Clin J Gastroenterol DOI 10.1007/s12328-013-0407-9
CASE REPORT
Paraneoplastic diarrhea in a patient with lung adenocarcinoma Anh D. Nguyen • Mark A. Valasek Ezra Burstein
•
Received: 15 April 2013 / Accepted: 11 July 2013 Ó Springer Japan 2013
Abstract We present a case of newly diagnosed lung adenocarcinoma and a five-month history of diarrhea. The patient was found to have elevated chromogranin A serum levels and the tumor displayed histologic and immunohistochemical features of neuroendocrine differentiation. Upon lobectomy and tumor resection, the chromogranin A levels normalized and the diarrhea resolved completely. This is the first reported case of paraneoplastic diarrhea associated with lung adenocarcinoma. Keywords Secretory diarrhea Paraneoplastic Lung cancer
Introduction Paraneoplastic diarrhea has been reported primarily in the setting of carcinoid, pancreatic neuroendocrine tumors and medullary thyroid cancer. While paraneoplastic syndromes are common in lung cancer, chronic diarrhea is a rare clinical manifestation that has been previously reported in the setting of small cell lung cancer, but not previously among patients with lung adenocarcinoma. We present a case of paraneoplastic diarrhea in a patient with lung adenocarcinoma.
A. D. Nguyen E. Burstein (&) Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9151, USA e-mail: [email protected] M. A. Valasek Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Case report A 59-year-old African American woman was admitted to the hospital after presenting to the Emergency Room with diabetic ketoacidosis. She had no prior diagnosis of diabetes, but had been placed on prednisone two months prior to presentation for a tentative diagnosis of rheumatoid arthritis. She had been complaining of joint aches for 6 months and also reported cough and subjective fevers for several weeks prior to admission. Upon evaluation of her respiratory symptoms, a right upper lobe lung mass with post-obstructive pneumonia was discovered (Fig. 1a). Therefore, the patient underwent a computer tomographyguided biopsy which revealed a poorly differentiated lung adenocarcinoma (Fig. 1b, left upper panel). The patient was a significant smoker (45 pack-year history), and her past medical history was largely unremarkable, except for mild hypertension, seasonal allergies, and depression. She had undergone a prior hysterectomy for fibroids. In addition to prednisone, the patient was receiving escitalopram, venlafaxine, loratadine, and lisinopril. Her family history was significant for multiple relatives with malignancies including breast cancer (grandmother), cervical cancer (aunt), head/neck cancer (uncle) and leukemia (uncle). In addition to the above symptoms, the patient reported having diarrhea for about 5 months. The diarrhea was described as episodic, profuse, watery and non-bloody in nature. These episodes worsened at night with improvement during the day and did not change with fasting. She denied recent travel, consumption of uncooked meats, fish or poultry or sick contacts. During her hospitalization, the patient’s intermittent profuse diarrhea became evident, as demonstrated by the daily stool output reaching as much as 5 L/day. Her diarrhea persisted despite fasting, and upon
123
Clin J Gastroenterol Table 1 Laboratory evaluation of the cause of diarrhea Laboratory test (reference range)
Result
General studies Stool sodium (0–159 mEq/kg)
94
Stool potassium (0–199 mEq/kg)
107
Stool chloride (0–39 mEq/kg)
158
Stool osmolarity (220–280 mEq/kg)
390
Fecal fat (\20 % fat)
16 %
Infectious studies Bacterial studies Stool leukocytes
Negative
Stool culture for Campylobacter, Salmonella, Shigella and Vibrio cholera
Negative
Clostridium difficile toxin PCR assay
Negative
Acid-fast bacilli stool smear
Negative
Parasitic studies Ova and parasites
Negative
Cryptosporidium antigen
Negative
Giardia antigen
Negative
Cyclospora smear
Negative
Microsporidia smear
Negative
Fungal studies Fungal stool smear
Negative
Fungal antibodies
Negative
Endocrine studies 5-HIAA, 24 h urine (\8 mg/24 h)
