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ABSTRACT: The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients.
The American Journal of dermatopathology 06/2012; · 1.30 Impact Factor
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ABSTRACT: BACKGROUND: Margin status is a predictor of outcome for patients with liver malignancies, although what constitutes a negative margin is controversial. Traditionally, the completeness of resection is estimated by surgical histopathology of the resected specimen margin, despite the in situ margin being potentially more important. The true margin is often altered by parenchymal transection techniques. The authors propose that cytologic assessment of the in situ margin is more specific for determining the true margin. METHODS: A total of 84 patients with primary or metastatic liver tumors who were undergoing surgical resection were enrolled in this prospective Institutional Review Board-approved study. Specimen and in situ (patient) margins were assessed using a "scrape preparation" cytologic technique and compared with traditional surgical histopathology. Patients were followed for assessment of local disease recurrence. RESULTS: Follow-up data were complete for 64 patients for a median of 37 months (range, 12 months-56 months). Twenty patients were excluded because of perioperative death (6 patients; 7%) or a follow-up of < 12 months. Seven patients (12.2%) had positive histopathologic specimen margins, but only 1 was found to be positive by cytology (1.8%). No in situ cytologically positive margins were identified along the cut edge of the liver remnant. The rate of intra- or extrahepatic recurrences was 56.7%, whereas the local recurrence rate was 1.8%. One patient with local recurrence demonstrated simultaneous intra- and extrahepatic disease recurrences and had negative margins by all methods of evaluation. CONCLUSIONS: To the authors' knowledge, the current study is the first to demonstrate that in situ margins can be assessed using cytopathology. This method is quick and can be universally applied. Given the difficulty of accurately assessing margins after hepatectomy, cytopathologic evaluation may be more reflective of the true margin. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.
Cancer Cytopathology 05/2012; · 3.33 Impact Factor
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ABSTRACT: DOG1, a transmembrane calcium-regulated chloride channel protein, is a sensitive and specific marker for gastrointestinal stromal tumors compared with other spindle cell and epithelioid neoplasms. Overexpression has also been described in a variety of both benign and malignant epithelial neoplasms. Recently, DOG1 immunoreactivity has been reported in pancreatic solid pseudopapillary tumors (SPT), suggesting a role as a marker for SPT. Utilizing immunohistochemistry, we evaluated DOG1 expression in pancreatic neoplasms to determine the prevalence of staining and establish diagnostic utility. Multiple tissue microarrays (TMA) were created from cores of formalin-fixed paraffin-embedded blocks containing pancreatic adenocarcinomas (n=112), neuroendocrine tumors (n=99), serous cystadenomas (n=28), and SPT (n=14) as well as normal pancreas (n=12). Immunoreactivity for DOG1 (clone K9) was assessed for intensity (1 to 3+), percentage of tumor positivity and location. Of the 99 cases of neuroendocrine tumors, only 2 (2%) were focally positive. Patchy staining was identified in 8 cases (7%) of adenocarcinoma of 1 to 2+ intensity, involving 15% to 80% of the tumor cells and primarily seen in a membranous and luminal distribution. In contrast to a previous report, no DOG1 positivity was observed in SPT, evaluated by both TMA and full sections. The TMAs of serous cystadenomas and normal pancreas were negative for DOG1. Rarely, pancreatic islets displayed granular, cytoplasmic staining. DOG1 antibody clone K9 is not a useful marker for SPT or other primary pancreatic neoplasms. Additional studies may be helpful to evaluate differences between clones of DOG1.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 04/2012; 20(4):397-401. · 1.63 Impact Factor
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ABSTRACT: Osteopontin (OPN) is a secreted protein of the extracellular matrix. It has been used as a marker for tumor aggressiveness and correlated with clinical outcomes in several solid tumors, such as liver, lung, and breast. We determined the OPN expression and its influence on survival in patients with resected pancreatic adenocarcinoma.
Tissue microarrays were constructed from 245 resected pancreatic adenocarcinomas. Immunohistochemical staining for OPN was undertaken and compared to normal pancreas (n = 12). OPN expression was then correlated with patient demographics, tumor size, grade, node, and margin status. Survival curves were created by the Kaplan-Meier method and compared by log rank analysis.
