A 41-year-old male prisoner presented to the ENT clinic with a
four-month history of a 3.5 cm left neck mass, level 4-region, which was firm and non-tender. An FNA was
performed (Figures A,B,C).
Case 6 - Figure A - Hypercellular aspirate. Neoplastic cells arranged in an organoid pattern (Papanicolaou stain, low power).
Case 6 - Figure B - Aspirate shows loosely-cohesive cluster of neoplastic epithelial cells with Moderately abundant cytoplasm, finely granular chromatin, and round to ovoid nuclear shapes(Papanicolaou stain, high power).
Case 6 - Figure C - Neoplastic epithelial cells in a dispersed-cell pattern. Notice plasmacytoid to spindle cell forms (Papanicolaou stain, high power).
Direct smears from the left neck mass stained with
Papanicolaou revealed hypercellular aspirates consisting of abnormal, monotonous, small to ovoid
epithelioid cells that arranged in an organoid distribution (Image B-1), in sheets, and in
loosely-cohesive clusters (Image B-2) occasionally associated with vascular septae. Focally, the
epithelioid cells presented in a dispersed-cell pattern and exhibited occasional plasmacytoid and spindle
shapes (Image B-3). The nuclear chromatin was finely granular. Cytoplasm was delicate and moderate to
abundant. Rare pleomorphic nuclei, nuclear pseudoinclusions, and mitoses were noted. No background
material –other than blood- was identified. Immunocytochemical stains were performed on smears and
Cytospin ™ preparations, as follows: the abnormal cells were strongly immunoreactive with cytokeratin
(AE1/3) and calcitonin, focally reactive with chromogranin and synaptophysin, and non-reactive with
smooth muscle actin and desmin immunostains.
Histology and Clinical Follow-up
Total thyroidectomy with excision of seven (7) left cervical lymph nodes was performed a month after
the FNA. The larger excised lymph node measured 5.0 x 3.7 x 2.1 cm. On gross examination the left
thyroid lobe exhibited a 0.5 x 0.4 cm white, firm nodule. Histologic examination revealed medullary
carcinoma extending focally to the thyroid capsule. Main tumor nodule was on left lobe, although a
microscopic focus of tumor was identified on the right. The largest excised cervical lymph node was
entirely replaced by metastatic medullary carcinoma and 5 of 6 remaining cervical lymph nodes showed
evidence of metastasis. Furthermore, in 3 of the lymph nodes having metastatic disease there was extra
capsular extension. Special histochemical and immunohistochemical stains for Congo red and calcitonin,
respectively, yielded positive results. DNA ploidy by flow cytometric analysis was performed on tumor
samples and revealed a diploid DNA stemline with a low S-phase fraction of 4.20%.
No other associated neoplasm indicative of multiple endocrine neoplasia
(MEN) syndrome was identified. Clinical follow-up consisted of periodical thyroid and whole body scans,
along with determination of serum calcitonin levels and computed tomography (CT) scan of suspicious
areas. The discovery on CT scan of a suspicious cervical lymph node a year after thyroidectomy prompted
radiation therapy. Follow-up was uneventful until 5 years later when serum calcitonin levels were found
to be markedly elevated suggesting the possibility of recurrence. Computed tomography scans of neck and
chest, with contrast, revealed left neck lymphadenopathy and numerous non-calcified pulmonary nodules in
both lungs, the largest in the lingula measuring 1.3 cm. The imaging findings were consistent with
metastases. Superficial FNA of an enlarged left neck lymph node and CT-guided FNA of a left pulmonary
nodule were performed and metastatic medullary carcinoma with strong reaction to calcitonin immunostain
was established cytologically on both specimens.
Left supraclavicular mass, FNA: metastatic medullary
Thyroid, total thyroidectomy with excision of cervical
lymph nodes: medullary thyroid carcinoma (left lobe, 0.7 cm with smaller focus of carcinoma on right
lobe) and metastases in 6 out of 7 excised lymph nodes.
