Case 5 -
Thymic Carcinoid Tumor in Association with Type-1 Multiple Endocrine Neoplasm Syndrome (MEN1)
Laura H. Tang
Memorial Sloan-Kettering Cancer Center
New York, NY
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17 years old male with an anterior mediastinal mass, multiple liver lesions (biopsied), and Cushing's syndrome.
Case 5 - Figure 1
Liver biopsy reveals several large and irregular tumor nests with prominent spindle cell morphology with noticeable whorl-formation.
Case 5 - Figure 2
The epithelioid nature of the tumor is better appreciated at a higher magnification.
Case 5 - Figure 3
The tumor cells reveal low nuclear to cytoplasmic (N/C) ratio with identifiable mitoses and single cell necrosis.
Case 5 - Figure 4
Significant nuclear pleomorphism is depicted by enlarged and bizarre nuclei with intranuclear inclusions.
Case 5 - Figure 5
The highest proliferative activity, assessed by Ki67 nuclear immunoreactivity, is 2%.
Case 5 - Figure 6
The tumor cells are diffusely positive for chromogranin.
Case 5 - Figure 7
The tumor cells are focally positive for ACTH.
Case 5 - Figure 8
Surgical resection of the mediastinal tumor reveals an epithelial neoplasm with typical histologic pattern of a carcinoid tumor.
The case encapsulates the intricacy of pathology practice, in that, every time one believes that a
pathologic puzzle is resolved, it is only one half of a clinical riddle. Clinical History The patient is
a 17 years old male who presented with an anterior mediastinal mass, Cushing's syndrome, and multiple
liver lesions. The latter was biopsied and submitted for pathologic evaluation. The mediastinal tumor
was subsequently resected to ameliorate tracheal compression symptoms. Upon acquisition of the family
history it emerged that the father had neck surgery for a parathyroid tumor; has and had been prescribed
a proton pump inhibitor for peptic ulcer disease.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
A core liver biopsy reveals several large and irregular tumor nests (Figure 1). At low magnification,
there is prominent spindle cell morphology with noticeable whorl- formation (Figure 1). However, at
higher magnification, the tumor is better appreciated as epithelial/epithelioid in nature (Figure 2, 3),
and a cytokeratin immunostain (AE1:AE3) is positive in tumor cells. The neoplasm exhibits significant
nuclear pleomorphism although, in the presence of abundant cytoplasm, the nuclear to cytoplasmic (N/C)
ratio is relatively low. While the severe cytologic atypia present in this tumor (Figure 4) creates the
impression of a high grade carcinoma, the estimated mitotic activity is 2 mitoses per 10 high power
fields and the proliferative index (MIB-1/Ki67) is 2% (Figure 5). Single tumor cell necrosis/apoptosis
is also apparent in this biopsy (Figure 4). Immunohistochemical studies reveal that the tumor cells are
positive for chromogranin, synaptophysion, and ACTH (Figure 6, 7); they are negative for TTF1, Napsin-A,
CD30, PLAP, and hCGH. Surgical resection specimen of the thymic tumor reveals a 3.0 cm
well-circumscribed fleshy tumor. Microscopically, the tumor demonstrates a nested pattern surrounded by
abundant and delicate vasculature (Figure 8). Apparent vascular invasion by tumor is appreciated
throughout the tumor. The morphological features are most consistent with a well differentiated
neuroendocrine tumor (carcinoid) with intermediated cytologic grade.
1. Based upon anatomical location (anterior mediastinum): a. Primary thymic tumor: Thymoma/thymic
carcinoma, thymic carcinoid tumor b. Lymphoma: Hodgkin's disease, large B-cell type, lymphoblastic type
c. Primary or metastatic germ cell tumor: mature teratoma, seminoma, nonseminomatous germ cell tumor d.
Thyroid - Substernal Goiter e. Parathyroid - Ectopic parathyroid adenoma
2. Based upon combined
morphologic features and anatomic location: a. Epithelial neoplasm: thymic carcinoma, thymic carcinoid
tumor, lung carcinoma b. Spindle cell features may suggest a mesenchymal neoplasm: solitary fibrous
tumor, smooth muscle tumor, and synoviosarcoma
3. Based upon combined information (clinical, radiology,
morphology, immunohistochemistry, and additionally acquired family history) A primary thymic epithelial
neoplasm, possibly arising against a background of a hereditary condition
Thymic carcinoid tumor in association with type-1 Multiple Endocrine Neoplasm syndrome (MEN1)
Thymic carcinoid tumor (TCT) was historically classified as a foregut carcinoid tumor. This group
also includes carcinoid tumors of the bronchus, stomach, and the pancreas. The entity of TCT was
initially described by Rosai in 1972 with the recognition of its hisopathologic features, malignant
clinical behavior, and its association other clinical syndromes  . The onset age for thymic
carcinoid tumor is ~50 years with a male predominance (3:1). Approximately 40% patients with thymic
carcinoid tumors present with ectopic Cushing's syndrome secondary to ACTH production by the tumor. The
tumor is highly malignant with an estimated recurrence of 67% after surgical resection of the primary
tumor  .
