Metastatic Neuroendocrine Tumor of Unknown Primary Presenting As Acute Pancreatitis SUNIL DHAR, MD; CRAIG E. GROSSMAN, MD, PHD; TEJ KOKROO, MD
ABSTRACT: Neuroendocrine tumors of unknown primary site are rare. Among all the tumors of unknown primary, neuroendocrine tumors account for less than 5% of such cases. They are identified by immunohistochemical staining which is strongly positive for chromogranin, synaptophysin, or electron microscopy identification of neurosecretory granules. We present a case of metastatic poorly differentiated neuroendocrine tumor with no
identifiable primary, presenting as acute pancreatitis, hypercalcemia, and disseminated bony metastasis. Such presentation has been rarely reported before. Although the nature of these tumors remains undefined, the diagnosis of poorly differentiated neuroendocrine carcinoma identifies a potentially treatable subgroup. KEY INDEXING TERMS: Neuroendocrine tumor; Unknown primary; Pancreatitis. [Am J Med Sci 2008;335(4):304–306.]
had tenderness over rib cage, abdomen, spine, and shoulders. Her bowel sounds were hypoactive. Biochemical studies revealed creatinine 1.7 mg/dL, corrected calcium 13.7 mg/dL, serum amylase 1835 U/L, and lipase 2600 U/L. Computerized tomography (CT) showed pancreatic inflammatory changes consistent with diagnosis of pancreatitis. Patient was treated with intravenous normal saline, furosemide and opiates for pain. Her clinical condition deteriorated despite above management. Patient had increasing severity of pain, sustained elevation of calcium and normal phosphorus, and elevated serum amylase and lipase. During the course of hospitalization, she became anemic and received transfusion for worsening anemia. Opiates were administered via patient controlled analgesia device for pain management. Bleeding scan was performed which showed no definite site of bleeding. A bone scan was done to ascertain the etiology of bony pain and hypercalcemia which showed generalized increase in activity in the central bony skeleton, mild discrete lesions in calvarium, and mild increased uptake in mid sacrum and inhomogeneous appearance of the ribs without a discrete dominant lesion; finding suspicious of generalized metastasis (Figure 1). Subsequent MRI showed no definite compression fracture or destructive lesions. Skull and chest radiography showed no definite fracture, focal osteolytic, or blastic lesions. Concurrently, patients extensive biochemical work up for hypercalcemia revealed mildly elevated alkaline phosphates, normal 24-hour urine hydroxyproline, normal serum protein electrophoresis ruling out multiple myeloma, and a normal CA 19-9 levels ruling out pancreatic cancer. Bone marrow biopsy along with immunohistochemistry was performed which showed features typical of poorly differentiated tumor (high mitotic activity with round to oval nuclei, nuclear chromatin finely granular or stippled, and spotty tumor cell necrosis and crush artifacts). Immunoperoxidase stains were strongly positive for CAM5.2, chromogranin, synaptophysin, and CD56 consistent with neuroendocrine tumor (Figure 2). Staining for thyroid transcription factor-1 (TTF-1) for lung cancer, estrogen receptors/BRST2 (for breast cancer), CD 99 (for Ewing’s sarcoma) were negative. Despite all the above workup, no primary source of malignancy was found radiologically. Eventually patient developed respiratory distress due to pneumonia and needed mechanical ventilation. The following day, patient became febrile, and went into septic shock. Intensive resuscitation with intravenous fluids and pressers was performed; however, her condition continued to deterio-
oorly differentiated metastatic neuroendocrine tumors of unknown primary site are extremely rare.1,2 Among all the tumors of unknown primary, neuroendocrine tumors account for less than 5% of such cases. We present a case of neuroendocrine tumor with no identifiable primary presenting as acute pancreatitis, hypercalcemia, and disseminated bony metastasis. Despite lack of clear understanding of the nature of this malignancy, it is important that the diagnosis is made promptly, because of the favorable outcome with combination chemotherapy in certain cases. Case Presentation
A 63-year-old white woman presented with upper abdominal pain radiating to back for last 7 to 10 days. She denied nausea, vomiting and her pain was worse on lying down. She also complained of generalized body ache, decreased appetite, fatigue and constipation. One week before current admission, patient was discharged from emergency department with similar complaints on naproxen, opiates, and cyclobenzaprine for pain management. Her previous medical history was significant for intraductal breast cancer (treated 29 years ago with right mastectomy), gastrointestinal reflux disease, anxiety disorder, and lumbar strain. Her outpatient medications were famotidine, cyclobenzaprine, alprazolam, and naproxen. Socially she had a 40 pack year history of smoking. She had been menopausal for 13 years. On examination she was uncomfortable, writhing in pain, afebrile, tachycardic (heart rate 116), and normotensive. Her mucus membranes were dry, and complained of pain on neck flexion. She
From the Temple University Hospital (SD, TK), Episcopal Division, Philadelphia, Pennsylvania; and Frankford Hospital (CEG), Philadelphia, Pennsylvania. Submitted April 10, 2007; accepted in revised form July 27, 2007. Correspondence: Sunil Dhar, MD, Temple University Hospital, Episcopal Division, 100 E Lehigh Avenue, Philadelphia, PA 19125 (E-mail: [email protected]
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Figure 1. Bone scan showing generalized increased activity in central skeleton.
rate. Finally her family made a decision to withdraw care and patient subsequently died.
