Neuroendocrine Carcinoma in an Adolescent With Hypercortisolemia
Emily L. Fagan, MD,* Jeremy S. Slone, MD,* Ashley H. Shoemaker, MD,* Jennifer Black, MD,t Jordan Berlin, MD, ¿§ and Michael E. Engel, MD, PhD,*§|
Summary: We present a 16-year-old boy with weakness, hyper- cortisolemia, and markedly elevated adrenocorticotropic hormone. Computed tomographic imaging revealed hepatic lesions and a calcified pancreatic mass. Biopsy of the hepatic lesions revealed moderately differentiated neuroendocrine carcinoma. The primary tumor could not be determined. The patient received neoadjuvant chemotherapy with carboplatin and etoposide followed by ther- apeutic bilateral adrenalectomy and tumor debulking. Despite significant clinical improvement, restaging revealed progressive hepatic disease. The patient died 9 months after diagnosis. Autopsy revealed disseminated neuroendocrine carcinoma. The rarity of this tumor compels a cooperative investigational model involving pe- diatric and adult oncologists.
Key Words: neuroendocrine carcinoma, hypercortisolemia, ACTH, pediatric hematology-oncology, tumors, liver
(J Pediatr Hematol Oncol 2012;34:e117-e119)
N euroendocrine carcinoma of unknown primary site (NUP) is an uncommon malignancy, accounting for < 5% of all cancers of unknown primary site in adults.1 In children, NUP is exceedingly rare. Broaddus et al2 reviewed the experience with the 5 cases of neuroendocrine carcino- ma identified in children at the M.D. Anderson Cancer Center and Texas Children’s Hospital between 1969 and 2003. They concluded that neuroendocrine carcinoma in children is often accompanied by widespread metastases at diagnosis, making determination of the primary tumor site difficult and thus complicating subsequent treatment deci- sions. We present a case of a 16-year-old boy diagnosed with a NUP, presenting with multiple abdominal tumors involving the liver and the pancreas, prominent ectopic adrenocorticotropic hormone (ACTH) secretion, and with clinical and metabolic findings pathognomonic of hyper- cortisolism.
CASE REPORT
A 16-year-old boy from India presented to the emergency department with a 6-week history of weakness, dizziness, and in- somnia. Symptoms were present during the last 2 weeks of a trip to India and persisted for the 4 weeks that followed his return to the United States. Assuming an infectious etiology, no evaluation was
sought by the family while overseas or before his emergency department presentation. In the emergency department, initial laboratory studies revealed profound hypokalemia (1.4mEq/L) and a metabolic alkalosis (pH 7.52). Urine free cortisol level was 10,016.4 µg/dL, (normal < 56 µg/dL) and serum cortisol was 146 µg/dL (normal <32 µg/dL). Further evaluation showed an ACTH level of 1170 pg/mL (normal, 7 to 51 pg/mL). Alpha-feto- protein level was 8.0 (normal level, 0 to 9.9 ng/mL). The differential diagnosis included an ectopic ACTH-secreting tumor, cortisol releasing hormone-secreting tumor, or pituitary ACTH-secreting tumor (Cushing disease). Brain magnetic resonance imaging re- vealed a normal appearing pituitary gland. Abdominal computed tomography (CT) revealed numerous hepatic masses (the largest, 19 x 8 x8 cm), diffuse peritoneal and mesenteric lymphadenopathy, a calcified mass in the pancreas, and bilateral adrenal gland en- largement with hypodense renal lesions (Fig. 1). Multiple sub- centimeter nodules involving both the lungs were revealed by chest CT.