The most significant clinical relationship in the diagnosis of a thymic carcinoid tumor is the
association with MEN-I in ~25% cases. Conversely, ~ 8% patients with MEN-I develop thymic
carcinoid tumor. Thymic carcinoid tumor is a major cause of death in MEN-I, and the estimated 5-year
survival is 30-40%  .
In respect of the different neoplasms arising in MEN-1 syndrome (Table 1), the most malignant tumors
are gastrinoma and thymic carcinoid tumor. Gastrinoma is commonly located in duodenum and presents as
functional albeit often occult lesion before clinically evident metastasis are evident. Despite the
presumption of "successful" surgical resection of thymic carcinoid tumors, the majority (67%) of patients
will have recurrent disease and <50% survive in 5 years  .
Table 1. MEN-1 Associated Neoplasia
|Parathyroid adenoma 75-95% ||Adrenal adenoma 20%|
|Pancreatic endocrine tumor 70% |
|Foregut carcinoid Tumor 18%|
|Pituitary adenoma 47%|
ACTH producing 1%
GH producing 3-6%
|Skin lesions 80%|
MEN-1 associated tumors develop in a genetic background of germline MEN1
gene mutation on the first allele followed by somatic inactivation of the gene on the 2nd
allele by LOH  .
MEN1 constitutes a 9 kb genomic DNA with 10
exons, and 4-kb transcript is present in the pancreas, thymus and stomach. The mRAN of 1.83 kb encodes a
610 amino acid nuclear protein of menin, which regulates gene transcription and is involved in chromatin
remolding  .
MEN1 mutation/LOH has been recognized in many
forget neuroendocrine tumors
which include functional (up to 80%) and non-functional
pancreatic neuroendocrine tumors (43%), thymic carcinoid (25%), gastric carcinoid (up to 75%), and
pulmonary neuroendocrine tumors (20-60%).
Given the potential for a number of predictable life threatening malignancies in MEN-1, MEN1 gene mutation analysis is recommend for individuals at risk (Table 2)
 . In addition, patients with established or suspected MEN-1 syndrome should be clinically
monitored with certain guidelines (Table 3)
Table 2. Criteria for Mutation Analysis of MEN1
- Diagnosis of three of five major MEN-1- associated lesions
- First degree family members of MEN-1 patients with a confirmed MEN1 germline mutation, family members of clinical MEN-1 patients without an identified germline mutation or who declined mutation analysis
- First degree family members of asymptomatic MEN1 germline mutation carriers
- Suspected MEN-1 patients:
2/5 major MEN-I tumors
>2 MEN-1-associated tumors within one organ
MEN-1-associated lesion at a young age (<35 years)
Table 3. Recommended Periodical Clinical Monitoring of MEN-1
- MEN-1 patients
- MEN-1 gene germline mutation carriers
- Suspected MEN-1 patients without a confirmed mutation
From the age of 5 - Biannual clinical examination
Laboratory investigation (calcium, chloride, phosphate, parathyroid hormone, glucose, insulin, c-peptide, glucagon, gastrin, pancreatic polypeptide, prolactin, IGF-I, serotonin and chromogranin A)
From the age of 15 - Once every two years
MRI of the upper abdomen, pituitary, and mediastinum in males (prophylactic thymectomy?)
- Thymic carcinoid is not benign (on the
- Atypical features provide diagnostic clues
- Additional work up is necessary to ensure an
accurate clinical and pathologic diagnosis
- A personal or family history of
endocrine/neuroendocrine tumors or multiple endocrine tumors in one organ should elevate the threshold
for consideration of MEN-1
In conclusion, in current pathology practice, it is the responsibility of the pathologist to provide
recommendations based upon specific pathologic findings. This is a matter of practical necessity to
facilitate multi-disciplinary clinical management of the disease and optimize outcome.
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