Pancreas • Volume 44, Number 4, May 2015
Letters to the Editor
characteristic of type 1 AIP and IgG4RD.1,2 In this case, we observed a MCN accompanied by all 3 of these features. Moreover, the number of IgG4+ plasma cells over 50/hpf and the IgG4+/IgG+ ratio greater than 40% fulfilled the Boston criteria for AIP/ IgG4-RD.2 The pancreatic tissue away from the cyst was completely normal, and further clinical and radiologic work-up did not reveal extrapancreatic manifestations of IgG4-RD. Furthermore, the clinical symptoms resolved after resection of the tumor. Therefore, we consider that the dense lymphoplasmacytic infiltrate with features of IgG4-RD surrounding the MCN in this case is not indicative of AIP/IgG4-RD, and likely represents an inflammatory antitumor response driven by Th2 cytokines. There is accumulating evidence that increased IgG4+ plasma cells may be associated not only with classic IgG4-RD but also with a variety of non-neoplastic and neoplastic conditions. The IgG4+ plasma cells may be significantly increased in inflammatory processes, including rheumatoid synovitis, oral cavity lesions including epulis plasmacellularis, radicular cysts, and oral lichen ruber.9 Elevated numbers of IgG4 have also been described as a component of antitumor inflammatory response in several malignancies from different sites, including pancreatic ductal adenocarcinoma3 and IPMN 4–8 (Table 1). It is not clear whether the morphologic features characteristic of AIP/IgG4-RD occur synchronously or precede IPMNs, or longstanding IPMNs induce IgG4+ plasma cell response. Although some authors proposed that IPMN may develop in a background of AIP based on the presence of lymphoplasmacytic infiltration with abundant plasma cells and storiform fibrosis at a location distant from IPMN,6 other hypothesized that the histologic changes consistent with type 1 AIP may be a secondary phenomenon that appeared several years after IPMN.7,8 The characteristic feature common to both pancreatic MCN and IPMN is mucin production. We have recently described that the sclerosing variant of mucoepidermoid carcinoma of salivary glands is associated with increased IgG4+ plasma cells.10 All 6 cases of sclerosing mucoepidermoid carcinoma demonstrated small areas of mucin extravasation composing 5% to 10% of the tumor mass. Although no definitive mucus extravasation was identified in this case, we hypothesize that mucin extravasation in these tumors may elicit an unusual immune response. In summary, we described the first case of pancreatic MCN associated with histologic features of AIP/IgG4-RD. This appears to be a relatively rare phenomenon, but one which should be considered when evaluating
676
www.pancreasjournal.com
mucinous neoplasms of the pancreas, including MCNs. A needle biopsy sampling the periphery of MCN may be misdiagnosed as AIP/IgG4-RD. Therefore, careful clinical and radiologic correlation with histologic findings is crucial in these cases. The authors declare no conflict of interest. Evgeny Yakirevich, MD, DSc Kammi J. Henriksen, MD Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI [email protected]
with intraduct papillary mucinous neoplasm: report of two cases. Pancreatology. 2014;14: 316–318. 9. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64: 237–243. 10. Tian W, Yakirevich E, Matoso A, et al. IgG4(+) plasma cells in sclerosing variant of mucoepidermoid carcinoma. Am J Surg Pathol. 2012;36:973–979.
