following parameters: serum creatinine level (P < 0.0001) and proteinuria (P = 0.004) at the time of diagnosis, presence of FSGS (P = 0.03), and degree of interstitial fibrosis and tubular atrophy (CN score; P < 0.0001, Cox). Of interest, the use of lipid-reducing agents was also associated with improved graft survival in patients with CN (P = 0.0002, univariate Cox), although total lipid levels were not significantly less in patients receiving these drugs. In conclusion, de novo FSGS presents late after transplantation and in association with arteriolar hyalinosis, suggesting these lesions may be related to chronic cyclosporine toxicity. In CN, the presence of FSGS and the severity of interstitial fibrosis are negative independent predictors of graft survival. The possible relationship between lipid-reducing agents and graft survival clearly needs to be examined carefully in future studies.

Wheat bran decreases aberrant crypt foci, preserves normal proliferation, and increases intraluminal butyrate levels in experimental colon cancer.

BACKGROUND: Dietary wheat bran protects against colon cancer, but the mechanism(s) of this effect is not known. Butyrate, produced by colonic bacterial fermentation of dietary polysaccharides, such as wheat bran, induces apoptosis and decreases proliferation in colon cancer cell lines. Whether similar effects occur in vivo is not well defined. We hypothesized that wheat bran's antineoplastic effects in vivo may be mediated in part by butyrate's modulation of apoptosis and proliferation. METHODS: Male F344 rats were fed wheat bran-supplemented or an isocaloric, isonitrogenous fiber-free diet. Rats were treated with one dose of the carcinogen azoxymethane or vehicle with sacrifice after 5 days (tumor initiation); or two doses (days O and 7) with sacrifice after 56 days (tumor promotion). Study variables included fecal butyrate levels and the intermediate biomarkers of colon carcinogenesis, aberrant crypt foci (ACF), and changes in crypt cell proliferation and apoptosis. RESULTS: During tumor initiation, wheat bran produced greater apoptosis (p = .01), a trend toward less proliferation, and preserved the normal zone of proliferation (p = .01). At tumor promotion, wheat bran decreased the number of ACF (proximal colon, p = .005; distal colon, p = .047) and maintained the normal proliferative zone. The fiber-free diet shifted the zone of proliferation into the premalignant pattern in both studies. Wheat bran produced significantly higher fecal butyrate (p = .01; .004, .00001) levels than the fiber-free diet throughout the tumor promotion study. CONCLUSIONS: Wheat bran increased apoptosis and controlled proliferation during tumor initiation and resulted in decreased ACF. Wheat bran's antineoplastic effects occurred early after carcinogen exposure, and were associated with increased fecal butyrate levels.

Gastric carcinoma with osteoclast-like giant cells.

Extraskeletal neoplasms with osteoclast-like giant cells are uncommon. These tumors are most frequently reported in the breast and pancreas, and are relatively rare in other sites. We report a case of primary gastric adenocarcinoma with an infiltrate of osteoclast-like giant cells. The patient is a 64-yr-old black woman who presented with epigastric pain and was found to have a mass in the gastric antrum. Histological examination showed a poorly differentiated adenocarcinoma with an infiltrate of osteoclast-like giant cells. The giant cells were present both in the primary gastric adenocarcinoma and in the lymph node metastases. Immunohistochemical stains demonstrated that the giant cells were of monocytic/histiocytic origin and probably represent a distinctive host response to the tumor. The patient is alive and well 12 months after resection. This is the second published report of gastric carcinoma with osteoclast-like giant cells. Based on this limited experience, gastric carcinoma with osteoclast-like giant cells may represent a distinct clinicopathological entity with a more favorable prognosis.

Malignant mixed Müllerian tumor with rhabdoid features: a report of two cases and a review of the literature.

Rhabdoid tumors were originally described as a type of pediatric renal neoplasm that contains cells resembling rhabdomyoblasts but lacking muscle differentiation. Extrarenal rhabdoid tumors have since been reported in multiple anatomic sites in the pediatric and adult population. These tumors are characterized by an aggressive clinical course, resistance to treatment, and a rapidly fatal outcome. Eight cases of uterine neoplasms with rhabdoid differentiation have been previously reported. In the three cases where clinical follow-up was available, the patients died of disease within 3 to 17 months after the diagnosis was established. We report two cases of uterine malignant mixed Müllerian tumor (carcinosarcoma) with rhabdoid differentiation. The findings and clinical outcome confirm the aggressive nature of uterine tumors with rhabdoid differentiation. One of the patients died of disease 3 months after initial operative treatment while the other patient's tumor recurred in 1 month and she died within 10 weeks. The poor prognosis of these neoplasms makes their histopathologic recognition important.