In total, 181 (74 %) of pancreatic adenocarcinoma tissues expressed OPN compared to 7 (58 %) of normal controls (p = 0.004). Expression was observed predominantly in the cytoplasm of the tumor cells. The median and 2 year overall survival was longer when OPN was expressed (17.1 vs. 11.6 months, and 38 vs. 24 %, respectively, p = 0.04). Multivariate analysis showed OPN expression and T stage to be independent predictors of overall survival, while other histopathologic factors such as tumor grade, tumor size, and nodal status were not.
These results suggest that the presence of OPN expression in pancreatic adenocarcinoma may have a protective effect independent of tumor stage. This emphasizes the importance of the interaction between pancreatic cancer cells and their stromal elements.
Annals of Surgical Oncology 03/2012; 19(8):2673-8. · 4.17 Impact Factor
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ABSTRACT: Hematologic malignancies often involve the pancreas, causing potential diagnostic pitfalls and, rarely, potentially avoidable surgical resection. We review the spectrum of hematologic malignancies involving the pancreas and describe features useful in preoperative distinction from adenocarcinoma. Archived clinical, pathologic, and radiologic data (1965 to present) for hematologic malignancies involving the pancreas were reviewed and compared with the data for 157 surgically resected pancreatic adenocarcinomas. Of 42 cases, 27 (64%) were clinically "suspicious" for hematologic malignancies. Of the remaining 15 cases, 4 patients underwent resection for presumed pancreatic adenocarcinoma. Isolated pancreatic masses proved most difficult to identify clinically. Significant factors in distinguishing hematologic malignancies from adenocarcinoma included history of hematologic malignancy, young age, large tumor size, low CA19-9 level, B symptoms, and lack of jaundice or diabetes mellitus. Various hematologic malignancies involve the pancreas, most commonly diffuse large B-cell lymphoma. Pancreatic masses are usually correctly identified clinically. Preoperative and operative sampling is strongly recommended when hematologic malignancies cannot be excluded.
American Journal of Clinical Pathology 03/2012; 137(3):414-22. · 2.60 Impact Factor
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ABSTRACT: The primary goal of all frozen section analysis is to help determine the best treatment during the operative procedure. In
order to accomplish this goal, it is vital to have an understanding of the surgeons’ expectations and his/her likely response
to a stated diagnosis. This perspective may help determine what the more conservative response would be in a given situation.
We may want to favor the diagnosis that would stop a major resection or defer to permanents, rather than making a diagnosis
that would prompt the resection in a diagnostically difficult case. Depending on the question and site of the biopsy (pancreatic
lesion or metastatic site), a “malignant” diagnosis may either prompt resection or stop the procedure.
KeywordsPancreatic surgery-Frozen section analysis-Pancreaticoduodenectomy-Whipple resection-Pancreatic adenocarcinoma
02/2011: pages 3-7;
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ABSTRACT: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase critical to cell growth and proliferation through its effects on protein translation. Activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway has been described in various tumor types. Earlier studies have demonstrated loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function in some pancreatic ductal adenocarcinomas (PDAs). We performed immunohistochemistry for PTEN and p-RPS6 (major downstream mTOR effector) in a group of PDAs. An assessment of chronic pancreatitis (CP) and normal pancreas (NL) was performed in parallel.
Tissue microarrays were constructed from 49 PDA, 27 CP, and 12 NL. Cases were scored as follows: PTEN (intact: ≥ 5% staining and lost: < 5%) and p-RPS6 (0, 1+: modest intensity in ≥ 5% of cells and 2+: strong intensity ≥ 5% of cells).
