Carcinoid syndrome

* 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.

COMMENT

Based on this study, extra-appendiceal carcinoid tumors and neuroendocrine carcinomas in the pediatric patient population primarily involve the lungs or liver. These neuroendocrine neoplasms have the ability to metastasize, regardless of whether the primary tumor is considered a carcinoid tumor or neuroendocrine carcinoma at the time of initial diagnosis. In our series, 6 of 13 (46%) of the patients had recurrent tumor or metastasis following the initial diagnosis or disseminated disease at the time of diagnosis. Carcinoid tumors most commonly arise from the appendix.2 Moertel et al3 retrospectively studied 23 patients, age 20 years or younger, with appendiceal carcinoid tumors. With a follow-up ranging from 9 months to 51 years, these authors found no evidence of recurrent carcinoid in any of their patients. Overall, appendiceal carcinoids are rarely associated with metastatic disease,4 with the exception of rumors 2.0 cm or larger in diameter.5 Therefore, the results from our study suggest that carcinoid tumors/neuroendocrine carcinomas arising outside the appendix have a greater chance of recurrence or metastatic spread compared with carcinoids arising in the appendix.

In this series, 5 of 13 cases were initially diagnosed in the liver, with no other primary sites identified. It is not known if these tumors represent true primary hepatic neoplasms or metastases from asymptomatic, occult gastro-intestinal, pancreatic, or pulmonary primary tumors. For the 2 patients in which clinical follow-up was available, however, liver recurrence was discovered in 1 and liver recurrence, followed by advanced dissemination, was discovered in the other. In both cases, recurrence occurred 3 or more years after the initial diagnosis. Interestingly, during this extended clinical follow-up, there was no evidence of small intestinal, appendiceal, pancreatic, or pulmonary primary tumors. These cases suggest that carcinoids initially diagnosed in the liver can have a more aggressive clinical course than carcinoids initially diagnosed in the appendix.

In our series, 6 of 13 cases were first discovered in the lung. Half of these (3/6; 50%) were associated with distant metastases. Patient 4 had an extensive clinical evaluation, including CT of the chest, CT of the abdomen, and a SPECT nuclear medicine tumor localization study, that ruled out extrapulmonary disease at the time of initial diagnosis. For the remainder of these cases, there was limited follow-up and limited clinical evaluation available due to the consultative nature of the cases; therefore, we cannot characterize these tumors as primary lung neoplasms with absolute certainty. Carcinoid tumors are the most common primary pulmonary neoplasm of childhood.6-9 A large compilation of primary pulmonary neoplasms in 383 children showed that 9 of 118 (8%) of "bronchial adenomas" (including carcinoid, mucoepidermoid carcinoma, and adenoid cystic carcinoma) were associated with distant metastases or recurrence.8 Unfortunately, this study did not indicate which specific "bronchial adenomas" were associated with metastatic disease or tumor recurrence. In one series of 17 patients with bronchial carcinoid tumors, metastasis was detected in 2 patients (12%).9 In another literature review of pulmonary carcinoid tumors in 15 children, 4 of 15 (27%) demonstrated metastases.10 These cumulative results suggest that, in contrast with appendiceal carcinoids, pulmonary carcinoid tumors are associated with a greater risk for distant metastasis.

As was evident in this series, the elucidation of the primary site of origin of carcinoid tumors and neuroendocrine carcinomas can be clinically difficult if the initial presentation site is the liver, lung, or lymph node or if the disease is disseminated at the time of diagnosis. A recent article using molecular biology techniques compared small-cell neuroendocrine carcinomas from the lung, gastrointestinal tract, and larynx.11 These investigators analyzed point mutations in K-ras and loss of heterozygosity of p53, L-myc, OGG1, APC, p16, and PTEN in these tumors with a microdissection technique using formalin-fixed paraffin-embedded tissue sections. They found that small cell neuroendocrine carcinomas from 3 distinct anatomic sites had unique patterns of genetic abnormalities. If these studies were extended to carcinoid tumors and non-small cell neuroendocrine carcinomas, it may be possible to determine the primary site of tumor origin in clinically difficult cases. Furthermore, such molecular analyses may provide clues to the observed differences in biological behavior between appendiceal carcinoid tumors versus extra-appendiceal carcinoid tumors.

