Surg Today DOI 10.1007/s00595-014-1073-3
CASE REPORT
Non‑secreting benign glucagonoma diagnosed incidentally in a patient with refractory thrombocytopenic thrombotic purpura: report of a case Georgios K. Georgiou · Ioannis Gizas · Konstantinos P. Katopodis · Christos S. Katsios
Received: 5 July 2013 / Accepted: 21 July 2014 © Springer Japan 2014
Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder, which may be idiopathic or secondary to a variety of diseases. However, there are very few reports of TTP in the context of pancreatic neoplasms. We report a case of relapsing TTP after initial treatment with plasmapheresis, corticosteroids, and rituximab, in a 59-year-old woman. During diagnostic work-up, a pancreatic lesion 35 × 25 mm in size was discovered incidentally and splenopancreatectomy was performed. The pathological diagnosis was benign glucagonoma. The hematological symptoms resolved completely after the procedure and 3 years later, the patient is well with no sign of recurrence of TTP or glucagonoma. To our knowledge, this represents the first documented case of a non-secreting benign pancreatic neuroendocrine tumor (glucagonoma) associated with TTP that is refractory to standard treatment. Keywords Glucagonoma · TTP · Pancreatectomy · Splenectomy · Plasmapheresis
syndrome as a combination of thrombocytopenia, microangiopathic hemolytic anemia and kidney failure. It is considered to be a rare hematologic disorder with a reported prevalence of 3.7/1000000 per year [2]. In 1996, Amorosi and Ultmann added fever and neurological disorders to the initial triad of symptoms, thus creating the typical pentad of symptoms and signs characteristic of this disease [3]. TTP may be idiopathic or occurs secondary to certain drugs, chemotherapeutic agents and various other pathologic entities [4]. TTP in the context of paraneoplastic manifestations has been associated with certain malignancies and in many cases, the initial diagnosis of idiopathic TTP is changed subsequently to secondary TTP, when a tumor is discovered by a more thorough diagnostic work-up [4, 5]. However, we found only two reports of pancreatic neoplasms associated with TTP [6], but no previous case of TTP associated with a pancreatic neuroendocrine tumor. We report what, to the best of our knowledge, is the first documented case of a non-secreting pancreatic glucagonoma in a patient with relapsing TTP.
Introduction Case report Thrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz et al. [1]. They recognized this G. K. Georgiou and I. Gizas contributed equally to this work. G. K. Georgiou (*) · I. Gizas · C. S. Katsios Department of Surgery, University Hospital of Ioannina, Stavros Niarchos Avenue, 45500 Ioannina, Greece e-mail: [email protected] K. P. Katopodis Department of Nephrology, University Hospital of Ioannina, Stavros Niarchos Avenue, 45500 Ioannina, Greece
A 59-year-old woman, taking atorvastatin 40 mg once daily for hyperlipidemia, was admitted to the emergency department of another institution for investigation of upper limb numbness. An ultrasonographic examination of both carotid arteries and brain magnetic resonance imaging (MRI) was performed. The patient was prescribed antiplatelet treatment (clopidogrel 75 mg once daily) for microischemic lesions in the right cerebral hemisphere and discharged. However, 1 month later, she returned to the same hospital with fever (38.2 °C) and severe changes in her mental status, with dysarthria and disorientation regarding time and
13
place. During the subsequent hours, her clinical picture deteriorated, with a further drop in her level of consciousness. As a central nervous system infection was suspected, computed tomography (CT) of the brain and lumbar puncture were performed, but were non-contributory. A complete blood count and biochemical analysis revealed a platelet count of 19,000/mm3 and 4–6 schistocytes per high optic field, confirming a diagnosis of TTP. She was given seven units of fresh frozen plasma and prednisolone 75 mg iv, as well as ceftriaxone 1G iv twice daily for antibiotic coverage. The following day, the patient was transferred to the unit for hematological diseases at our hospital for plasmapheresis. After the second plasmapheresis session, the fever subsided and the overall clinical status of the patient improved, as did her neurological condition. After five sessions, she complained of loss of vision in her right optical field, but examination by an ophthalmologist revealed no pathology. The platelet count was within the normal range (242,000/mm3), with 2–3 schistocytes/1000 red blood cells and no signs of hemolysis. However, the thrombocytopenia seemed to recur