Forty-one percent of PDAs demonstrated loss of PTEN, and 75% demonstrated p-RPS6 immunoreactivity (1+ in 22 and 2+ in 3). PTEN was uniformly intact in NL and CP. Although p-RPS6 immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was observed in 62% of CP.
mTOR pathway activation, as evidenced by p-RPS6 immunoreactivity, is frequent in PDA. p-RPS6 expression was also frequent in CP, highlighting the importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR represents a logical target for directed biologic therapy.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 10/2010; 18(5):442-7. · 1.63 Impact Factor
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ABSTRACT: Discerning primary versus metastatic lung lesions is problematic. Comparative mutational profiling (CMP) involves genetic and point mutation analysis of lesions to facilitate this. We sought to review our experience in cases of two lung lesions or head and neck cancer and lung lesions to determine whether a significantly clinical problem existed, what standard processes were in place to address it, and whether a new diagnostic standard was required.
Between January 1, 2007, and October 31, 2008, CMP was used in 24 cases of two lung lesions or a head and neck cancer and lung lesion. Routine hematoxylin and eosin stain examination and immunohistochemistry were performed as appropriate. The CMP involved DNA sequencing for specific oncogene point mutations and a panel of allelic imbalance markers. Metastatic cancer required demonstration of concordant mutations affecting the same allele copy in different cancer deposits.
The patient mean age was 62 years; there were 13 men and 11 women. The cases involved two lung lesions (n = 13) or a head and neck cancer and a lung lesion (n = 11). Standard pathology examination was unable to discriminate the lesions, and they were subsequently differentiated by CMP. Fifteen discordant CMP results were interpreted as independent primaries; 9 cases were concordant, consistent with metastatic disease.
Discerning primary versus metastatic disease when dealing with lung lesions is a clinically significant problem. Comparative mutational profiling was found to be useful and reliable to assess the relatedness of multiple cancer lesions when routine pathology assessment was unable to.
The Annals of thoracic surgery 08/2010; 90(2):388-96. · 3.74 Impact Factor
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ABSTRACT: We performed a histologic and immunohistochemical assessment of 53 noninvasive appendiceal epithelial proliferations, appropriating terminology and using markers shown useful in differentiating serrated colorectal polyps. These were classified as hyperplastic polyp (HP), sessile serrated adenoma (SSA), mixed serrated and adenomatous lesion (MSAL), mucinous cystadenoma (MCA), or conventional adenoma (CAD). Immunohistochemical analysis for cytokeratin (CK) 20, Ki-67, MUC6, and beta-catenin was performed. Diagnoses were as follows: HP, 6; SSA, 12; HP vs SSA, 3; MSAL, 16; MCA, 14; and CAD, 2. All HPs showed expanded (beyond surface) CK20 and expanded or normal (base) Ki-67; 1 was MUC6+. Most SSAs and MSALs were CK20-expanded or expanded with random expression in deep crypts (Ex/I) and Ki-67-expanded, Ex/I (expanded with asymmetry), or normal. All SSAs and 8 of 16 MSALs were MUC6+. CADs were CK20-Ex/I, Ki-67-Ex, and MUC6-; 1 showed nuclear beta-catenin expression. Serrated appendiceal lesions can be categorized using colorectal terminology. MUC6 is associated with SSA morphologic features. Similar immunohistochemical patterns in SSA and MSAL suggest a link between these lesions.
American Journal of Clinical Pathology 04/2010; 133(4):623-32. · 2.60 Impact Factor
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ABSTRACT: To determine whether DNA mismatch repair (MMR) modifies the response to chemotherapy or radiotherapy in patients with endometrial cancer.
Immunohistochemistry (IHC) for the DNA MMR proteins MLH1, MSH2, MSH6, and PMS2 was performed on a tissue microarray of specimens of primary endometrial cancer. MMR deficiency was defined as lack of expression of one or more proteins. Expression of all proteins classified a tumor as having an intact MMR system. Recurrence rates were calculated for women treated with platinum-based chemotherapy or pelvic external beam radiation. Comparisons were made using the log-rank test. Multiple comparisons were controlled for by utilizing the Bonferroni correction method.