Fig. 1 Lung mass in a patient with profuse diarrhea. a Computed tomography of the chest demonstrating a peripheral lung mass (arrow). b Histology and immunohistochemical (IHC) studies of the lung adenocarcinoma resection specimen: (1) H&E staining of the tumor shows poorly differentiated adenocarcinoma arranged in nested proliferations with vague cribiform glands and diffuse cohesive sheets, with increased nuclear to cytoplasmic ratio, and abnormal nuclear features including hyperchromatic and/or vesicular chromatin and occasional macronucleoli, 9100 (inset, 9600). (2) IHC for CD56 with patchy positive staining, 9100. (3) IHC for chromogranin with rare positive cells, 9100. (4) IHC for synaptophysin with rare positive cells, 9100
withdrawal of the anti-depressant medications. The stool osmolar gap and fecal fat content were not elevated (Table 1). An infectious work-up, including a vast array of microbiologic and parasitologic analyses was negative. A colonoscopy was performed which showed a normal colonic mucosa, and random biopsies also displayed normal mucosal architecture. The patient’s diarrhea was treated with loperamide, requiring high doses of up to 12 mg a day to control her stool output. Given the patient’s lung malignancy, the possibility of an endocrine-mediated secretory diarrhea was pursued. Although all other tests, including vasoactive intestinal polypeptide (VIP) levels, were normal, a slight elevation of serum chromogranin A levels and urinary 5-hydroxyindoleacetic acid was noted (Table 1). During the same
123
8.4 (preoperative) 3.5 (post-resection)
ACTH (6–58 pg/mL)
17
Cortisol (AM 5–23 lg/dL and PM 3–16 lg/dL)
8.2
Calcitonin (0–5.1 pg/mL)
3.3
Chromogranin A (0–95 ng/mL)
123 (preoperative) 90 (postresection)
Gastrin (\100 pg/mL)
286
Serotonin (\330 ng/mL)
102
Somatostatin (\25 pg/mL)
16
VIP, plasma (\75 pg/mL)
\15
5-HIAA 5-hydroxyindoleacetic acid, ACTH adrenocorticotropic hormone, VIP vasoactive intestinal polypeptide
hospitalization, the patient underwent resection of the lung mass (right upper lobectomy). Pathologic evaluation of the surgical specimen demonstrated a peripherally located poorly differentiated lung adenocarcinoma with visceral pleural penetration and lymph node metastases (pathologic stage T2b N2). After extensive sampling, we found that the tumor had only a single uniform histology compatible with adenocarcinoma, and no mixed histologies were noted. Although no histologic evidence of neuroendocrine
Clin J Gastroenterol
differentiation was apparent, immunohistochemical studies using neuroendocrine markers demonstrated that the adenocarcinoma had patchy positive staining for CD56 and rare (\1 %) positively staining cells for both chromogranin A and synaptophysin (Fig. 1b). The neuroendocrine staining was not localized to one area of the tumor, but was scattered throughout the tumor. These findings are consistent with so-called occult neuroendocrine differentiation within a lung adenocarcinoma and support the hypothesis that the mild elevation in serum chromogranin A was tumor derived. After surgery, there was complete resolution of her diarrhea, and loperamide was completely withdrawn without recurrent diarrhea in the subsequent 2 week hospital course. The only other medications withdrawn after surgery were enoxaparin and acetaminophen, which were not deemed likely causes of her diarrhea as they were not temporally related to her symptoms at home. Moreover, during her three-month follow-up appointment after discharge, the patient again confirmed that the diarrhea had completely resolved after tumor resection. After recovering from the operation and upon a pathologic diagnosis of Stage IIIA lung adenocarcinoma (T2bN2M0), the patient underwent four sessions of carboplatin/pemetrexed. By the time the chemotherapy had been initiated, her diarrhea had completely resolved. Unfortunately, despite treatment she developed vertebral metastasis and underwent palliative radiation, but continued to have disease progression. The patient is now under hospice care.