and a new series of plasmapheresis sessions was begun. Methylprednisolone was given once again, orally, with Rituximab as the anti CD-20 antibody. CT scan of the chest and abdomen showed three cystic lesions in the liver, the largest of which was 17 mm in diameter and located in part II, as well as a well-depicted multilocular cystic mass at the border between the pancreatic body and tail, 25 × 35 mm in size. Its characteristics were more similar to those of a cystic pancreatic neoplasm and we suspected a pancreatic mucus cystadenoma (Fig. 1). The patient thus underwent distal pancreatectomy with splenectomy. On postoperative day (POD) 6, deep vein thrombosis (DVT) was diagnosed, based on the ultrasonographic examination of thrombi along the course of the right superficial femoral vein. She was initially treated with low molecular weight heparin, which was changed later to oral warfarin anticoagulants. A high fever developed on POD 8 and she was commenced on antibiotic cover of imipenem– cilastatin 500 mg iv, three times a day, for common pathogens. A new triplex showed DVT of the contralateral leg; however, diagnostic tests for thrombophilia proved negative. Abdominal CT imaging revealed a collection of fluid at the site of the pancreatectomy. The drainage tubes had already been removed on POD 7 since serial samples of the drainage fluid were negative for amylase. Percutaneous drainage under radiological guidance was unavailable at our hospital during that period, so the patient was taken back to the operating room for open drainage. A pancreatic fistula developed which was treated conservatively and resolved spontaneously in time. She was finally discharged 6 weeks after surgery.
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Surg Today
Fig. 1 Abdominal computed tomography (CT) scan showed the pancreatic cystic neoplasm, which was originally suspected to be a mucus cystadenoma. After distal splenopancreatectomy, histological examination confirmed that it was a glucagonoma
Histological examination revealed an endocrine neoplasm of the pancreas with a maximum diameter of 4.3 cm, with indefinite biological behavior. Mitoses were rare, at fewer than 2 per HOF. Immunohistochemistry was positive for chromogranin, synaptophysin, and glucagen, but negative for gastrin, cholecystokinin, insulin and somatostatin, and VIP. The patient is in good health with no signs of diabetes mellitus or purpura recurrence 3 years after her admission. Moreover, routine oncological follow-up has shown no evidence of distant metastases of the pancreatic neuroendocrine tumor.
Discussion The etiology of TTP is related to congenital or acquired autoimmune disorders of the metalloproteinase ADAMTS 13, which decomposes the polymers of factor von Willebrand. Laboratory findings associated with microangiopathic hemolytic anemia are the characteristic sign of this disorder and, together with thrombocytopenia, comprise the basic diagnostic criteria. Patients show the typical signs of hemolysis; namely, increased levels of uncoagulated bilirubin and decreased levels of haptoglobin. LDH levels are extremely high because of the hemolysis and systemic ischemic injury that occurs [2]. The presence of ≥2 schistocytes per high optic field under 100× augmentation is compatible with microangiopathic hemolysis [7]. Clotting tests appear normal and this can be used as a means of differentiating between TTP and disseminated intravascular coagulation (DIC). Neurologic signs are usually mild, and include headache and confusion. Focal disorders such as temporary aphasia, transient ischemic attack, or stroke
Surg Today
are less likely to occur, although spasms or even grand mal seizures are not infrequent [8]. The diagnosis of TTP is based on clinical criteria and should be established soon after the onset of symptoms, with the prompt initiation of proper treatment with plasmapheresis [9]. Before 1960, fewer than 3 % of patients would survive, but plasmapheresis has increased the survival rate dramatically, to 82–90 % [10, 11]. A means of measuring ADAMTS 13 and its inhibitors are not routinely available in every hospital and the procedure may take a long time to perform. This supports the existing trend of establishing the diagnosis of TTP based solely in the presence of thrombocytopenia and microangiopathetic hemolysis [9]. In our laboratory, it is not possible to measure ADAMTS 13 levels in every day clinical practice. Thus, TTP was diagnosed in this patient in accordance with the aforementioned practice, taking into consideration the characteristic hematological findings. The patient was submitted to multiple plasmapheresis sessions, with an