Four hundred seventy-seven cases of endometrial cancer were evaluated on a tissue microarray (TMA). One hundred fifty-eight patients (41%) received chemotherapy. Sixty-six patients (17%) received pelvic teletherapy. Overall and progression-free survival were not different between patients whose tumors had intact MMR and those with defective MMR when stratified by adjuvant treatment with radiation or chemotherapy. Subgroup analyses stratified by histology (non-endometrioid versus endometrioid) and stage did show significant survival differences. There was a significant increase in overall (p=0.003) and progression-free (p=0.004) survival in those with MMR-deficient, non-endometrioid tumors treated with teletherapy compared to those with an intact MMR system. Improved progression-free survival was noted in patients with intact MMR with stage III/IV disease treated with adjuvant chemotherapy (p=0.031).
Subgroups of patients with non-endometrioid endometrial cancer and defective MMR may have improved survival after adjuvant radiotherapy. Patients with advanced stage endometrial cancer and defects in mismatch repair may receive less benefit from adjuvant chemotherapy.
Gynecologic Oncology 02/2010; 117(2):234-8. · 3.89 Impact Factor
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ABSTRACT: Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome attributable to deleterious germline mutations in mismatch repair (MMR) genes. The syndrome is typified by early-onset, frequently right-sided colorectal cancers (CRCs) with characteristic histologic features and tendency for multiplicity and an increased risk for extracolonic tumors at particular sites; it accounts for 1% to 5% of CRC. Deficient mismatch repair (dMMR) function manifests as immunohistochemically detectable absence of one or more MMR proteins and microsatellite instability (MSI). Approximately 15% of sporadic, noninherited CRC are characterized by high-level MSI, nearly always owing to transcriptional silencing of MLH1; these sporadic and LS cases exhibit considerable phenotypic overlap. Identification of CRC with dMMR is desirable to identify LS and because MSI status is prognostic and potentially predictive. This review will discuss the history of LS, the principles of MMR and MSI, the clinicopathologic features of LS-associated and sporadic high-level MSI CRC, the fundamentals of clinical testing for dMMR CRC, and the results of the Columbus-area Lynch syndrome study. We conclude with our approach to population-based LS screening based on institutional experience with nearly 2000 cases.
Advances in anatomic pathology 11/2009; 16(6):405-17. · 3.22 Impact Factor
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ABSTRACT: The diagnosis of serous microcystic adenoma (SMA) is usually straightforward. For small biopsies and/or unusual variants, the differential diagnosis includes other pancreatic or metastatic neoplasms showing cystic or clear cell features. We evaluated immunostains for potential use in the diagnosis of SMA. Cases of SMA were identified from archival files. Tissue cores (2 per block) were arrayed to create a microarray of cores measuring 2mm each. Additionally, microarrays previously constructed from 56 pancreatic adenocarcinomas (PACs) and 64 pancreatic endocrine tumors (PENs) were studied. The microarrays were stained with calponin, chromogranin, CD10, alpha-inhibin, and monoclonal neuron-specific enolase (m-NSE). Subsequently, some were stained with MUC6, melan-A, D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. For SMAs, staining was seen with calponin (85.2%), alpha-inhibin (96.2%), and m-NSE (96.2%). Focal weak staining was seen with MUC6 (65%). All SMAs were negative with chromogranin, CD10, melan-A, D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. In contrast, calponin was negative in all PACs and PENs. Staining for alpha-inhibin was absent in PACs and present in 4.1% of PENs; whereas immunoreactivity for m-NSE was present in 26.8% of PACs and 73.7% of PENs. Chromogranin staining was present in 9.1% of PACs and 100% of PENs. An immunohistochemical profile of staining with calponin, alpha-inhibin, and m-NSE and absent staining with chromogranin supports the diagnosis of SMA, and distinguishes SMA from PAC and PEN. Calponin and alpha-inhibin are the most useful positive markers for SMA, and are negative in most entities in the differential diagnosis.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 06/2009; 17(3):216-9. · 1.63 Impact Factor
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ABSTRACT: Immunohistochemical (IHC) stains for mismatch repair (MMR) proteins help screen for Lynch syndrome and identify microsatellite unstable colorectal carcinomas, providing prognostic information. It has been suggested that colorectal and endometrial carcinomas should be screened routinely for a MMR defect, but data are lacking on the practical application of this policy. We report our experience with the prospective evaluation of MMR protein expression in endometrial cancer.