Discussion Given the complete resolution of symptoms after lung resection, we believe that the diarrhea in this patient was a paraneoplastic phenomenon caused by her lung primary tumor. An extensive work-up for alternative causes of diarrhea was unrevealing and no medication was found to be temporally related to her symptoms and the resolution of her diarrhea post-operatively. From the stand-point of a paraneoplastic syndrome, she also had an elevated chromogranin A level, which subsequently resolved to normal levels after tumor resection. However, the patient did not have any other symptoms classic for paraneoplastic syndromes such as neurologic manifestations, hematologic abnormalities or mucocutaneous findings prior to or after surgery. Interestingly, paraneoplastic disorders are most commonly seen among lung cancer patients, with the dominant syndromes being humoral hypercalcemia, Cushing’s syndrome, and syndrome of inappropriate antidiuretic hormone secretion. The vast majority of these cases are associated with small cell lung carcinoma, a poorly differentiated neuroendocrine carcinoma that can
also be associated with paraneoplastic autoantibodies such as Hu, Yo and CV2/CRMP 5, resulting at times in neurologic symptoms and gastrointestinal dysmotility. In contrast, symptoms of secretory diarrhea are extremely rare in lung cancer. This paraneoplastic process has been most often associated with pancreatic neuroendocrine tumors, carcinoid tumors and medullary thyroid cancer. Pancreatic neuroendocrine tumors that can lead to diarrhea include gastrinomas, VIPomas, and somatostatinomas [1]. While gastrinoma patients typically present with recurrent peptic ulcers, diarrhea is present in about 50 % of patients, and 10 % of patients actually have diarrhea as their only symptom [2]. The mechanism of diarrhea in gastrinoma is thought to be an exaggerated gastric secretion of acid which inactivates pancreatic enzymes overwhelming the absorptive capacity of the gastrointestinal tract. While this patient had an elevated gastrin level during her evaluation, she had been on omeprazole when the gastrin levels were obtained, and therefore a secondary cause of hypergastrinemia could not be ruled out. In fact, repeat gastrin levels postoperatively (while still on omeprazole) were higher than preoperatively, increasing from 286 to 891 pg/mL, while the diarrhea had completely resolved. Moreover, gastrin staining on the tumor specimen was negative for this hormone suggesting that her hypergastrinemia was related to the use of proton pump inhibitors, and not the primary etiology of her diarrhea. Other tumors associated with secretory diarrhea are VIPomas, which lead to socalled ‘pancreatic cholera’ due to direct secretory effects of VIP on the intestinal mucosa. Patients present with profuse diarrhea, hypokalemia and achlorhydria/hypochlorhydria which is also known as the WDHA (watery diarrhea, hypokalemia, achlorhydria) or Verner-Morrison syndrome. Although it is possible that such a mechanism might exist in our patient, her VIP levels were within normal range. Somatostatinomas cause diarrhea secondary to decreased pancreatic enzyme and bicarbonate secretion, leading to maldigestion and steatorrhea [3]. Carcinoid tumors, which also have neuroendocrine characteristics, can lead to diarrhea, particularly in tumors that have metastasized to the liver. In this setting, the systemic release of tumor-derived compounds, such as serotonin, can lead to carcinoid syndrome characterized by diarrhea, cutaneous flushing and bronchospasm [4]. Similar to carcinoid syndrome, medullary thyroid cancers can cause diarrhea and flushing and this is due to the systemic release of calcitonin which occurs with hepatic metastasis. Diarrhea occurs with calcitonin levels [10 and portends a poor prognosis [5]. Among patients with lung cancer, paraneoplastic secretory diarrhea has only been rarely reported. Coners et al. [6] described a case of small cell lung cancer presenting with diarrhea and metabolic abnormalities
123
Clin J Gastroenterol
secondary to elevated adrenocorticotropic hormone and calcitonin production. They postulated that the diarrhea was secondary to ectopic calcitonin production. Two other case reports described diarrhea associated with large cell lung cancer with positive neuroendocrine staining, including a case with elevated VIP and calcitonin levels causing diarrhea, and another case with elevated gastrin [7, 8]. In our case, the paraneoplastic secretory diarrhea was associated with lung adenocarcinoma, and to our knowledge, this is the first such report associated with this specific histologic type. While this tumor lacked overt histologic features of neuroendocrine differentiation, it is interesting to note that it had immunohistochemical evidence of neuroendocrine differentiation (so-called occult neuroendocrine differentiation). However, none of the hormones previously implicated in paraneoplastic diarrhea, such as VIP, calcitonin or gastrin, were clearly elevated in the context of this patient’s diarrhea. Thus, an unidentified hormone was likely responsible for the observed diarrhea. Finally, a paraneoplastic cause for unexplained diarrhea needs to be considered in patients with lung adenocarcinoma. Conflict of interest The authors declare no financial, professional, or personal conflict of interest. EB is supported by an NIH R01 Grant
123
(DK073639) and a CCFA award (SRA # 2373). For the remaining authors none were declared.