initial response, followed by deterioration of both her clinical and laboratory profiles. This prompted us to investigate further by ordering abdominal and chest CT scans to exclude an underlying malignancy [4, 5], leading to the diagnosis of a pancreatic neoplasm, later revealed to be a glucagonoma. Glucagonomas are rare pancreatic tumors, which typically arise during the fifth decade of life [12]. In a series of 340 patients with pancreatic endocrine neoplasms, only 7 % of them appeared to have glucagonomas [13]. The great majority of glucagonomas shows malignant behavior since they carry a metastatic potential, which increases proportionally according to their size and in most cases, metastases are present at the time of diagnosis [13, 14]. However, in rare cases where the tumor is contained within the pancreas and can be excised, there is a chance for definitive treatment [15]. Clinically, glucagonomas can manifest as isolated, intrapancreatic, non-secreting lesions or they can sometimes be related to MEN 1 syndrome, a pathologic entity in which patients have a family history of hypophyseal tumors, parathyroid tumors, and tumors of the pancreatic islet cells [16]. Secreting glucagonomas may cause the characteristic syndrome of glucagonoma, which is associated with pancreatic islet alpha cells [12, 17]. Typical symptoms include necrolytic migratory erythema, cheilitis, weight loss, diarrhea, vein thrombosis and neuropsychiatric disorders. However, about half of glucagonomas are asymptomatic, meaning that early diagnosis is usually only made when discovery is incidental, as a definite diagnosis is only possible after surgical excision and histological examination [18]. In the present case, the fact that the TTP was refractory to standard treatment modalities led to a more thorough diagnostic work-up, including abdominal and chest imaging. The pancreatic neoplasm discovered was well defined and thought initially to be a mucus cystadenoma. Although
local excision of a small, well defined, and non-metastatic pancreatic neuroendocrine tumor may be considered acceptable [19], rather than performing enucleation of the tumor, we proceeded with a more radical resection, including the spleen, since splenectomy has been shown to be effective against relapsing purpura in some cases [20]. There are very few similar reports of non-secreting pancreatic neuroendocrine tumors positive for glucagen, which have been discovered incidentally [21]. However, laparoscopic surgery has already been successfully employed in the management of such tumors [22]. After a thorough research in the existing literature, we were unable to find a single case of a patient suffering simultaneously from both TTP and glucagonoma. We did find a case report of idiopathic thrombocytopenic purpura [23] in a patient with newly diagnosed pancreatic adenocarcinoma [24] and one case of TTP in a patient with metastatic pancreatic adenocarcinoma [6]. In the present case, the neoplasm ‘revealed itself’ incidentally, while we were attempting to treat persistent TTP. This implies that a possible correlation between glucagonoma and TTP might exist, perhaps in the context of the paraneoplastic secretion of yet unknown factors. The complete resolution of purpura after removal of the tumor together with the spleen reinforces this notion. In conclusion, we reported a case of non-secreting glucagonoma, which was diagnosed incidentally during the diagnostic work-up for refractory TTP, and was successfully treated with distal splenopancreatectomy. To our knowledge, this is the first such case ever to be documented, although a clear association between these two pathologic entities would require a far greater number of patients. Conflict of interests GK Georgiou declares no conflict of interest. I Gizas declares no conflict of interest. K P Katopodis declares no conflict of interest. C S Katsios declares no conflict of interest.
References 1. Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. 1925. Mt Sinai J Med. 2003;70:352–5. 2. Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apher. 1998;13:16–9. 3. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore). 1966;45:139–60. 4. Socola F, Loaiza-Bonilla A, Bustinza-Linares E, Correa R, Rosenblatt JD. Recurrent thrombotic thrombocytopenic purpuralike syndrome as a paraneoplastic phenomenon in malignant peritoneal mesothelioma: a case report and review of the literature. Case Rep Oncol Med. 2012;2012:619348. 5. Francis KK, Kalyanam N, Terrell DR, Vesely SK, George JN. Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: a report of 10 patients and a systematic review of published cases. Oncologist. 2007;12:11–9.