Medullary thyroid carcinoma (MTC)
is a neuroendocrine malignancy
originating in the parafollicular C-cells of the thyroid. This cancer accounts for up to 10% of all
thyroid malignancies. Secretion of calcitonin is distinctive of all MTC. Elevation of this hormone in
serum in combination with a thyroid nodule is practically pathognomonic of MTC. Calcitonin is a tumor
marker and determination of its serum levels is useful in the clinical assessment of possible
recurrences. The great majority of MTCs occur sporadically and are not associated with other neoplasms.
A familial form inherited in an autosomal dominant pattern is seen in association with the multiple endocrine neoplasia (MEN) syndromes.
| Types of MTC & Frequency ||Age of Presentation ||Clinical Presentation ||Associated Multi-organ Syndrome|
|Sporadic(70-80%) ||36-51 years ||Solitary or bilateral (40%) thyroid nodule with or without cervical lymphadenopathy ||None|
|Familial MEN IIA |
Familial MEN IIB (III)
|15-20 years ||Multicentric thyroid nodules (bilateral) with or without cervical lymphadenopathy|| IIA:Adrenal Medullary hyperplasia or pheochromocytoma+ parathyroid hyperplasia or adenoma|
IIB:Adrenal Medullary hyperplasia or pheochromocytoma+ GI and ocular ganglioneuromas+ Skeletal abnormalities
The index patient presented with a left neck mass, which on FNA cytology revealed a hypercellular
pattern most indicative of metastatic malignancy. Relative monotony of the cells on aspirates with small
epithelioid, ovoid, spindle, and plasmacytoid cell shapes, along with a fine granular (salt and
pepper-type) chromatin suggested a neuroendocrine neoplasm. Although no thyroid or other neck mass was
palpated, MTC was a high consideration in the differential diagnosis of this likely metastasis. Special
immunochemical stains on aspirates, which included strong reaction with calcitonin immunostain, were
diagnostic of medullary thyroid carcinoma. The initial cytological diagnosis of MTC was further
confirmed on the thyroidectomy specimen. Bilateral involvement of the thyroid with metastases to
cervical lymph nodes was demonstrated on the excisional specimen. Absence of neoplasms arising at other
organs indicated sporadic –rather than familial- MTC. Additional FNA cytology of a cervical lymph node
and a pulmonary nodule, performed several years after diagnosis, revealed recurrent MTC with
cytomorphology identical to that at the initial presentation.
On aspirates of thyroid nodules the FNA cytology of MTC is usually diagnostic. The tumor is
characterized by different cell-types presenting singly or in any combination: round to oval, spindle, and plasmacytoid. Neoplastic
cells often show relative monotony with mild to moderate pleomorphism, including occasional bi or
multinucleated cells, or may display marked pleomorphism with bizarre cells mimicking anaplastic
carcinoma of the thyroid. Intranuclear inclusions are occasionally seen in aspirates from MTC. The
cytoplasm of MTC cells on Papanicolaou-stained smears is granular, while on Diff Quik stain presence of
metachromatic red granulation in the cytoplasm of tumor cells is not uncommon. Amyloid has been
identified in up to 80% of MTC on surgical specimens; however, on aspirates stained with Papanicolaou
amyloid may be impossible to distinguish from colloid. Performance of Congo red stain and demonstration
of "apple-green" birefringence is diagnostic. Immunohistochemically the cells of MTC are thyroglobulin
negative, but positive for calcitonin and for neuroendocrine markers (synaptophysin and chromogranin).
Worse prognosis has been reported for MTC with flow cytometry showing higher proportion of cells in S,
G1, and M phases.
Hurthle-cell neoplasms: aspirates of MTC displaying round, eccentric nuclei with abundant
granular cytoplasm can be misinterpreted as Hurthle-cell tumors. Presence of amyloid and/or stippled
nuclear chromatin is clue that suggests a neuroendocrine (MTC) neoplasm, which can be demonstrated with
special immunostains for neuroendocrine markers. Also, different from MTC Hurthle cell tumors are
thyroglobulin positive and calcitonin negative.