Discussion Our present patient, a 63-year-old woman, had extensive skeletal metastasis of poorly differentiated neuroendocrine tumor of unknown primary. This diagnosis was based on neuroendocrine morphology and neuroendocrine properties, such as positive staining for chromogranin and synaptophysin on bone biopsy. Cancers of unknown primary are a common clinical finding and account for about 2% of all cancer diagnosis.2 However, poorly differentiated neuroendocrine tumors are rare. Usually such patients present with symptoms referable to metastatic site or complications thereof, as in our case generalized bony pain and symptoms of pancreatitis. Metastasis usually involves liver and bone. The disease process involves both genders in equal frequency. There is some evidence that poorly differentiated histolo-
gies are more frequent in younger patient groups. As per current National Comprehensive Cancer Network (NCCN) guidelines, the patients with carcinoma of unknown primary site have early dissemination, and unpredictable metastatic pattern. Overall, these patients have median survival of 6 to 9 months, depending upon histology. Patients with neuroendocrine histology have a relatively favorable prognosis.3 The initial workup, as in our patient, involving physical examination, laboratory and radiological examinations like CT chest, abdomen, and pelvis fail to locate a primary lesion in these cases. Microscopic analysis helps to identify and categorize the lesion into various histological types. Tumor specific workup of neuroendocrine primary lesion involves assessment of various tumor markers such as gastrin, glucogan, TSH, prolaction to name a few. Neuroendocrine tumors are broadly subdivided into those with and those without clinical syndrome and are accordingly termed as “functional” or “nonfunctional” respectively. These tumors are further classified as low grade neuroendocrine tumors, small cell carcinomas and poorly differentiated neuroendocrine tumors based on histological features. Only 10% to 15% of neuroendocrine tumors fall into poorly differentiated category, as they lack morphological features of neuroendocrine differentiation. However they are identified by immunohistochemical staining which is strongly positive for chromogranin or synaptophysin, or electron microscopy identification of neurosecretory granules. Many patients with similar immunohistological features have a primary lesion in the lungs. TTF-1 is an important marker to distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites.4 Our patient had both TTF-1 and CT chest negative for any lung primary. The origin of these poorly differentiated neuroendocrine tumors remains unclear, but it is likely that the group is heterogeneous. Most of these patients have metastasis to multiple sites. Poorly differentiated neuroendocrine carcinomas have been described arising
Figure 2. Bone marrow biopsy and immunochemical staining. (A) Epithelial membrane antigen (EMA) positive consistent with carcinoma and not lymphoma. (B) Strong positive chromogranin staining. (C) Strong positive synaptophysin staining.
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Metastatic Neuroendocrine Tumor of Unknown Primary
from a wide variety of primary sites, including the bladder, prostate, cervix, esophagus, larynx, kidney, and others.5–11 In the undifferentiated form, the clinical, as well as the pathologic, characteristics no longer resemble the characteristics of their more differentiated counterparts. Although the nature of these tumors remains undefined, the diagnosis of poorly differentiated neuroendocrine carcinoma identifies a potentially treatable subgroup. All of these patients should be considered for a trial of combination chemotherapy. Although the optimum regimen is undefined, a platinum or etoposide based regimen as currently used for small cell lung cancer is a reasonable choice.12 Some patients with a single tumor site may be curable with local treatment modalities alone; however, a course of adjuvant chemotherapy should be considered in these patients, if clinically feasible. Metastatic anaplastic carcinoid tumors of gastrointestinal origin have also demonstrated sensitivity to cisplatin-based chemotherapy.13 References 1. Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site. A newly recognized clinicopathologic entity. Ann Intern Med 1988;109:364 –71. 2. Hainsworth JD, Wright EP, Johnson DH, et al. Poorly differentiated carcinoma of unknown primary site: clinical usefulness of immunoperoxidase staining. J Clin Oncol 1991; 9:1931– 8. 3. Pazdur R, Hoskins W, Wagman L. In: Pazdur R. Cancer management: a multidisciplinary approach. New York: F.A. Davis Company; 2003. p. 553– 63.
4. Oliveira AM, Tazelaar HD, Myers JL, et al. Thyroid transcription factor-1 distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites. Am J Surg Pathol 2001;25:815–9. 5. Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer 2005;103:1172– 8. 6. Papandreou CN, Daliani DD, Thall PF, et al. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol 2002;20:3072– 80. 7. Van Der Gaast A, Verwey J, Prins E, et al. Chemotherapy as treatment of choice in extrapulmonary undifferentiated small cell carcinomas. Cancer 1990;65:422– 4. 8. Hoskins PJ, Swenerton KD, Pike JA, et al. Small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based combination chemotherapy. J Clin Oncol 2003;21:3495–501. 9. Mills SE, Cooper PH, Garland TA, et al. Small cell undifferentiated carcinoma of the larynx. Report of two patients and review of 13 additional cases. Cancer 1983;51:116 –20. 10. Brenner B, Tang LH, Klimstra DS, et al. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 2004;22:2730 –9. 11. Majhail NS, Elson P, Bukowski RM. Therapy and outcome of small cell carcinoma of the kidney: report of two cases and a systematic review of the literature. Cancer 2003;97: 1436 – 41. 12. Hainsworth JD, Spigel DR, Litchy S, et al. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol 2006; 24:3548 –54. 13. Moertel CG, Kvols LK, O’Connell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227–32.
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