One of our patients (patient 2) initially had a liver carcinoid tumor, with no known primary site. Five years following initial diagnosis, this patient developed recurrence in the liver with distant spread to the omentum, abdominal cavity, and ovary without evidence for either an intestinal or appendiceal tumor. A second patient (patient 7) had a carcinoid initially diagnosed in the lung, with rapid dissemination to the liver, heart, small intestinal wall, and ovary without evidence for an appendiceal tumor. Lymphoma and leukemia often spread to the ovaries in children,12 but ovarian metastases from solid tumors in children are uncommon. Prior to our series on extra-appendiceal carcinoids, only 2 children had been reported with carcinoid metastases to the ovary.13,14

St. Jude Children's Research Hospital recently published their experience with childhood carcinoid tumors from 1977 through 1999.14 These investigators found a total of 8 carcinoid tumors. Five of the carcinoid tumors originated in the appendix, 1 carcinoid in the small intestine, 1 carcinoid in the lung, and 1 carcinoid was associated with widespread involvement of the liver, bone, and ovaries, with no definitive primary site identified. The latter patient was the only patient with metastatic tumor and is similar to patient 2 (liver carcinoid with eventual spread to omentum, abdominal cavity, and ovary with definitive primary site identified) and patient 13 (neuroendocrine carcinoma of unknown primary origin with numerous lesions involving the liver, bones, and bilateral lungs) in our series. The patient with metastatic tumor in the St. Jude's series was reported to be alive with disease 1.3 years following the initial diagnosis. In contrast, patient 2 in our study died with disease 5 years following the original diagnosis, while patient 13 died with disease 6 months after the original diagnosis.

In summary, based on the findings of this study and a review of the pertinent literature, carcinoid tumors and neuroendocrine carcinomas arising outside the appendix have the ability to metastasize, regardless of whether the primary tumor is considered to be a carcinoid tumor or a neuroendocrine carcinoma. Perhaps the pathologic diagnosis of carcinoid tumor in an extra-appendiceal site should be accompanied by a comment alerting the clinician that these tumors have an uncertain malignant potential and that metastasis and recurrence are much more common than for carcinoids diagnosed in the appendix. Such a comment would bring greater attention to the primary care clinician and oncologist to provide careful follow-up following the initial diagnosis. Close follow-up is necessary because some of these tumors may recur and/or metastasize years following the original diagnosis. In children and adolescents, these neuroendocrine tumors should be considered as potentially aggressive neoplasms requiring multidisciplinary attention from the pediatric oncology team, including oncologic assessment for extent of tumor, complete surgical excision, careful pathologic evaluation, oncologic management when unresectable, and continuing follow-up.

References

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11. Dacic S, Finkelstein SD, Baksh FK, Swalsky PA, Barnes LE, Yousem SA. Small-cell neuroendocrine carcinoma displays unique profiles of tumor-suppressor gene loss in relationship to the primary site of formation. Hum Pathol. 2002;33:927-932.

12. Ferry JA, Young RH. Malignant lymphomas, pseudolymphoma and hematopoiefic disorders of the female genual tract. Pathol Annu. 1991;26(pt 1):227-263.

13. Young RH, Kozakewich HPW, Scully RE. Metastatic ovarian tumors in children: a report of 14 cases and review of the literature. Int J Gynecol Pathol. 1993;12:8-19.

14. Spunt SL, Pratt CB, Rao BN, et al. Childhood carcinoid tumors: the St Jude Children's Research Hospital experience. J Pediatr Surg. 2000;35:1282-1286.

Russell R. Broaddus, MD, PhD; Cynthia E. Herzog, MD; M. John Hicks, MD, DDS, PhD

Accepted for publication April 17, 2003.

From the Departments of Pathology (Dr Broaddus) and Pediatrics (Dr Herzog), University of Texas M. D. Anderson Cancer Center, and the Department of Pathology, Texas Children's Hospital and Baylor College of Medicine (Dr Hicks), Houston.

This manuscript was presented in poster form at the United States and Canadian Academy of Pathology Annual meeting, Chicago, Illinois, February 25, 2002.

Reprints: Russell R. Broaddus, MD, PhD, Department of Pathology, Box 85, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: rbroaddu@mdanderson.org).

Copyright College of American Pathologists Sep 2003
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