References 1. Halperin DM, Kulke MH. Management of pancreatic neuroendocrine tumors. Gastroenterol Clin North Am. 2012;41:119–31. 2. Mignon M, Ruszniewski P, Haffar S, Riguad D, Rene E, Bonfils S. Current approach to the management of tumoral process in patients with gastrinoma. World J Surg. 1986;10:703–10. 3. Ellison TA, Edil BH. The current management of pancreatic neuroendocrine tumors. Adv Surg. 2012;46:283–96. 4. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128: 1717–51. 5. Robbins J, Merino MJ, Boice JD, Ron E, Ain KB, Alexander HR, et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med. 1991;115:133–47. 6. Coners K, Woods SE, Webb M. Dual paraneoplastic syndromes in a patient with small cell lung cancer: a case report. J Med Case Rep. 2011;5:318. 7. Pratz KW, Ma C, Aubry MC, et al. Large cell carcinoma with calcitonin and vasoactive intestinal polypeptide-associated VernerMorrison syndrome. Mayo Clin Proc. 2005;80:116–20. 8. Abou-Saif A, Lei J, McDonald TJ, Chakrabarti S, Waxman IF, Shojamanesh H, et al. A new cause of Zollinger-Ellison syndrome: non-small cell lung cancer. Gastroenterology. 2001;120:1271–8.
CASE REPORT
Paraneoplastic diarrhea in a patient with lung adenocarcinoma Anh D. Nguyen • Mark A. Valasek Ezra Burstein
•
Received: 15 April 2013 / Accepted: 11 July 2013 Ó Springer Japan 2013
Abstract We present a case of newly diagnosed lung adenocarcinoma and a five-month history of diarrhea. The patient was found to have elevated chromogranin A serum levels and the tumor displayed histologic and immunohistochemical features of neuroendocrine differentiation. Upon lobectomy and tumor resection, the chromogranin A levels normalized and the diarrhea resolved completely. This is the first reported case of paraneoplastic diarrhea associated with lung adenocarcinoma. Keywords Secretory diarrhea Paraneoplastic Lung cancer
Introduction Paraneoplastic diarrhea has been reported primarily in the setting of carcinoid, pancreatic neuroendocrine tumors and medullary thyroid cancer. While paraneoplastic syndromes are common in lung cancer, chronic diarrhea is a rare clinical manifestation that has been previously reported in the setting of small cell lung cancer, but not previously among patients with lung adenocarcinoma. We present a case of paraneoplastic diarrhea in a patient with lung adenocarcinoma.