Thomas Miner, MD
HNPCC-Associated Pheochromocytoma Expanding the Tumor Spectrum
Department of Surgery Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI
Murray B. Resnick, MD, PhD Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI
REFERENCES 1. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352–358. 2. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–1192. 3. Dhall D, Suriawinata AA, Tang LH, et al. Use of immunohistochemistry for IgG4 in the distinction of autoimmune pancreatitis from peritumoral pancreatitis. Hum Pathol. 2010;41: 643–652. 4. Tabata T, Kamisawa T, Hara S, et al. Intraductal papillary mucinous neoplasm of the pancreas and IgG4-related disease: a coincidental association. Pancreatology. 2013;13:379–383. 5. Bateman AC, Culver EL, Sommerlad M, et al. Intraduct papillary mucinous neoplasm of the pancreas: a tumour linked with IgG4-related disease? J Clin Pathol. 2013;66:671–675. 6. Naitoh I, Nakazawa T, Notohara K, et al. Intraductal papillary mucinous neoplasm associated with autoimmune pancreatitis. Pancreas. 2013;42:552–554. 7. Urata T, Naito Y, Izumi Y, et al. Localized type 1 autoimmune pancreatitis superimposed upon preexisting intraductal papillary mucinous neoplasms. World J Gastroenterol. 2013;19: 9127–9132. 8. Vaquero EC, Salcedo MT, Cuatrecasas M, et al. Autoimmune pancreatitis type-1 associated
To the Editor: ereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common inherited colorectal cancer susceptibility syndrome. First described in 1966 by Dr Henry Lynch with the description of 2 large midwest kindred, HNPCC is due to germ line mutations in MLH1, MSH2, MSH6, or PMS2, which result in a deficiency in DNA mismatch repair. Hereditary nonpolyposis colorectal cancer is not only associated with an increased risk for colorectal cancer but also extracolonic cancers including the endometrium, ovary, pancreas, and brain. By instituting routine screening of all newly diagnosed colorectal adenocarcinomas for microsatellite instability, health systems have increased the yield of identifying patients with HNPCC, allowing for appropriate genetic counseling and screening.1 Although the common extracolonic malignancies associated with HNPCC have been identified, there are an increasing number of case reports of established HNPCC patients with neuroendocrine tumors (NETs), raising the possibility that this type of tumor could represent another extracolonic manifestation for which these patients are at increased risk. The increased incidence much like in the general population may be due to the increased use of crosssectional imaging for screening purposes.
H
CASE REPORT We report a case of a pheochromocytoma developing in a patient known to
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
have HNPCC. The patient is a 52-year-old female with a family history of early-onset colon cancer, pancreatic cancer, and endometrial cancer. Despite her family history, the consideration of HNPCC did not arise until a skin lesion was removed from her nose in 2011 at the age of 49 years with pathology showing a sebaceous adenoma and immunohistochemistry revealing absent staining for MSH2. Sebaceous adenomas are strongly associated with Muir-Torre syndrome, a variant of HNPCC. Genetic testing was performed showing a pathogenic mutation of p.Q462X in MSH2 (c.1384C>T).2 Endoscopic ultrasound was performed to screen the pancreas, which was normal, but an incidental adrenal mass was identified. The lesion was nonsecretory on laboratory testing, and the patient underwent a laparoscopic adrenalectomy. Pathology was consistent with a pheochromocytoma. Immunohistochemistry staining was performed on the pheochromocytoma tissue,
Letters to the Editor
and this revealed an absence of both MSH2 and MSH6 expression (Fig. 1). Microsatellite studies also were performed, and the tumor was microsatellite instable. In addition, the patient had genetic testing with the Ambry Genetics PGLNext panel (genes in which inherited mutations are associated with an increased risk of pheochromocytoma), screening for both mutations and large genomic rearrangements of MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL, which were negative. The case presented previously adds to the growing case series reported in the literature of NETs occurring in the setting of HNPCC. The patient presented had a mutation in the DNA mismatch repair protein MSH2. MSH2 mutation is well established to play a role in human carcinogenesis by allowing for DNA repair defects and is seen in 40% of patients with HNPCC. Although the MSH2 mutation has been