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6. Wolff D, Brinkmann B, Emmrich J, Steiner M. Metastatic pancreatic carcinoma presenting as thrombotic thrombocytopenic purpura. Pancreas. 2003;26:314. 7. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060–9. 8. Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol. 2008;142:819–26. 9. Kessler CS, Khan BA, Lai-Miller K. Thrombotic thrombocytopenic purpura: a hematological emergency. J Emerg Med. 2012;43:538–44. 10. Kwaan HC, Soff GA. Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol. 1997;34:159–66. 11. Hayward CP, Sutton DM, Carter WH Jr, Campbell ED, Scott JG, Francombe WH, et al. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Intern Med. 1994;154:982–7. 12. Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. The glucagonoma syndrome clinical and pathologic features in 21 patients. Medicine (Baltimore). 1996;75(2):53–63. 13. Kindmark H, Sundin A, Granberg D, Dunder K, Skogseid B, Janson ET, et al. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007;24:330–7. 14. National Cancer Institute: PDQ® Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment. Bethesda, MD: National Cancer Institute; 2014. Available at: http://cancer.gov/cancertopics/ pdq/treatment/isletcell/HealthProfessional. Accessed 24 May 2013.
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Surg Today 15. Chu QD, Al-kasspooles MF, Smith JL, Nava HR, Douglass HO Jr, Driscoll D, et al. Is glucagonoma of the pancreas a curable disease? Int J Pancreatol. 2001;29:155–62. 16. Davies K, Conlon KC. Neuroendocrine tumors of the pancreas. Curr Gastroenterol Rep. 2009;11:119–27. 17. Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am. 1989;18:831–45. 18. Soga J, Yakuwa Y. Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J Hepatobiliary Pancreat Surg. 1998;5:312–9. 19. Zhang M, Xu X, Shen Y, Hu ZH, Wu LM, Zheng SS. Clinical experience in diagnosis and treatment of glucagonoma syndrome. Hepatobiliary Pancreat Dis Int. 2004;3:473–5. 20. Kremer Hovinga JA, Studt JD, Demarmels Biasiutti F, Solenthaler M, Alberio L, Zwicky C, et al. Splenectomy in relapsing and plasma-refractory acquired thrombotic thrombocytopenic purpura. Haematologica. 2004;89:320–4. 21. Li Destri G, Reggio E, Veroux M, Lanzafame S, Puleo S, Minutolo V. A rare cystic non-functioning neuroendocrine pancreatic tumor with an unusual presentation. Tumori. 2006;92:260–3. 22. Yada K, Hirano S, Himeno Y, Shibata K, Matsumoto T, Aramaki M, et al. Laparoscopic resection for nonfunctioning small glucagon-producing tumor: report of a case and review of the literature. J Hepatobiliary Pancreat Surg. 2003;10:382–5. 23. Petitpas I, Lepault J, Vachette P, Charpilienne A, Mathieu M, Kohli E, et al. Crystallization and preliminary X-Ray analysis of rotavirus protein VP6. J Virol. 1998;72:7615–9. 24. Bir A, Bshara W, George M, Fakih MG. Idiopathic thrombocytopenic purpura in a newly diagnosed pancreatic adenocarcinoma. JOP. 2006;7:647–50.