A. D. Nguyen E. Burstein (&) Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9151, USA e-mail: [email protected] M. A. Valasek Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Case report A 59-year-old African American woman was admitted to the hospital after presenting to the Emergency Room with diabetic ketoacidosis. She had no prior diagnosis of diabetes, but had been placed on prednisone two months prior to presentation for a tentative diagnosis of rheumatoid arthritis. She had been complaining of joint aches for 6 months and also reported cough and subjective fevers for several weeks prior to admission. Upon evaluation of her respiratory symptoms, a right upper lobe lung mass with post-obstructive pneumonia was discovered (Fig. 1a). Therefore, the patient underwent a computer tomographyguided biopsy which revealed a poorly differentiated lung adenocarcinoma (Fig. 1b, left upper panel). The patient was a significant smoker (45 pack-year history), and her past medical history was largely unremarkable, except for mild hypertension, seasonal allergies, and depression. She had undergone a prior hysterectomy for fibroids. In addition to prednisone, the patient was receiving escitalopram, venlafaxine, loratadine, and lisinopril. Her family history was significant for multiple relatives with malignancies including breast cancer (grandmother), cervical cancer (aunt), head/neck cancer (uncle) and leukemia (uncle). In addition to the above symptoms, the patient reported having diarrhea for about 5 months. The diarrhea was described as episodic, profuse, watery and non-bloody in nature. These episodes worsened at night with improvement during the day and did not change with fasting. She denied recent travel, consumption of uncooked meats, fish or poultry or sick contacts. During her hospitalization, the patient’s intermittent profuse diarrhea became evident, as demonstrated by the daily stool output reaching as much as 5 L/day. Her diarrhea persisted despite fasting, and upon
123
Clin J Gastroenterol Table 1 Laboratory evaluation of the cause of diarrhea Laboratory test (reference range)
Result
General studies Stool sodium (0–159 mEq/kg)
94
Stool potassium (0–199 mEq/kg)
107
Stool chloride (0–39 mEq/kg)
158
Stool osmolarity (220–280 mEq/kg)
390
Fecal fat (\20 % fat)
16 %
Infectious studies Bacterial studies Stool leukocytes
Negative
Stool culture for Campylobacter, Salmonella, Shigella and Vibrio cholera
Negative
Clostridium difficile toxin PCR assay
Negative
Acid-fast bacilli stool smear
Negative
Parasitic studies Ova and parasites
Negative
Cryptosporidium antigen
Negative
Giardia antigen
Negative
Cyclospora smear
Negative
Microsporidia smear
Negative
Fungal studies Fungal stool smear
Negative
Fungal antibodies
Negative
Endocrine studies 5-HIAA, 24 h urine (\8 mg/24 h)
Fig. 1 Lung mass in a patient with profuse diarrhea. a Computed tomography of the chest demonstrating a peripheral lung mass (arrow). b Histology and immunohistochemical (IHC) studies of the lung adenocarcinoma resection specimen: (1) H&E staining of the tumor shows poorly differentiated adenocarcinoma arranged in nested proliferations with vague cribiform glands and diffuse cohesive sheets, with increased nuclear to cytoplasmic ratio, and abnormal nuclear features including hyperchromatic and/or vesicular chromatin and occasional macronucleoli, 9100 (inset, 9600). (2) IHC for CD56 with patchy positive staining, 9100. (3) IHC for chromogranin with rare positive cells, 9100. (4) IHC for synaptophysin with rare positive cells, 9100
withdrawal of the anti-depressant medications. The stool osmolar gap and fecal fat content were not elevated (Table 1). An infectious work-up, including a vast array of microbiologic and parasitologic analyses was negative. A colonoscopy was performed which showed a normal colonic mucosa, and random biopsies also displayed normal mucosal architecture. The patient’s diarrhea was treated with loperamide, requiring high doses of up to 12 mg a day to control her stool output. Given the patient’s lung malignancy, the possibility of an endocrine-mediated secretory diarrhea was pursued. Although all other tests, including vasoactive intestinal polypeptide (VIP) levels, were normal, a slight elevation of serum chromogranin A levels and urinary 5-hydroxyindoleacetic acid was noted (Table 1). During the same
123
8.4 (preoperative) 3.5 (post-resection)
ACTH (6–58 pg/mL)
17
Cortisol (AM 5–23 lg/dL and PM 3–16 lg/dL)
8.2
Calcitonin (0–5.1 pg/mL)
3.3