All cases of primary endometrial cancer at a single institution regardless of age, family history or histologic features were prospectively stained for the MMR proteins MLH1, MSH2, MSH6 and PMS2. Clinical and pathologic correlates were collected from the medical record.
A total of 140 endometrial cancer cases were studied. Over 90% of cases were of endometrioid histology. 119 patients had stage I/II disease, and 21 stage III/IV. Nineteen percent of patients were < age 50. Overall, there was loss of 1 or more MMR proteins in 30 patients (21%), including MLH1 and PMS2 in 24, MSH2 and MSH6 in 4, and MSH6 in 2 patients. None of the patients met clinical criteria for Lynch syndrome. However, using MMR protein expression, age and family history, 11% of patients were referred for genetic counseling. Of these patients, three (20%) scheduled an appointment: one canceled and two tested negative.
Prospective staining for MMR proteins is feasible and allows for primary triage for the evaluation of Lynch syndrome in women with endometrial cancer. However, acceptance of genetic consultation and testing is surprisingly low and deserves further investigation.
Gynecologic Oncology 06/2009; 114(3):486-90. · 3.89 Impact Factor
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Heather Hampel, Wendy L Frankel,
Edward Martin,
Mark Arnold,
Karamjit Khanduja,
Philip Kuebler,
Mark Clendenning,
Kaisa Sotamaa,
Thomas Prior,
Judith A Westman,
Jenny Panescu,
Dan Fix,
Janet Lockman,
Jennifer LaJeunesse,
Ilene Comeras,
Albert de la Chapelle
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ABSTRACT: Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.
MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed.
Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations.
One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.
Journal of Clinical Oncology 10/2008; 26(35):5783-8. · 18.37 Impact Factor
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ABSTRACT: Versican is a large chondroitin sulfate proteoglycan that is an integral component of the extracellular matrix protein. It regulates cell proliferation, adhesion, and migration, and is expressed in a variety of normal tissues and tumors. We studied the pattern of versican expression in various epithelial, mesenchymal, neural, and hematopoietic tumors using immunohistochemistry on tissue microarrays. The primary antibody used was mouse monoclonal antibody to versican (clone 8S270, 1:4000, US Biological). Sections from 3 healing wounds were also included to demonstrate versican expression in reactive tissues. The extracellular matrix in all tissues including all tumors (epithelial and nonepithelial) was positive for versican. However, intracellular cytoplasmic expression of versican was seen only in spindle cells, for example, fibroblasts in healing wounds, 11 of 16 (69%) gastrointestinal stromal tumors and 12 of 42 (28%) smooth muscle tumors. Intracellular versican was not seen in any other tumor [0/344 carcinomas (64 breast, 63 prostate, 61 colorectal, 59 lung, 68 ovarian, and 29 thyroid), 0/22 glioblastoma multiforme, 0/46 lymphomas, and 0/21 melanomas]. As versican plays a role in cell proliferation, differentiation, adhesion, and migration, its differential expression in spindle cell tumors may be associated with the differentiation, progression, and spread of these tumors, which is different from epithelial tumors.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 06/2008; 16(3):263-6. · 1.63 Impact Factor
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Xianhua Cao,
Mark Bloomston,
Tao Zhang, Wendy L Frankel,
Guang Jia,
Bing Wang,
Nathan C Hall,
Regina M Koch,
Hao Cheng,
Michael V Knopp,
Duxin Sun
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ABSTRACT: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production.
The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging.
Hypoxia enhanced HIF-1alpha expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition.
The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.
Clinical Cancer Research 04/2008; 14(6):1831-9. · 7.74 Impact Factor
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ABSTRACT: Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2. Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome-associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations (P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome-associated skin lesions among patients with Lynch syndrome is recommended.
CancerSpectrum Knowledge Environment 02/2008; 100(4):277-81. · 14.07 Impact Factor
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ABSTRACT: To report the clinicopathological features of patients with serous cystadenomas of the pancreas.