shown to markedly increase the risk of colon cancer and the associated other HNPCC malignancies,3 no abnormalities in MSH2 protein levels have been demonstrated in pancreatic NET4 or small bowel carcinoids.5 To date, only 1 other case of pheochromocytoma in the setting of HNPCC has been reported in the literature. In that case, only MSH6 expression was absent. In our patient, both MSH2 and MSH6 were absent. This patient has an established germ line MSH2 mutation, and both her HNPCC-associated lesions, the sebaceous adenoma and the pheochromocytoma, lacked staining for MSH2 and MSH6, indicating a high likelihood that this was not a sporadic NET but rather an extracolonic manifestation of HNPCC. In many of the prior case reports of NET-associated tumors in HNPCC, there has remained a question of whether the NET was actually a metastatic lesion from the primary colonic adenocarcinoma with eventual neuroendocrine differentiation. Our case is unique in that our patient has never been diagnosed with a colonic adenocarcinoma but was diagnosed via family history, genetic testing, and the phenotypic presentation of Muir-Torre syndrome. In addition, pheochromocytomas are traditionally associated with hypermethylation of MSH2 in both the sporadic and MEN2 types rather than with an absence of MSH26 as we describe here. Although NETs traditionally develop in the absence of a mutation in the mismatch repair structure, the case reported previously and those in the literature with demonstratable MSH2 mutations add evidence that NETs can be seen as an extracolonic manifestation of Lynch syndrome. The authors declare no conflict of interest. Brian P. Riff, MD Bryson W. Katona, MD, PhD Division of Gastroenterology University of Pennsylvania Philadelphia, PA
Myra Wilkerson, MD Division of Pathology and Laboratory Medicine Geisinger Health System Wilkes-Barre, PA
Katherine L. Nathanson, MD Division of Medical Genetics University of Pennsylvania Philadelphia, PA FIGURE 1. A, Hematoxylin and eosin–stained section of pheochromocytoma with marked cytologic atypia. B, Tumor shows diffuse cytoplasmic staining for synaptophysin. C, Tumor demonstrates presence of mismatch repair proteins MLH1. D, Tumor demonstrates presence of PMS2. E, Tumor shows loss of mismatch repair proteins MSH2. F, Tumor shows loss of mismatch repair proteins MSH6. All photos presented at 400. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
David C. Metz, MD Division of Gastroenterology University of Pennsylvania Philadelphia, PA [email protected] www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreas • Volume 44, Number 4, May 2015
Letters to the Editor
REFERENCES 1. Hampel H, Frankel WL, Martin E, et al. Screening for the HNPCC (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–1860. 2. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with HNPCC due to deletion of the 3′ exons of TACSTD1. Nat Genet. 2008; 41:112–117. 3. Vasen HFA, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19: 4074–4080. 4. Arnason T, Sapp HL, Rayson D, et al. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch Pathol Lab Med. 2011;135:1539–1544. 5. Kidd M, Eick G, Shapiro MD, et al. Microsatellite instability and gene mutations in transforming growth factor‐beta type II receptor are absent in small bowel carcinoid tumors. Cancer. 2005;103:229–236. 6. Dammann R, Schagdarsurengin U, Seidel C, et al. Frequent promoter methylation of tumor-related genes in sporadic and MEN2-associated pheochromocytomas. Exp Clin Endocrinol Diabetes. 2005;113:1–7.
Serum Markers of Myocardial Damage in Acute Pancreatitis A Prospective Time Course Study To the Editor: ain is the hallmark of acute pancreatitis (AP), and it may mimic an acute coronary syndrome.1 We have extended previous observations on the elevated levels of cardiac troponin T (cTnT) in AP patients2 by determining other markers such as creatine kinase (CK) and CK-MB; serum B type natriuretic factor level (NT-proBNP)3,4 was also evaluated because it was reported to be an indicator of AP severity.5 Thirty-seven consecutive patients with a firm diagnosis of AP (23 males, 14 females; mean age, 55.8 years; range, 19–89 years) were studied within 24 hours after the onset of pain, having normal renal function at the time of the study and without clinical or electrocardiographic signs of acute myocardial infarction; no patient included in this study received parenteral drugs before hospitalization, and none were drug addicts or had developed signs and symptoms