A biopsy of the largest hepatic lesion revealed an epithelial tumor composed of nests of uniform cells with neuroendocrine features, including immunohistochemical evidence of synaptophy- sin, ACTH, pan-cytokeratin (AE1/AE3), and epithelial membrane antigen expression. Nuclear MIB-1 staining was positive in 22% of the tumor cells, whereas TP53 expression was identified in 30% of the tumor cells. Immunohistochemical staining for insulin and glucagon were negative. Similarly, there was no evidence of CDX2, TTF1, HEPR1, smooth muscle actin, desmin, or myogenin
Received for publication February 24, 2011; accepted June 7, 2011.
From the Departments of *Pediatrics; | Cancer Biology; }Pathology; ¿Medicine, Vanderbilt University School of Medicine; and §Van- derbilt-Ingram Cancer Center, Nashville, TN.
Reprints: Michael E. Engel, MD, PhD, 2000 Circle of Hope Drive, Room 4243, Salt Lake City, UT 84112-5550 (e-mail: michael.engel @hci.utah.edu).
Copyright @ 2011 by Lippincott Williams & Wilkins
expression by the tumor. These findings were consistent with a non- small cell, moderately differentiated neuroendocrine carcinoma.
The patient began neoadjuvant chemotherapy with carbo- platin on day 1, dosed to an area under the curve (AUC) of 6 using the modified Calvert formula, and etoposide 100 mg/m2/d for 3 consecutive days on days 1 through 3. Long-acting somatostatin (30 mg) was administered by intramuscular injection for hormonal suppression. Chemotherapy cycles were followed by granulocyte- colony stimulating factor to facilitate neutrophil recovery. ACTH hypersecretion caused significant morbidity, including disturbances in electrolyte homeostasis, irritability, insomnia, paroxysmal psy- chotic episodes, and prominent hyperpigmentation. In an effort to mitigate these effects, our patient received suppressive therapy with ketoconazole, to which he ultimately became refractory, followed by bilateral adrenalectomy and postoperative medical management for adrenal insufficiency. Resected adrenal glands showed diffuse cortical hyperplasia, consistent with ACTH hypersecretion. No malignancy was identified.
Restaging after 2 cycles of chemotherapy showed progressive disease, accompanied by continued ACTH hypersecretion. The pa- tient underwent a left hepatectomy, radiofrequency ablation of right hepatic lobe lesions, and exploration for the primary tumor that included biopsy of the calcified pancreatic mass and gastric lymph node sampling. The biopsy specimen from the pancreas showed sclerotic, calcified tissue with no evidence of malignancy. However, gastric lymph nodes containing metastatic tumor were identified, providing tissue confirmation of extrahepatic disease. At this time, an octreotide scan was performed but failed to identify the primary disease source. After surgery, the patient’s symptoms improved considerably and his serum ACTH level declined to 79 pg/mL. The family declined further chemotherapy. Bland embolization of the right hepatic artery was performed in an effort to control disease progression. Repeat CT imaging of the chest revealed evolution of pulmonary nodules consistent with progression of pulmonary metastatic foci. At 9 months from diagnosis, the patient acutely developed severe transaminitis and coagulopathy. Abdominal ul- trasound revealed absence of hepatic venous and inferior vena cava blood flow due to compression of the inferior vena cava by tumor
and associated venous stasis thrombosis. He died secondary to ful- minant hepatic failure. A limited autopsy was performed, and it revealed a pancreatic neuroendocrine carcinoma with extensive calcification. The premortem biopsy of the pancreas mass sampled only this calcified region of the tumor and not the surrounding, viable carcinoma. There was also extensive metastatic tumor in the lungs, residual liver parenchyma, and abdominal lymph nodes that histologically resembled the pancreatic mass and premortem tissue samples. No renal lesions were identified.