Chromogranin A (0–95 ng/mL)
123 (preoperative) 90 (postresection)
Gastrin (\100 pg/mL)
286
Serotonin (\330 ng/mL)
102
Somatostatin (\25 pg/mL)
16
VIP, plasma (\75 pg/mL)
\15
5-HIAA 5-hydroxyindoleacetic acid, ACTH adrenocorticotropic hormone, VIP vasoactive intestinal polypeptide
hospitalization, the patient underwent resection of the lung mass (right upper lobectomy). Pathologic evaluation of the surgical specimen demonstrated a peripherally located poorly differentiated lung adenocarcinoma with visceral pleural penetration and lymph node metastases (pathologic stage T2b N2). After extensive sampling, we found that the tumor had only a single uniform histology compatible with adenocarcinoma, and no mixed histologies were noted. Although no histologic evidence of neuroendocrine
Clin J Gastroenterol
differentiation was apparent, immunohistochemical studies using neuroendocrine markers demonstrated that the adenocarcinoma had patchy positive staining for CD56 and rare (\1 %) positively staining cells for both chromogranin A and synaptophysin (Fig. 1b). The neuroendocrine staining was not localized to one area of the tumor, but was scattered throughout the tumor. These findings are consistent with so-called occult neuroendocrine differentiation within a lung adenocarcinoma and support the hypothesis that the mild elevation in serum chromogranin A was tumor derived. After surgery, there was complete resolution of her diarrhea, and loperamide was completely withdrawn without recurrent diarrhea in the subsequent 2 week hospital course. The only other medications withdrawn after surgery were enoxaparin and acetaminophen, which were not deemed likely causes of her diarrhea as they were not temporally related to her symptoms at home. Moreover, during her three-month follow-up appointment after discharge, the patient again confirmed that the diarrhea had completely resolved after tumor resection. After recovering from the operation and upon a pathologic diagnosis of Stage IIIA lung adenocarcinoma (T2bN2M0), the patient underwent four sessions of carboplatin/pemetrexed. By the time the chemotherapy had been initiated, her diarrhea had completely resolved. Unfortunately, despite treatment she developed vertebral metastasis and underwent palliative radiation, but continued to have disease progression. The patient is now under hospice care.
Discussion Given the complete resolution of symptoms after lung resection, we believe that the diarrhea in this patient was a paraneoplastic phenomenon caused by her lung primary tumor. An extensive work-up for alternative causes of diarrhea was unrevealing and no medication was found to be temporally related to her symptoms and the resolution of her diarrhea post-operatively. From the stand-point of a paraneoplastic syndrome, she also had an elevated chromogranin A level, which subsequently resolved to normal levels after tumor resection. However, the patient did not have any other symptoms classic for paraneoplastic syndromes such as neurologic manifestations, hematologic abnormalities or mucocutaneous findings prior to or after surgery. Interestingly, paraneoplastic disorders are most commonly seen among lung cancer patients, with the dominant syndromes being humoral hypercalcemia, Cushing’s syndrome, and syndrome of inappropriate antidiuretic hormone secretion. The vast majority of these cases are associated with small cell lung carcinoma, a poorly differentiated neuroendocrine carcinoma that can
also be associated with paraneoplastic autoantibodies such as Hu, Yo and CV2/CRMP 5, resulting at times in neurologic symptoms and gastrointestinal dysmotility. In contrast, symptoms of secretory diarrhea are extremely rare in lung cancer. This paraneoplastic process has been most often associated with pancreatic neuroendocrine tumors, carcinoid tumors and medullary thyroid cancer. Pancreatic neuroendocrine tumors that can lead to diarrhea include gastrinomas, VIPomas, and somatostatinomas [1]. While gastrinoma patients typically present with recurrent peptic ulcers, diarrhea is present in about 50 % of patients, and 10 % of patients actually have diarrhea as their only symptom [2]. The mechanism of diarrhea in gastrinoma is thought to be an exaggerated gastric secretion of acid which inactivates pancreatic enzymes overwhelming the absorptive capacity of the gastrointestinal tract. While this patient had an elevated gastrin level during her evaluation, she had been on omeprazole when the gastrin levels were