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compatible with acute myocardial infarction. The pancreatitis was of biliary origin in 21 patients, due to alcohol abuse in 2, due to dyslipidemia in 2, post-endoscopic retrograde cholangiopancreatography in 4, and of unknown origin in the remaining 8. According to the Atlanta Clinical Classification System,6 the patients were divided into 2 groups: 22 patients had mild AP and 15 had the severe form of the disease. Forty complications were observed in the 15 patients with severe AP with a mean value of 2.7 complications per patient (range, 1–5 complications). Initially, all patients were treated conservatively; 4 of the 15 patients with severe AP eventually underwent surgery due to progressive deterioration despite intensive medical treatment, and 2 patients died from multiorgan failure. Blood samples from all the participants were taken on admission and in the following 2 days. All serum molecules were assayed using the following commercially available kits: cTnTwas supplied by Roche Diagnostics GmbH, Mannheim, Germany (upper reference limit, 14 pg/mL; 99th percentile); CK (reference range, 30–135 U/L), CK-MB (reference range, 0–3.77 ng/mL in females and 0–6.73 ng/mL in males), and NT-pro-BNP7 (reference ranges, 0–98 pg/mL from 0 to 44 years, 0–121 pg/mL from 45 to 54 years, 0–198 pg/mL from 55 to 64 years, 0–285 pg/mL from 65 to 74 years, and 0–530 pg/mL for 75 years or more) were supplied by Ortho-Clinical Diagnostics, Johnson & Johnson, and High Wycombe, Buckinghamshire, United Kingdom, respectively. In addition, in all patients at each time point, serum amylase (AMYL, Roche Diagnostics GmbH, Mannheim, Germany; reference range, 17–115 IU/L), serum lipase (LIP, Roche Diagnostics GmbH, Mannheim, Germany; reference range, 13–60 IU/L), and serum high sensitivity C-reactive protein (hs-CRP) (CRP; Radim S.p.A., Pomezia, Rome, Italy; reference range, 0–3 mg/L)8 were also assayed. Oral informed consent was obtained from each patient. Due to the different sex reference ranges of CK-MB and the age reference range of NT-proBNP, the values of serum CK-MB and NT-pro-BNP were normalized to the normal and upper reference limits (ie, values from 0 to 1 represent values within the reference range, and values greater than 1 represent values above the upper reference limit). Data are reported as mean (SD) or frequencies. The Mann-Whitney U test, the Wilcoxon test for paired data, and the Fisher exact test were applied for the statistical analysis. No significant modification of overall serum cTnT, CK, CK-MB, and NT-pro-BNP serum levels was found during the 3 days of the study, whereas amylase and lipase activity significantly
decreased from the first to the third day of the study, and hs-CRP significantly increased during the study period (Table 1). Taking into account the frequencies of elevated values of cTnT, CK-MB, and NT-pro-BNP, we found that there were no significant differences in abnormally high values of cTnT, CK-MB, and NT-proBNP between patients with mild and those with severe pancreatitis, whereas on the second day of the study, 40.0% of the patients with severe pancreatitis had abnormally high values of CK as compared with the 9.1% with mild AP (P = 0.042). Finally, there were no significant differences in abnormally high values of cTnT, CK-MB, and NT-pro-BNP between patients with biliary and those with nonbiliary pancreatitis; however, on the third day of the study, 37.5% of the patients with nonbiliary AP had abnormally high values of CK versus 4.8% of those with the biliary form of the disease (P = 0.029). Our data support the hypothesis that cTnT and CK are of muscular origin.9,10 NT-pro-BNP was elevated in more than two thirds of AP patients, whereas no significant differences were found in patients with severe pancreatitis versus those with mild illness and in those with different etiologies of the disease. Even if echocardiography was not carried out in our patients, these data do confirm those of Bugdaci et al.5 In conclusion, the presence of elevated levels of cTnT in AP patients should be interpreted as the possible presence of rhabdomyolysis; clinical observation is better than the NT-pro-BNP determination to detect cardiac failure in AP patients.
The authors declare no conflict of interest.