Anaplastic carcinoma: MTC presenting on aspirates with significant pleomorphism and markedly
bizarre and multinucleated neoplastic cells can be difficult to differentiate from anaplastic giant-cell
carcinoma. Given the unfavorable prognosis associated with anaplastic carcinoma versus a more indolent
course of MTC, it is essential to exclude MTC or other thyroid carcinoma before establishing a diagnosis
of anaplastic carcinoma. Presence of amyloid and/or stippled nuclear chromatin suggests MTC, which can
be higlighted with special immunostains for calcitonin and for neuroendocrine markers.
Hyperplastic colloid nodules: hypocellular aspirates of MTC containing abundant amyloid and
few neoplastic -otherwise minimally atypical cells- may lead to a false negative diagnosis of colloid
goiter or goitrous nodule. Amyloid often presents on aspirates as homogenous globules, as opposed to the
usual amorphous appearances of colloid. When in doubt it is always helpful to perform Congo red stain.
Papillary carcinoma: difficulties arise in MTC with cells displaying pseudopapillary arrays,
along with nuclear grooves and "inclusions". Presence of amyloid or stippled nuclear chromatin can
suggest neuroendocrine (MTC) neoplasm, which can be demonstrated with special immunostains for calcitonin
and for neuroendocrine markers.
Lymphoma: cases of MTC presenting on aspirates in a dispersed-cell pattern with
plasmacytoid-type cells can be quite difficult to differentiate from plasmacytoma, lymphoma, or from
lymphocytic thyroiditis. Presence of amyloid and granular nuclear chromatin pattern are clues that
suggest a neuroendocrine (MTC) neoplasm, which can be demonstrated with immunostains for calcitonin and
neuroendocrine markers (synaptophysin, chromogranin). Conversely, on immunostains lymphomas would
express a B or T-cell immunophenotype distinctive of a lymphoid malignancy.
The diagnostic difficulties encountered during evaluation of MTC on aspiration cytology of thyroid
nodules are dwarfed by the much wider range of diagnostic dilemmas posed when encountering a malignant
neoplasm such as MTC presenting as metastasis on a cervical lymph node or a pulmonary nodule. In these
circumstances the differential diagnosis needs to be more inclusive and consider other diagnostic
possibilities. For example a cervical lymph node can harbor granulomatous infections, lymphoma, or
metastases. Metastatic disease on cervical lymph nodes usually arises from head & neck cancer.
Cervical metastases from undifferentiated neoplasms such as squamous (basaloid) carcinoma and
esthesioneuroblastoma (olfactory neuroblastoma) can pose significant challenges to the pathologist and
their differentiation from cases of MTC presenting as a metastatic deposit in a lymph node can be
difficult. Only with a high index of suspicion can the pathologist establish the correct diagnosis.
- Rosai J, Carcangiu ML, DeLellis RA (eds). Atlas of Tumor Pathology. Tumors of the Thyroid Gland. Washington: The Armed Forces Institute of Pathology, 1992: 207- 239.
- DeMay RM. The Art & Science of Cytopathology. Chicago: ASCP Press, 1996: 735- 737.
- Green I, Ali SZ, Allen EA, Zakowski MF. A spectrum of cytomorphologic variations in medullary thyroid carcinoma. Cancer (Cancer Cytopathol) 1997;81:40-44.
- Collins BT, Cramer HM, Tabatowski K, Hearn S, Raminhos A, Lampe H. Fine needle aspiration of medullary carcinoma of the thyroid. Cytomorphology, immunocytochemistry and electron microscopy. Acta Cytol 1995;39:920-930.
- Kumar PV, Hodjati H, Monabati A, Talei A. Medullary thyroid carcinoma. Rare cytologic findings. Acta Cytol 2000;44:181-184.
- Galera-Davidson H. Diagnostic problems in thyroid FNAs. Diagn Cytopathol 1997;17:422-428.