DISCUSSION
Neuroendocrine tumors characterized by ACTH hy- persecretion are rare in the pediatric setting. Among 10 patients, younger than 20 years with ectopic ACTH syn- drome identified between 1985 and 2008 from 18 university- based endocrinology practices in France, 8 were found to have tumors of neuroendocrine origin.3 These included 7 patients with either typical or atypical carcinoid and 1 patient with poorly differentiated, large cell thymic carcinoma. A primary tumor was identified in each cir- cumstance. These findings suggest that, as in adults, well- differentiated neuroendocrine tumors are more common among those patients who present with ectopic ACTH se- cretion. Furthermore, Broaddus and colleagues reported 5 cases of neuroendocrine carcinoma in adolescents in a review of 34 years of records at the Texas Children’s Hos- pital and the M.D. Anderson Medical Center. Disease sites included the liver, lungs, bones, and the lymph nodes with 2 of 5 patients not having a primary site identified.2 NUP is exceptionally rare, and no cases presenting with the paraneoplastic syndrome of ACTH hypersecretion have been described in the pediatric literature.1,4 Poorly differ- entiated NUP is uniformly aggressive and often multifocal at diagnosis. Moreover, Dhar et al6 suggest that poorly
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differentiated neuroendocrine tumors with early dissem- ination and unpredictable metastatic patterns are more common in younger patient groups. For adult patients with high-grade NUP, an overall survival rate of 13% has been reported.1
Although extensive evaluation for a primary tumor in our patient was unrevealing, common sites for occult pri- mary lesions in neuroendocrine carcinomas are the gas- trointestinal and pulmonary systems.1,7 In children, the most common site for gastrointestinal neuroendocrine carcinomas is the appendix. Appendiceal neuroendocrine tumors often present with symptoms of appendicitis and rarely metastasize.8 Wang et al9 reviewed 123 adult patients (mean age, 57y; range, 18 to 96y) with neuroendocrine tumors and liver metastases, where the pancreas was the most common site of primary tumor. CT identified 100% of primary pancreatic tumors in this study suggesting that primary pancreatic neuroendocrine tumors were unlikely to be occult in nature. Despite the initial negative pancreatic biopsy in our patient, the findings of a calcified pancreatic lesion, gastric lymph nodes positive for tumor, prominent metastatic disease in the liver, and the rarity of tumors metastasizing to the pancreas collectively suggest an ag- gressive primary tumor of pancreatic origin. Although the presence of pulmonary tumor foci complicates this deter- mination, immunohistochemical studies and the findings at autopsy support this hypothesis. TP53 and MIB-1 ex- pression, observed in our patient, are frequently found in tumors with neuroendocrine differentiation.1º MIB-1 pos- itivity, characteristic of early neuroendocrine differentia- tion, often accompanies a more aggressive phenotype than is seen in well-differentiated carcinoid tumors.11 CDX2 and TTF1 staining, which correlate with neuroendocrine tu- mors arising from the distal gastrointestinal tract and lung, respectively,12,13 were not observed in our patient. The possibility of hepatocellular carcinoma was considered, as it can manifest with ectopic ACTH secretion.14 However, HEPR1 staining was negative. Likewise, tests for smooth muscle actin, desmin, and myogenin were negative, re- ducing the likelihood of rhabdomyosarcoma, desmoplastic small round blue cell tumor, or other malignancies of mesenchymal origin as diagnostic considerations (Fig. 2).
For gastrointestinal primary tumors including the pancreas, survival rates after resection of liver metastases are disappointing.15 Because of the rarity and aggressive nature of NUP, there are little data on the most effective treatment. Discovering the primary tumor site may inform the pathogenesis of the disease and direct therapy, but in the face of disseminated disease may not alter the outcome. Chemotherapy consisting of carboplatin and etoposide, with somatostatin augmentation failed to produce a ra- diographic response in our patient. Given the rarity of neuroendocrine carcinoma in the pediatric population and the similar behavior of the disease in children and adults, we believe it is prudent to develop and enroll patients with
neuroendocrine carcinoma on therapeutic trials in collab- oration with adult oncology colleagues. Furthermore, we believe studies directed toward defining the molecular pathogenesis of this rare and aggressive malignancy, and ultimately exploiting this information for therapeutic benefit, are paramount.
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