Alessandra Barassi, MD Clinical Biochemistry Laboratory Department of Health Sciences San Paolo Hospital University of Milan Milan, Italy
Raffaele Pezzilli, MD Pancreas Unit Department of Digestive Diseases and Internal Medicine Sant' Orsola-Malpighi Hospital Bologna, Italy [email protected]
Massimiliano Corsi Romanelli, MD Department of Biomedical Sciences for Health University of Milan Milan, Italy and Operative Unit of Laboratory Medicine IRCCS Policlinico San Donato, Italy
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
characteristic of type 1 AIP and IgG4RD.1,2 In this case, we observed a MCN accompanied by all 3 of these features. Moreover, the number of IgG4+ plasma cells over 50/hpf and the IgG4+/IgG+ ratio greater than 40% fulfilled the Boston criteria for AIP/ IgG4-RD.2 The pancreatic tissue away from the cyst was completely normal, and further clinical and radiologic work-up did not reveal extrapancreatic manifestations of IgG4-RD. Furthermore, the clinical symptoms resolved after resection of the tumor. Therefore, we consider that the dense lymphoplasmacytic infiltrate with features of IgG4-RD surrounding the MCN in this case is not indicative of AIP/IgG4-RD, and likely represents an inflammatory antitumor response driven by Th2 cytokines. There is accumulating evidence that increased IgG4+ plasma cells may be associated not only with classic IgG4-RD but also with a variety of non-neoplastic and neoplastic conditions. The IgG4+ plasma cells may be significantly increased in inflammatory processes, including rheumatoid synovitis, oral cavity lesions including epulis plasmacellularis, radicular cysts, and oral lichen ruber.9 Elevated numbers of IgG4 have also been described as a component of antitumor inflammatory response in several malignancies from different sites, including pancreatic ductal adenocarcinoma3 and IPMN 4–8 (Table 1). It is not clear whether the morphologic features characteristic of AIP/IgG4-RD occur synchronously or precede IPMNs, or longstanding IPMNs induce IgG4+ plasma cell response. Although some authors proposed that IPMN may develop in a background of AIP based on the presence of lymphoplasmacytic infiltration with abundant plasma cells and storiform fibrosis at a location distant from IPMN,6 other hypothesized that the histologic changes consistent with type 1 AIP may be a secondary phenomenon that appeared several years after IPMN.7,8 The characteristic feature common to both pancreatic MCN and IPMN is mucin production. We have recently described that the sclerosing variant of mucoepidermoid carcinoma of salivary glands is associated with increased IgG4+ plasma cells.10 All 6 cases of sclerosing mucoepidermoid carcinoma demonstrated small areas of mucin extravasation composing 5% to 10% of the tumor mass. Although no definitive mucus extravasation was identified in this case, we hypothesize that mucin extravasation in these tumors may elicit an unusual immune response. In summary, we described the first case of pancreatic MCN associated with histologic features of AIP/IgG4-RD. This appears to be a relatively rare phenomenon, but one which should be considered when evaluating
676
www.pancreasjournal.com
mucinous neoplasms of the pancreas, including MCNs. A needle biopsy sampling the periphery of MCN may be misdiagnosed as AIP/IgG4-RD. Therefore, careful clinical and radiologic correlation with histologic findings is crucial in these cases. The authors declare no conflict of interest. Evgeny Yakirevich, MD, DSc Kammi J. Henriksen, MD Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI [email protected]
with intraduct papillary mucinous neoplasm: report of two cases. Pancreatology. 2014;14: 316–318. 9. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64: 237–243. 10. Tian W, Yakirevich E, Matoso A, et al. IgG4(+) plasma cells in sclerosing variant of mucoepidermoid carcinoma. Am J Surg Pathol. 2012;36:973–979.
