Carcinoid syndrome liver cancer

* Objective.-Epithelial neuroendocrine neoplasms arising outside the appendix are extremely rare in the pediatric population. We reviewed the clinicopathologic characteristics of 13 carcinoid tumors and neuroendocrine carcinomas presenting at extra-appendiceal sites to better characterize this rare set of neoplasms in childhood.

Design.-The pathology archives of M. D. Anderson Cancer Center and Texas Children's Hospital were searched for cases of carcinoid tumor and neuroendocrine carcinoma arising at extra-appendiceal sites in children. Hematoxylin-eosin-stained sections and, when available, immunohistochemistry, electron photomicrographs and gross photographs were reviewed. The tumors were classified as either carcinoid tumor or neuroendocrine carcinoma based upon histopathologic features. Demographic information was obtained from review of the surgical pathology reports, autopsy reports, and clinical charts.

Patients.-The study population included 8 males and 5 females, ranging in age from 8 to 18 years.

Results.-The majority of the cases were classified as carcinoid tumors (8/13), with the remainder being neuroendocrine carcinomas (5/13). The lung was the initial site of presentation in most children (6/13). The liver was the next most common site (5/13) of tumor presentation with no other primary site identified. Neuroendocrine carcinoma within an inguinal lymph node, with no primary tumor site identified, was present in a single case. The final case was a neuroendocrine carcinoma with widespread involvement of multiple organs with no definitive primary site identified.

Conclusion.-Carcinoid tumors and neuroendocrine carcinomas presenting at extra-appendiceal sites in children primarily involve the lungs or liver. These neuroendocrine neoplasms have the ability to metastasize, regardless of histology at initial diagnosis.

Neuroectodermal tumors comprise a large proportion of childhood neoplasms. These include neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma), central nervous system primitive neuroectodermal tumors (PNET; medulloblastoma and retinoblastoma), and the peripheral PNETs (Ewing sarcoma and Askin tumor).1 These tumors have been widely studied, and their clinical, pathologic, and molecular characteristics are being actively examined. A smaller subgroup of childhood neuroectodermal neoplasms, however, includes extra-appendiceal carcinoid tumors and neuroendocrine carcinomas.1 These tumors are relatively rare and have been poorly characterized in the pediatric population. Based primarily on anecdotal evidence, these tumors typically have a clinical course and biologic behavior distinct from that of tumors derived from the neural crest, such as tumors in the PNET/Ewing sarcoma family. Therefore, we reviewed the clinicopathologic characteristics of 13 extraappendiceal carcinoid tumors and neuroendocrine carcinomas to better characterize this rare set of neoplasms in childhood.

METHODS

The surgical pathology archives of M. D. Anderson Cancer Center and Texas Children's Hospital were searched for cases of carcinoid tumor and neuroendocrine carcinoma arising outside the appendix in children. Routine hematoxylin-eosin-stained sections and, when available, immunohistochemistry, electron photomicrographs, gross photographs, and clinical records were reviewed. The tumors were classified as either carcinoid tumor or neuroendocrine carcinoma based upon histopathologic features. The carcinoids typically had a nested, trabecular, or microacinar architecture and were composed of small, uniform tumor cells with round nuclei and granular chromatin. The neuroendocrine carcinomas resembled poorly differentiated carcinomas, with nuclear atypia and hyperchromasia, frequent mitoses, and cellular pleomorphism. Neuroendocrine features in these more poorly differentiated tumors were confirmed by positive immunohistochemical staining for synaptophysin and/or chromogranin. In some cases, material was also available for electron microscopy, which demonstrated dense core granules characteristic of neuroendocrine neoplasms. Demographic information was obtained from review of the surgical pathology reports, autopsy reports, and clinical charts.

RESULTS

Thirteen cases of carcinoid tumor and neuroendocrine carcinoma initially presenting at extra-appendiceal sites were retrieved from the archives of the Departments of

Pathology at M. D. Anderson Cancer Center and Texas Children's Hospital, dating back to 1969. The Table summarizes the clinicopathologic features for each patient. The patients included 8 males and 5 females, ranging in age from 8 years to 18 years (mean, 12.7 years). Most of the cases were classified as carcinoid tumors (8/13), with the remainder being neuroendocrine carcinomas (5/13). The lung was the presenting site in most children (6/13), with 5 carcinoid tumors and 1 neuroendocrine carcinoma. One half (3/6) of these patients developed distant metastases. The liver was the next most common site (5/13) of tumor presentation, with no other primary site identified. Liver tumors were classified as carcinoid tumors (3/5) and neuroendocrine carcinoma (2/5). Neuroendocrine carcinoma within an inguinal lymph node, with no primary tumor site identified, was present in a single case. Finally, one patient had neuroendocrine carcinoma with widespread involvement of the liver, bilateral lungs, and multiple bones at the time of diagnosis. Therefore, no definitive primary site could be identified with this patient.

Most of these cases were received in consultation, so there was limited follow-up information available. Patient 9 had a neuroendocrine carcinoma involving the right inguinal lymph node diagnosed at age 10 years. At the time of diagnosis, no other sites of involvement were identified. However, mucosal neuromas involving the tongue and oral mucosa were present. This patient was subsequently shown to have a mutation in the RET proto-oncogene, codon 918 (ATG to ACG), allowing for the diagnosis of multiple endocrine neoplasia (MEN) IIb. The patient's thyroid was resected 2.5 years later, demonstrating multifocal medullary thyroid carcinoma. Currently, this patient has no other known tumor sites. To our knowledge, none of the remaining 12 patients in this study fulfilled diagnostic criteria for MEN syndrome.

Patient 1 was first diagnosed with a liver carcinoid at 8 years of age. Three years later, a recurrent tumor in the liver was resected. Seven years after the initial diagnosis, this patient currently shows no evidence of disease. Patient 2 was first diagnosed with a liver carcinoid tumor, with no other known primary site. Three years following the initial diagnosis, this patient developed a liver recurrence. Then, 2 years after this recurrence, the tumor again recurred in the liver, with additional spread to the ovary and omentum/abdominal cavity, with no evidence of either intestinal or appendiceal tumor. This patient died 5 years following the initial diagnosis. Patient 4 was diagnosed with a lung carcinoid at 11 years of age (Figure, B). This was clinically believed to be a primary lung neoplasm because extensive clinical work-up, including a computed tomographic (CT) scan of the chest, CT of the abdomen, and a nuclear medicine single photon emission computed tomography (SPECT) tumor localization study, failed to detect extrapulmonary disease. No intestinal or appendiceal masses were detected. Five years later, liver and brain metastases were discovered. The brain metastasis was resected, but the patient has persistent liver metastases 7 years after the lung carcinoid was first diagnosed. For patient 7, carcinoid tumor was first diagnosed in the lung. Eight months later, at autopsy, disseminated tumor was discovered in the liver, heart, ovary, and small intestine (Figure, A). In this case, it was difficult to determine with certainty the primary site because of the rapid dissemination of tumor. An occult primary tumor, at presentation, in the small intestine could not be ruled out. For patient 13, diagnosed with neuroendocrine carcinoma at age 15 years, tumor extensively involved the liver, bilateral lungs, and numerous bones (Figure, C and D). No definitive primary site was evident. This patient died 6 months following the initial diagnosis.

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