obtained, and therefore a secondary cause of hypergastrinemia could not be ruled out. In fact, repeat gastrin levels postoperatively (while still on omeprazole) were higher than preoperatively, increasing from 286 to 891 pg/mL, while the diarrhea had completely resolved. Moreover, gastrin staining on the tumor specimen was negative for this hormone suggesting that her hypergastrinemia was related to the use of proton pump inhibitors, and not the primary etiology of her diarrhea. Other tumors associated with secretory diarrhea are VIPomas, which lead to socalled ‘pancreatic cholera’ due to direct secretory effects of VIP on the intestinal mucosa. Patients present with profuse diarrhea, hypokalemia and achlorhydria/hypochlorhydria which is also known as the WDHA (watery diarrhea, hypokalemia, achlorhydria) or Verner-Morrison syndrome. Although it is possible that such a mechanism might exist in our patient, her VIP levels were within normal range. Somatostatinomas cause diarrhea secondary to decreased pancreatic enzyme and bicarbonate secretion, leading to maldigestion and steatorrhea [3]. Carcinoid tumors, which also have neuroendocrine characteristics, can lead to diarrhea, particularly in tumors that have metastasized to the liver. In this setting, the systemic release of tumor-derived compounds, such as serotonin, can lead to carcinoid syndrome characterized by diarrhea, cutaneous flushing and bronchospasm [4]. Similar to carcinoid syndrome, medullary thyroid cancers can cause diarrhea and flushing and this is due to the systemic release of calcitonin which occurs with hepatic metastasis. Diarrhea occurs with calcitonin levels [10 and portends a poor prognosis [5]. Among patients with lung cancer, paraneoplastic secretory diarrhea has only been rarely reported. Coners et al. [6] described a case of small cell lung cancer presenting with diarrhea and metabolic abnormalities
123
Clin J Gastroenterol
secondary to elevated adrenocorticotropic hormone and calcitonin production. They postulated that the diarrhea was secondary to ectopic calcitonin production. Two other case reports described diarrhea associated with large cell lung cancer with positive neuroendocrine staining, including a case with elevated VIP and calcitonin levels causing diarrhea, and another case with elevated gastrin [7, 8]. In our case, the paraneoplastic secretory diarrhea was associated with lung adenocarcinoma, and to our knowledge, this is the first such report associated with this specific histologic type. While this tumor lacked overt histologic features of neuroendocrine differentiation, it is interesting to note that it had immunohistochemical evidence of neuroendocrine differentiation (so-called occult neuroendocrine differentiation). However, none of the hormones previously implicated in paraneoplastic diarrhea, such as VIP, calcitonin or gastrin, were clearly elevated in the context of this patient’s diarrhea. Thus, an unidentified hormone was likely responsible for the observed diarrhea. Finally, a paraneoplastic cause for unexplained diarrhea needs to be considered in patients with lung adenocarcinoma. Conflict of interest The authors declare no financial, professional, or personal conflict of interest. EB is supported by an NIH R01 Grant
123
(DK073639) and a CCFA award (SRA # 2373). For the remaining authors none were declared.
References 1. Halperin DM, Kulke MH. Management of pancreatic neuroendocrine tumors. Gastroenterol Clin North Am. 2012;41:119–31. 2. Mignon M, Ruszniewski P, Haffar S, Riguad D, Rene E, Bonfils S. Current approach to the management of tumoral process in patients with gastrinoma. World J Surg. 1986;10:703–10. 3. Ellison TA, Edil BH. The current management of pancreatic neuroendocrine tumors. Adv Surg. 2012;46:283–96. 4. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128: 1717–51. 5. Robbins J, Merino MJ, Boice JD, Ron E, Ain KB, Alexander HR, et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med. 1991;115:133–47. 6. Coners K, Woods SE, Webb M. Dual paraneoplastic syndromes in a patient with small cell lung cancer: a case report. J Med Case Rep. 2011;5:318. 7. Pratz KW, Ma C, Aubry MC, et al. Large cell carcinoma with calcitonin and vasoactive intestinal polypeptide-associated VernerMorrison syndrome. Mayo Clin Proc. 2005;80:116–20. 8. Abou-Saif A, Lei J, McDonald TJ, Chakrabarti S, Waxman IF, Shojamanesh H, et al. A new cause of Zollinger-Ellison syndrome: non-small cell lung cancer. Gastroenterology. 2001;120:1271–8.