Thomas Miner, MD
HNPCC-Associated Pheochromocytoma Expanding the Tumor Spectrum
Department of Surgery Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI
Murray B. Resnick, MD, PhD Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Warren Alpert Medical School at Brown University Providence, RI
REFERENCES 1. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352–358. 2. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–1192. 3. Dhall D, Suriawinata AA, Tang LH, et al. Use of immunohistochemistry for IgG4 in the distinction of autoimmune pancreatitis from peritumoral pancreatitis. Hum Pathol. 2010;41: 643–652. 4. Tabata T, Kamisawa T, Hara S, et al. Intraductal papillary mucinous neoplasm of the pancreas and IgG4-related disease: a coincidental association. Pancreatology. 2013;13:379–383. 5. Bateman AC, Culver EL, Sommerlad M, et al. Intraduct papillary mucinous neoplasm of the pancreas: a tumour linked with IgG4-related disease? J Clin Pathol. 2013;66:671–675. 6. Naitoh I, Nakazawa T, Notohara K, et al. Intraductal papillary mucinous neoplasm associated with autoimmune pancreatitis. Pancreas. 2013;42:552–554. 7. Urata T, Naito Y, Izumi Y, et al. Localized type 1 autoimmune pancreatitis superimposed upon preexisting intraductal papillary mucinous neoplasms. World J Gastroenterol. 2013;19: 9127–9132. 8. Vaquero EC, Salcedo MT, Cuatrecasas M, et al. Autoimmune pancreatitis type-1 associated
To the Editor: ereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common inherited colorectal cancer susceptibility syndrome. First described in 1966 by Dr Henry Lynch with the description of 2 large midwest kindred, HNPCC is due to germ line mutations in MLH1, MSH2, MSH6, or PMS2, which result in a deficiency in DNA mismatch repair. Hereditary nonpolyposis colorectal cancer is not only associated with an increased risk for colorectal cancer but also extracolonic cancers including the endometrium, ovary, pancreas, and brain. By instituting routine screening of all newly diagnosed colorectal adenocarcinomas for microsatellite instability, health systems have increased the yield of identifying patients with HNPCC, allowing for appropriate genetic counseling and screening.1 Although the common extracolonic malignancies associated with HNPCC have been identified, there are an increasing number of case reports of established HNPCC patients with neuroendocrine tumors (NETs), raising the possibility that this type of tumor could represent another extracolonic manifestation for which these patients are at increased risk. The increased incidence much like in the general population may be due to the increased use of crosssectional imaging for screening purposes.
H
CASE REPORT We report a case of a pheochromocytoma developing in a patient known to
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
have HNPCC. The patient is a 52-year-old female with a family history of early-onset colon cancer, pancreatic cancer, and endometrial cancer. Despite her family history, the consideration of HNPCC did not arise until a skin lesion was removed from her nose in 2011 at the age of 49 years with pathology showing a sebaceous adenoma and immunohistochemistry revealing absent staining for MSH2. Sebaceous adenomas are strongly associated with Muir-Torre syndrome, a variant of HNPCC. Genetic testing was performed showing a pathogenic mutation of p.Q462X in MSH2 (c.1384C>T).2 Endoscopic ultrasound was performed to screen the pancreas, which was normal, but an incidental adrenal mass was identified. The lesion was nonsecretory on laboratory testing, and the patient underwent a laparoscopic adrenalectomy. Pathology was consistent with a pheochromocytoma. Immunohistochemistry staining was performed on the pheochromocytoma tissue,
Letters to the Editor
and this revealed an absence of both MSH2 and MSH6 expression (Fig. 1). Microsatellite studies also were performed, and the tumor was microsatellite instable. In addition, the patient had genetic testing with the Ambry Genetics PGLNext panel (genes in which inherited mutations are associated with an increased risk of pheochromocytoma), screening for both mutations and large genomic rearrangements of MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL, which were negative. The case presented previously adds to the growing case series reported in the literature of NETs occurring in the setting of HNPCC. The patient presented had a mutation in the DNA mismatch repair protein MSH2. MSH2 mutation is well established to play a role in human carcinogenesis by allowing for DNA repair defects and is seen in 40% of patients with HNPCC. Although the MSH2 mutation has been
