Case 1 -
True Mixed Medullary-Follicular Derived Carcinoma
Jennifer L. Hunt
Massachusetts General Hospital
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This is a 55 year old female with a known history of MEN 2A. She had a total
thyroidectomy in 1976 for medullary carcinoma and bilateral adrenalectomy in 1977 for pheochromocytoma.
In 2007, she had a new swelling in her neck and an increased calcitonin level. At surgery, she was found
to have a 1.5 cm hard lymph node in the lower right jugular chain and a second node in the right central
compartment. The lymph node is shown in the histologic slide.
Pertinent Laboratory Data:
Elevated calcitonin level
Case 1 - Slide 1
The C-cells, or the parafollicular cells of the thyroid are derived embryologically
from the branchial pouch and are usually seen in the upper-outer areas of the thyroid gland. The c-cells
secrete calcitonin, which is a hormone that plays some role in calcium homeostasis, but the circumstances
where it modulates its effects are poorly understood
A painless thyroid nodule is the most
common presentation for both hereditary and sporadic cases of medullary thyroid carcinoma. Most affected
individuals are adults, although familial cases may present at a younger age. Cervical lymph node
metastases are present in up to 75% of cases at initial diagnosis
Distant metastases to
lung, bone or liver have been described at initial diagnosis in up to 15% of cases, or they can occur in
follow-up in up to 48% of cases . The 10-year overall survival rate for patients with medullary
carcinoma is between 50 and 75%, which is significantly lower than that for other well-differentiated
thyroid tumors, such as papillary and follicular carcinomas, which have survival rates of approximately
93 and 85% respectively
Tumor stage is currently considered the best predictor of prognosis,
but it does not completely predict survival
Other reported favorable factors are young age and
extensive cervical lymph node dissection at initial surgery . Distant metastasis is a more consistent
adverse prognostic indicator with up to 90% of patients dying within 5 years of presentation . A
tumor of the C-cells is always defined as a medullary carcinoma and there is no recognized benign
pre-malignant condition neoplasm (such as "C-cell adenoma"). Medullary carcinoma is composed of cells
with neuroendocrine differentiation. The tumor cells can have varying morphology, including spindled,
epithelioid, or plasmacytoid cell types. In most of tumors, amyloid will be detectable, either on an
H&E stain or using a congo red stain. Nearly all MTCs secrete calcitonin (>95%) and
carcinoembryonic antigen (CEA, nearly 100%), both of which are features that are used diagnostically with
immunohistochemical staining .
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
demonstrates very unusual morphologic findings of both a component of more typical medullary carcinoma
and a component of papillary carcinoma, within the metastatic focus in the cervical lymph nodes. The
tumor components are intimately mixed within the node. At the immunohistochemical staining level, the
follicular derived component stains positive for thyroglobulin and the medullary carcinoma component
stains for calcitonin and CEA. The primary medullary carcinoma from this patient was not available for
review or comparison.
- Collision tumor: Papillary carcinoma and medullary carcinoma, co-existing
and metastasizing simultaneously, but as separate lesions
- True mixed medullary-follicular derived carcinoma
True mixed medullary-follicular derived carcinoma
This case represents a rare case of a mixed medullary-follicular derived lesion, as
evidenced by the metastasis that contains well defined, but intimately ademixed components of both
papillary carcinoma and medullary carcinoma. Immunohistochemistry supported this diagnosis, by
demonstrating both thyroglobulin positivity and calcitonin positivity in the metastatic foci.
Review of the Literature/Treatment Options:
Rare medullary carcinomas have been
reported with mixed morphology, including medullary carcinoma components and follicular-derived
components (either follicular or papillary lesions)
on these tumors includes well-defined mixed tumors (those that have medullary carcinoma with calcitonin
expression and follicular derived tumor components with thyroglobulin expression) and then a host of
other medullary carcinomas with unusual growth patterns (follicular and papillary) but no evidence of
follicular differentiation. Furthermore, because medullary carcinomas are invasive tumors, the edges of
typical tumors can demonstrate neuroendocrine tumor cells overtaking and surrounding normal follicular
structures. And, since thyroglobulin can be leaky in the thyroid gland, reliance on thyroglobulin
positivity alone, particularly at the edges of lesions, should also be avoided. In general, strict
criteria ought to be applied for defining mixed tumors, with inclusion of only those tumors with
immunohistochemical or molecular evidence of divergent differentiation (preferably away from the edges of
the tumor or in metastatic foci) . Histologically, mixed medullary-follicular tumors have
morphologic evidence of these two components, either intimately admixed or in separate areas . When
metastases are present, they also can be mixed. The follicular derived component can have follicular,
tubular, or solid growth or it can demonstrate papillary growth with papillary carcinoma nuclear features
The amount of each component is highly variable from tumor to tumor. It remains unclear
whether these tumors are truly mixed, and the tumor components are arising from a common progenitor cell,
or whether they represent collision tumors  The molecular genetic events in medullary carcinoma are
dominated by the well-characterized mutations in the RET proto-oncogene, which were first isolated and
cloned in 1993 . Mutations are clustered in exons 10, 11, and 16 in hereditary cases. Somatic
mutations are also seen in sporadic tumors. Mixed medullary-follicular tumors have only been
occasionally studied at the molecular level. One study examined 12 cases with an analysis of clonality
(using loss of heterozygosity and X-inactivation studies) and RET mutational analysis . Their
results suggested that the follicular derived component, at least in some cases, was clonally different
from the medullary carcinoma component. Mixed medullary-papillary carcinomas have not been adequately
studied at the molecular level for the typical mutations associated with papillary carcinoma (RET/PTC
translocation and BRAF gene mutation). Because of lack of effective treatment for recurrence, an
aggressive approach at initial presentation, with near- total or total thyroidectomy and selective neck
dissection, is recommended for MTC . Patients are then followed with serum calcitonin and CEA to
detect early recurrent or metastatic disease. Unlike papillary and follicular carcinomas, which can be
treated with radioactive iodine therapy, no medical therapy has proven effective for recurrent or
metastatic MTC. The effectiveness of external radiotherapy and chemotherapy remains controversial; recent
reports suggest no cures and only partial responses in patients treated with adjuvant therapies
However, surgically unresectable lesions may be treated with palliative radiotherapy . Because so
few mixed medullary-follicular lesions have been described in the literature, the prognosis and treatment
options are not well understood. It does appear that the behavior is similar to other conventional, pure
medullary carcinoma, with a high metastatic and recurrence rate and relatively long-term poor prognosis,
as compared to well differentiated follicular derived carcinomas.
This is a rare case of mixed medullary-follicular derived (papillary) carcinoma of the
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