CASE REPORT
Non‑secreting benign glucagonoma diagnosed incidentally in a patient with refractory thrombocytopenic thrombotic purpura: report of a case Georgios K. Georgiou · Ioannis Gizas · Konstantinos P. Katopodis · Christos S. Katsios
Received: 5 July 2013 / Accepted: 21 July 2014 © Springer Japan 2014
Abstract Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder, which may be idiopathic or secondary to a variety of diseases. However, there are very few reports of TTP in the context of pancreatic neoplasms. We report a case of relapsing TTP after initial treatment with plasmapheresis, corticosteroids, and rituximab, in a 59-year-old woman. During diagnostic work-up, a pancreatic lesion 35 × 25 mm in size was discovered incidentally and splenopancreatectomy was performed. The pathological diagnosis was benign glucagonoma. The hematological symptoms resolved completely after the procedure and 3 years later, the patient is well with no sign of recurrence of TTP or glucagonoma. To our knowledge, this represents the first documented case of a non-secreting benign pancreatic neuroendocrine tumor (glucagonoma) associated with TTP that is refractory to standard treatment. Keywords Glucagonoma · TTP · Pancreatectomy · Splenectomy · Plasmapheresis
syndrome as a combination of thrombocytopenia, microangiopathic hemolytic anemia and kidney failure. It is considered to be a rare hematologic disorder with a reported prevalence of 3.7/1000000 per year [2]. In 1996, Amorosi and Ultmann added fever and neurological disorders to the initial triad of symptoms, thus creating the typical pentad of symptoms and signs characteristic of this disease [3]. TTP may be idiopathic or occurs secondary to certain drugs, chemotherapeutic agents and various other pathologic entities [4]. TTP in the context of paraneoplastic manifestations has been associated with certain malignancies and in many cases, the initial diagnosis of idiopathic TTP is changed subsequently to secondary TTP, when a tumor is discovered by a more thorough diagnostic work-up [4, 5]. However, we found only two reports of pancreatic neoplasms associated with TTP [6], but no previous case of TTP associated with a pancreatic neuroendocrine tumor. We report what, to the best of our knowledge, is the first documented case of a non-secreting pancreatic glucagonoma in a patient with relapsing TTP.
Introduction Case report Thrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz et al. [1]. They recognized this G. K. Georgiou and I. Gizas contributed equally to this work. G. K. Georgiou (*) · I. Gizas · C. S. Katsios Department of Surgery, University Hospital of Ioannina, Stavros Niarchos Avenue, 45500 Ioannina, Greece e-mail: [email protected] K. P. Katopodis Department of Nephrology, University Hospital of Ioannina, Stavros Niarchos Avenue, 45500 Ioannina, Greece
A 59-year-old woman, taking atorvastatin 40 mg once daily for hyperlipidemia, was admitted to the emergency department of another institution for investigation of upper limb numbness. An ultrasonographic examination of both carotid arteries and brain magnetic resonance imaging (MRI) was performed. The patient was prescribed antiplatelet treatment (clopidogrel 75 mg once daily) for microischemic lesions in the right cerebral hemisphere and discharged. However, 1 month later, she returned to the same hospital with fever (38.2 °C) and severe changes in her mental status, with dysarthria and disorientation regarding time and
13
place. During the subsequent hours, her clinical picture deteriorated, with a further drop in her level of consciousness. As a central nervous system infection was suspected, computed tomography (CT) of the brain and lumbar puncture were performed, but were non-contributory. A complete blood count and biochemical analysis revealed a platelet count of 19,000/mm3 and 4–6 schistocytes per high optic field, confirming a diagnosis of TTP. She was given seven units of fresh frozen plasma and prednisolone 75 mg iv, as well as ceftriaxone 1G iv twice daily for antibiotic coverage. The following day, the patient was transferred to the unit for hematological diseases at our hospital for plasmapheresis. After the second plasmapheresis session, the fever subsided and the overall clinical status of the patient improved, as did her neurological condition. After five sessions, she complained of loss of vision in her right optical field, but examination by an ophthalmologist revealed no pathology. The platelet count was within the normal range (242,000/mm3), with 2–3 schistocytes/1000 red blood cells and no signs of hemolysis. However, the thrombocytopenia seemed to recur and a new series of plasmapheresis sessions was begun. Methylprednisolone was given once again, orally, with Rituximab as the anti CD-20 antibody. CT scan of the chest and abdomen showed three cystic lesions in the liver, the largest of which was 17 mm in diameter and located in part II, as well as a well-depicted multilocular cystic mass at the border between the pancreatic body and tail, 25 × 35 mm in size. Its characteristics were more similar to those of a cystic pancreatic neoplasm and we suspected a pancreatic mucus cystadenoma (Fig. 1). The patient thus underwent distal pancreatectomy with splenectomy. On postoperative day (POD) 6, deep vein thrombosis (DVT) was diagnosed, based on the ultrasonographic examination of thrombi along the course of the right superficial femoral vein. She was initially treated with low molecular weight heparin, which was changed later to oral warfarin anticoagulants. A high fever developed on POD 8 and she was commenced on antibiotic cover of imipenem– cilastatin 500 mg iv, three times a day, for common pathogens. A new triplex showed DVT of the contralateral leg; however, diagnostic tests for thrombophilia proved negative. Abdominal CT imaging revealed a collection of fluid at the site of the pancreatectomy. The drainage tubes had already been removed on POD 7 since serial samples of the drainage fluid were negative for amylase. Percutaneous drainage under radiological guidance was unavailable at our hospital during that period, so the patient was taken back to the operating room for open drainage. A pancreatic fistula developed which was treated conservatively and resolved spontaneously in time. She was finally discharged 6 weeks after surgery.