shown to markedly increase the risk of colon cancer and the associated other HNPCC malignancies,3 no abnormalities in MSH2 protein levels have been demonstrated in pancreatic NET4 or small bowel carcinoids.5 To date, only 1 other case of pheochromocytoma in the setting of HNPCC has been reported in the literature. In that case, only MSH6 expression was absent. In our patient, both MSH2 and MSH6 were absent. This patient has an established germ line MSH2 mutation, and both her HNPCC-associated lesions, the sebaceous adenoma and the pheochromocytoma, lacked staining for MSH2 and MSH6, indicating a high likelihood that this was not a sporadic NET but rather an extracolonic manifestation of HNPCC. In many of the prior case reports of NET-associated tumors in HNPCC, there has remained a question of whether the NET was actually a metastatic lesion from the primary colonic adenocarcinoma with eventual neuroendocrine differentiation. Our case is unique in that our patient has never been diagnosed with a colonic adenocarcinoma but was diagnosed via family history, genetic testing, and the phenotypic presentation of Muir-Torre syndrome. In addition, pheochromocytomas are traditionally associated with hypermethylation of MSH2 in both the sporadic and MEN2 types rather than with an absence of MSH26 as we describe here. Although NETs traditionally develop in the absence of a mutation in the mismatch repair structure, the case reported previously and those in the literature with demonstratable MSH2 mutations add evidence that NETs can be seen as an extracolonic manifestation of Lynch syndrome. The authors declare no conflict of interest. Brian P. Riff, MD Bryson W. Katona, MD, PhD Division of Gastroenterology University of Pennsylvania Philadelphia, PA
Myra Wilkerson, MD Division of Pathology and Laboratory Medicine Geisinger Health System Wilkes-Barre, PA
Katherine L. Nathanson, MD Division of Medical Genetics University of Pennsylvania Philadelphia, PA FIGURE 1. A, Hematoxylin and eosin–stained section of pheochromocytoma with marked cytologic atypia. B, Tumor shows diffuse cytoplasmic staining for synaptophysin. C, Tumor demonstrates presence of mismatch repair proteins MLH1. D, Tumor demonstrates presence of PMS2. E, Tumor shows loss of mismatch repair proteins MSH2. F, Tumor shows loss of mismatch repair proteins MSH6. All photos presented at 400. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
David C. Metz, MD Division of Gastroenterology University of Pennsylvania Philadelphia, PA [email protected] www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pancreas • Volume 44, Number 4, May 2015
Letters to the Editor
REFERENCES 1. Hampel H, Frankel WL, Martin E, et al. Screening for the HNPCC (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–1860. 2. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with HNPCC due to deletion of the 3′ exons of TACSTD1. Nat Genet. 2008; 41:112–117. 3. Vasen HFA, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19: 4074–4080. 4. Arnason T, Sapp HL, Rayson D, et al. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors. Arch Pathol Lab Med. 2011;135:1539–1544. 5. Kidd M, Eick G, Shapiro MD, et al. Microsatellite instability and gene mutations in transforming growth factor‐beta type II receptor are absent in small bowel carcinoid tumors. Cancer. 2005;103:229–236. 6. Dammann R, Schagdarsurengin U, Seidel C, et al. Frequent promoter methylation of tumor-related genes in sporadic and MEN2-associated pheochromocytomas. Exp Clin Endocrinol Diabetes. 2005;113:1–7.
Serum Markers of Myocardial Damage in Acute Pancreatitis A Prospective Time Course Study To the Editor: ain is the hallmark of acute pancreatitis (AP), and it may mimic an acute coronary syndrome.1 We have extended previous observations on the elevated levels of cardiac troponin T (cTnT) in AP patients2 by determining other markers such as creatine kinase (CK) and CK-MB; serum B type natriuretic factor level (NT-proBNP)3,4 was also evaluated because it was reported to be an indicator of AP severity.5 Thirty-seven consecutive patients with a firm diagnosis of AP (23 males, 14 females; mean age, 55.8 years; range, 19–89 years) were studied within 24 hours after the onset of pain, having normal renal function at the time of the study and without clinical or electrocardiographic signs of acute myocardial infarction; no patient included in this study received parenteral drugs before hospitalization, and none were drug addicts or had developed signs and symptoms
P