Thirty-three cases of serous cystadenoma diagnosed between 1977 and 2006 were retrieved from the files of the Ohio State University Medical Center. Clinical data and microscopic slides were reviewed.
The patients included 27 women and 6 men with an age range of 38-83 (mean 64.3) years. The clinical presentation included 13 patients with abdominal pain and 8 patients with abdominal mass; 9 tumors were found incidentally. Abdominal CT scans in 25 patients were interpreted as suspicious for carcinoma in 8 (32%), suspicious for serous cystadenoma in 8, neoplasm not otherwise specified in 8, and suspicious for a pseudocyst in 1. Only 7 patients underwent a preoperative biopsy, and 5 of these were diagnosed as having a serous cystadenoma. All but 2 of the patients underwent surgical resection of the tumor. The serous cystadenomas varied in size from 1.0 to up to 13 cm in maximum dimension, and all but one had a multicystic appearance. Of the 33 serous cystadenomas, 20 (61%) were located in the pancreatic tail, 4 (12%) in the pancreatic body, 4 in the pancreatic body and tail, and 5 (15%) in the head of the pancreas. Follow-up in 17 patients (median 3 years, range from 1 month to 11 years) showed no recurrence of serous cystadenomas. One patient had von Hippel-Lindau syndrome, 4 patients had diabetes mellitus, 3 patients had metastatic cancer, and 2 patients had ovarian tumors.
Serous cystadenoma is an uncommon neoplasm that can be confused with malignancy both clinically and radiologically; a correct diagnosis is important in order to provide an accurate prognosis.
Pancreatology 02/2008; 8(2):135-41. · 1.99 Impact Factor
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ABSTRACT: We report a case of invasive micropapillary carcinoma of the sigmoid colon in a 72-year-old female with anemia and abdominal pain. Grossly, the tumor demonstrated a deeply invasive, ulcerated fungating mass. Microscopically, the carcinoma was predominantly composed of micropapillae with reversed cell polarity, abundant neutrophils, and surrounded by clear spaces. Multifocal lymphovascular invasion was present with extensive lymph node metastasis. Immunohistochemically, the carcinoma cells were positive for CDX2, CK20 and monoclonal carcinoembryonic antigen. They were negative for CK7. The stroma-facing surface of the micropapillae was positive for CD10 and villin, confirming the inside-out growth pattern characteristic of micropapillary carcinoma. Work-up for distance metastasis was negative. The patient was alive and well 1.5 years after sigmoidectomy and postoperative chemotherapy.
International journal of clinical and experimental pathology 02/2008; 1(5):457-60. · 1.89 Impact Factor
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ABSTRACT: A number of hereditary syndromes have been found to be associated with pheochromocytoma development, but there is a paucity of data regarding secondary molecular events, such as downregulation of the p16INK4A/Cdkn2a gene (hereafter p16), contributing to pheochromocytoma tumorigenesis. Using tissue microarray and immunohistochemistry, we evaluated the expression of p16 in 31 pheochromocytoma tumor specimens. Our results showed that the p16 gene was expressed at low level or even not expressed in all but one specimens [30/31 (96.8%)], indicative of the prevalence of p16 downregulation in pheochromocytomas. In contrast, high expression of pl6 was observed in the majority of control "normal" specimens [5/7 (71.6%)]. To further investigate the molecular mechanisms underlying pl6 downregulation in pheochromocytomas, we used quantitative real-time PCR, methylation-specific PCR, and direct DNA sequencing to analyze these specimens for potential genetic alterations of the p16 gene. Deletions and aberrant CpG methylation of pl6 were identified in 9 (29.0%) and 11 (35.5%) specimens, respectively, while one specimen harbored a point mutation, Ala --> Pro at residue 20 of P16, and this mutation led to an eightfold decrease in the CDK4-inhibitory activity of P16. The overall frequency of pl6 genetic alterations is 67.7%. Taken together, our results demonstrate that reduced expression of pl6 is a common event in human pheochromocytomas, and the primary cause for such downregulation is inactivating genetic abnormalities in the p16 gene.
Gene Expression 01/2008; 14(4):207-16. · 1.31 Impact Factor