13
Surg Today
Fig. 1 Abdominal computed tomography (CT) scan showed the pancreatic cystic neoplasm, which was originally suspected to be a mucus cystadenoma. After distal splenopancreatectomy, histological examination confirmed that it was a glucagonoma
Histological examination revealed an endocrine neoplasm of the pancreas with a maximum diameter of 4.3 cm, with indefinite biological behavior. Mitoses were rare, at fewer than 2 per HOF. Immunohistochemistry was positive for chromogranin, synaptophysin, and glucagen, but negative for gastrin, cholecystokinin, insulin and somatostatin, and VIP. The patient is in good health with no signs of diabetes mellitus or purpura recurrence 3 years after her admission. Moreover, routine oncological follow-up has shown no evidence of distant metastases of the pancreatic neuroendocrine tumor.
Discussion The etiology of TTP is related to congenital or acquired autoimmune disorders of the metalloproteinase ADAMTS 13, which decomposes the polymers of factor von Willebrand. Laboratory findings associated with microangiopathic hemolytic anemia are the characteristic sign of this disorder and, together with thrombocytopenia, comprise the basic diagnostic criteria. Patients show the typical signs of hemolysis; namely, increased levels of uncoagulated bilirubin and decreased levels of haptoglobin. LDH levels are extremely high because of the hemolysis and systemic ischemic injury that occurs [2]. The presence of ≥2 schistocytes per high optic field under 100× augmentation is compatible with microangiopathic hemolysis [7]. Clotting tests appear normal and this can be used as a means of differentiating between TTP and disseminated intravascular coagulation (DIC). Neurologic signs are usually mild, and include headache and confusion. Focal disorders such as temporary aphasia, transient ischemic attack, or stroke
Surg Today
are less likely to occur, although spasms or even grand mal seizures are not infrequent [8]. The diagnosis of TTP is based on clinical criteria and should be established soon after the onset of symptoms, with the prompt initiation of proper treatment with plasmapheresis [9]. Before 1960, fewer than 3 % of patients would survive, but plasmapheresis has increased the survival rate dramatically, to 82–90 % [10, 11]. A means of measuring ADAMTS 13 and its inhibitors are not routinely available in every hospital and the procedure may take a long time to perform. This supports the existing trend of establishing the diagnosis of TTP based solely in the presence of thrombocytopenia and microangiopathetic hemolysis [9]. In our laboratory, it is not possible to measure ADAMTS 13 levels in every day clinical practice. Thus, TTP was diagnosed in this patient in accordance with the aforementioned practice, taking into consideration the characteristic hematological findings. The patient was submitted to multiple plasmapheresis sessions, with an initial response, followed by deterioration of both her clinical and laboratory profiles. This prompted us to investigate further by ordering abdominal and chest CT scans to exclude an underlying malignancy [4, 5], leading to the diagnosis of a pancreatic neoplasm, later revealed to be a glucagonoma. Glucagonomas are rare pancreatic tumors, which typically arise during the fifth decade of life [12]. In a series of 340 patients with pancreatic endocrine neoplasms, only 7 % of them appeared to have glucagonomas [13]. The great majority of glucagonomas shows malignant behavior since they carry a metastatic potential, which increases proportionally according to their size and in most cases, metastases are present at the time of diagnosis [13, 14]. However, in rare cases where the tumor is contained within the pancreas and can be excised, there is a chance for definitive treatment [15]. Clinically, glucagonomas can manifest as isolated, intrapancreatic, non-secreting lesions or they can sometimes be related to MEN 1 syndrome, a pathologic entity in which patients have a family history of hypophyseal tumors, parathyroid tumors, and tumors of the pancreatic islet cells [16]. Secreting glucagonomas may cause the characteristic syndrome of glucagonoma, which is associated with pancreatic islet alpha cells [12, 17]. Typical symptoms include necrolytic migratory erythema, cheilitis, weight loss, diarrhea, vein thrombosis and neuropsychiatric disorders. However, about half of glucagonomas are asymptomatic, meaning that early diagnosis is usually only made when discovery is incidental, as a definite diagnosis is only possible after surgical excision and histological examination [18]. In the present case, the fact that the TTP was refractory to standard treatment modalities led to a more thorough diagnostic work-up, including abdominal and chest imaging. The pancreatic neoplasm discovered was well defined and thought initially to be a mucus cystadenoma. Although