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compatible with acute myocardial infarction. The pancreatitis was of biliary origin in 21 patients, due to alcohol abuse in 2, due to dyslipidemia in 2, post-endoscopic retrograde cholangiopancreatography in 4, and of unknown origin in the remaining 8. According to the Atlanta Clinical Classification System,6 the patients were divided into 2 groups: 22 patients had mild AP and 15 had the severe form of the disease. Forty complications were observed in the 15 patients with severe AP with a mean value of 2.7 complications per patient (range, 1–5 complications). Initially, all patients were treated conservatively; 4 of the 15 patients with severe AP eventually underwent surgery due to progressive deterioration despite intensive medical treatment, and 2 patients died from multiorgan failure. Blood samples from all the participants were taken on admission and in the following 2 days. All serum molecules were assayed using the following commercially available kits: cTnTwas supplied by Roche Diagnostics GmbH, Mannheim, Germany (upper reference limit, 14 pg/mL; 99th percentile); CK (reference range, 30–135 U/L), CK-MB (reference range, 0–3.77 ng/mL in females and 0–6.73 ng/mL in males), and NT-pro-BNP7 (reference ranges, 0–98 pg/mL from 0 to 44 years, 0–121 pg/mL from 45 to 54 years, 0–198 pg/mL from 55 to 64 years, 0–285 pg/mL from 65 to 74 years, and 0–530 pg/mL for 75 years or more) were supplied by Ortho-Clinical Diagnostics, Johnson & Johnson, and High Wycombe, Buckinghamshire, United Kingdom, respectively. In addition, in all patients at each time point, serum amylase (AMYL, Roche Diagnostics GmbH, Mannheim, Germany; reference range, 17–115 IU/L), serum lipase (LIP, Roche Diagnostics GmbH, Mannheim, Germany; reference range, 13–60 IU/L), and serum high sensitivity C-reactive protein (hs-CRP) (CRP; Radim S.p.A., Pomezia, Rome, Italy; reference range, 0–3 mg/L)8 were also assayed. Oral informed consent was obtained from each patient. Due to the different sex reference ranges of CK-MB and the age reference range of NT-proBNP, the values of serum CK-MB and NT-pro-BNP were normalized to the normal and upper reference limits (ie, values from 0 to 1 represent values within the reference range, and values greater than 1 represent values above the upper reference limit). Data are reported as mean (SD) or frequencies. The Mann-Whitney U test, the Wilcoxon test for paired data, and the Fisher exact test were applied for the statistical analysis. No significant modification of overall serum cTnT, CK, CK-MB, and NT-pro-BNP serum levels was found during the 3 days of the study, whereas amylase and lipase activity significantly
decreased from the first to the third day of the study, and hs-CRP significantly increased during the study period (Table 1). Taking into account the frequencies of elevated values of cTnT, CK-MB, and NT-pro-BNP, we found that there were no significant differences in abnormally high values of cTnT, CK-MB, and NT-proBNP between patients with mild and those with severe pancreatitis, whereas on the second day of the study, 40.0% of the patients with severe pancreatitis had abnormally high values of CK as compared with the 9.1% with mild AP (P = 0.042). Finally, there were no significant differences in abnormally high values of cTnT, CK-MB, and NT-pro-BNP between patients with biliary and those with nonbiliary pancreatitis; however, on the third day of the study, 37.5% of the patients with nonbiliary AP had abnormally high values of CK versus 4.8% of those with the biliary form of the disease (P = 0.029). Our data support the hypothesis that cTnT and CK are of muscular origin.9,10 NT-pro-BNP was elevated in more than two thirds of AP patients, whereas no significant differences were found in patients with severe pancreatitis versus those with mild illness and in those with different etiologies of the disease. Even if echocardiography was not carried out in our patients, these data do confirm those of Bugdaci et al.5 In conclusion, the presence of elevated levels of cTnT in AP patients should be interpreted as the possible presence of rhabdomyolysis; clinical observation is better than the NT-pro-BNP determination to detect cardiac failure in AP patients.
The authors declare no conflict of interest.
Alessandra Barassi, MD Clinical Biochemistry Laboratory Department of Health Sciences San Paolo Hospital University of Milan Milan, Italy
Raffaele Pezzilli, MD Pancreas Unit Department of Digestive Diseases and Internal Medicine Sant' Orsola-Malpighi Hospital Bologna, Italy [email protected]
Massimiliano Corsi Romanelli, MD Department of Biomedical Sciences for Health University of Milan Milan, Italy and Operative Unit of Laboratory Medicine IRCCS Policlinico San Donato, Italy
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