local excision of a small, well defined, and non-metastatic pancreatic neuroendocrine tumor may be considered acceptable [19], rather than performing enucleation of the tumor, we proceeded with a more radical resection, including the spleen, since splenectomy has been shown to be effective against relapsing purpura in some cases [20]. There are very few similar reports of non-secreting pancreatic neuroendocrine tumors positive for glucagen, which have been discovered incidentally [21]. However, laparoscopic surgery has already been successfully employed in the management of such tumors [22]. After a thorough research in the existing literature, we were unable to find a single case of a patient suffering simultaneously from both TTP and glucagonoma. We did find a case report of idiopathic thrombocytopenic purpura [23] in a patient with newly diagnosed pancreatic adenocarcinoma [24] and one case of TTP in a patient with metastatic pancreatic adenocarcinoma [6]. In the present case, the neoplasm ‘revealed itself’ incidentally, while we were attempting to treat persistent TTP. This implies that a possible correlation between glucagonoma and TTP might exist, perhaps in the context of the paraneoplastic secretion of yet unknown factors. The complete resolution of purpura after removal of the tumor together with the spleen reinforces this notion. In conclusion, we reported a case of non-secreting glucagonoma, which was diagnosed incidentally during the diagnostic work-up for refractory TTP, and was successfully treated with distal splenopancreatectomy. To our knowledge, this is the first such case ever to be documented, although a clear association between these two pathologic entities would require a far greater number of patients. Conflict of interests GK Georgiou declares no conflict of interest. I Gizas declares no conflict of interest. K P Katopodis declares no conflict of interest. C S Katsios declares no conflict of interest.
References 1. Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. 1925. Mt Sinai J Med. 2003;70:352–5. 2. Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apher. 1998;13:16–9. 3. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore). 1966;45:139–60. 4. Socola F, Loaiza-Bonilla A, Bustinza-Linares E, Correa R, Rosenblatt JD. Recurrent thrombotic thrombocytopenic purpuralike syndrome as a paraneoplastic phenomenon in malignant peritoneal mesothelioma: a case report and review of the literature. Case Rep Oncol Med. 2012;2012:619348. 5. Francis KK, Kalyanam N, Terrell DR, Vesely SK, George JN. Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: a report of 10 patients and a systematic review of published cases. Oncologist. 2007;12:11–9.
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6. Wolff D, Brinkmann B, Emmrich J, Steiner M. Metastatic pancreatic carcinoma presenting as thrombotic thrombocytopenic purpura. Pancreas. 2003;26:314. 7. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116:4060–9. 8. Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol. 2008;142:819–26. 9. Kessler CS, Khan BA, Lai-Miller K. Thrombotic thrombocytopenic purpura: a hematological emergency. J Emerg Med. 2012;43:538–44. 10. Kwaan HC, Soff GA. Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol. 1997;34:159–66. 11. Hayward CP, Sutton DM, Carter WH Jr, Campbell ED, Scott JG, Francombe WH, et al. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Intern Med. 1994;154:982–7. 12. Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. The glucagonoma syndrome clinical and pathologic features in 21 patients. Medicine (Baltimore). 1996;75(2):53–63. 13. Kindmark H, Sundin A, Granberg D, Dunder K, Skogseid B, Janson ET, et al. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007;24:330–7. 14. National Cancer Institute: PDQ® Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment. Bethesda, MD: National Cancer Institute; 2014. Available at: http://cancer.gov/cancertopics/ pdq/treatment/isletcell/HealthProfessional. Accessed 24 May 2013.
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