Thyroid >

Medullary Carcinoma

Definition

Thyroid malignancy with C (parafollicular) cell differentiation.

Clinical Features

  • Two forms:
    • sporadic (approximately 80% of cases)
    • familial

Familial Medullary Carcinoma

  • Autosomal dominant inheritance with virtually complete penetrance.
  • Becomes clinically apparent at mean age 35 years
  • Most cases in children are familial medullary carcinoma
  • Often multiple and bilateral

Metastases

  • Cervical and mediastinal lymph nodes
  • Distant organs, particularly lung, liver, and skeletal system6
  • More common with sporadic and multiple endocrine neoplasia (MEN)-IIB than MEN-IIA7
  • May be the first manifestation and a source of confusion to the pathologist8

Gross Pathology

  • Typically:
    • solid
    • firm
    • nonencapsulated
    • relatively well circumscribed
    • in the midportion or upper half of the gland, corresponding to a greater concentration of C cells in this region
  • Gray to yellowish cut surface (Fig. 1
    Medullary carcinoma. Gross appearance of the tumor. Note its unencapsulated quality, solid appearance, and yellowish tan color.

    Fig. 1: Medullary carcinoma. Gross appearance of the tumor. Note its unencapsulated quality, solid appearance, and yellowish tan color.

    )
  • Exceptionally, enveloped by a continuous fibrous capsule

Histopathology

  • Classically:
    • solid proliferation of round to polygonal cells with:
      • granular amphophilic cytoplasm
      • medium-sized nuclei
    • highly vascular stroma
    • hyalinized collagen
    • amyloid9 (Fig. 2
      Medullary carcinoma. Low-power microscopic view showing solid pattern of growth and deposition of amyloid.

      Fig. 2: Medullary carcinoma. Low-power microscopic view showing solid pattern of growth and deposition of amyloid.

      )
    • coarse calcification
      • can be prominent enough to be detected radiographically
  • Many cytoarchitectural variations
  • Pattern of growth can be:
    • carcinoid-like,
    • paraganglioma-like
    • trabecular
    • glandular (tubular and follicular)
    • pseudopapillary10–13 (Fig. 3
      Medullary carcinoma with pseudopapillary pattern of growth resulting from lack of cohesiveness of tumor cells.

      Fig. 3: Medullary carcinoma with pseudopapillary pattern of growth resulting from lack of cohesiveness of tumor cells.

      )
  • Stroma may be:
    • scanty
    • hemorrhagic
    • ossified
    • edematous.
  • Amyloid deposition may be:
    • widespread
    • limited to small psammomatoid concretions
    • absent
    • elicit a florid foreign body-type giant cell reaction
  • True psammoma bodies may be present
  • A heavy neutrophilic infiltrate is occasionally seen (so-called ‘inflammatory type’)
  • Tumor cells may be:
    • plasmacytoid (because of nuclear peripheralization)
    • spindle shaped
    • oncocytic
    • squamoid
    • squamous
    • bizarre (‘anaplastic’ or ‘giant cell’ type, not to be equated with undifferentiated carcinoma)14,15
  • Unusual varieties include:
    • a true papillary form16
    • a type exhibiting mucinous features (mucinous or amphicrine medullary carcinoma)17
    • a clear cell variant18
    • a small-cell type resembling the homonymous lung tumor
    • another small-cell type with features resembling neuroblastoma19
    • a pigmented (melanin-producing) variant20,21
  • Fine-needle aspiration preparations characteristically show:
  • Ultrastructurally:
    • cytoplasmic dense-core secretory granules are seen
      • variability in their size suggests the existence of multiple endocrine cell types in this tumor24
      • usually argyrophilic with the Grimelius stain, especially if the tissue has been fixed in Bouin's fluid25
      • mucin stains are often positive.26
    • the amyloid has a typical microfibrillary appearance (Fig. 5
      Portions of two cells from medullary carcinoma of thyroid gland showing multiple dense secretory granules in the cytoplasm. Each granule is surrounded by a single membrane, and the dense central portion is separated from it by a clear zone. Inset shows both oriented and randomly placed amyloid filaments that may be contrasted with larger banded collagen fibers. (Courtesy of Dr. J.S. Meyer, St Louis)

      Fig. 5: Portions of two cells from medullary carcinoma of thyroid gland showing multiple dense secretory granules in the cytoplasm. Each granule is surrounded by a single membrane, and the dense central portion is separated from it by a clear zone. Inset shows both oriented and randomly placed amyloid filaments that may be contrasted with larger banded collagen fibers. (Courtesy of Dr. J.S. Meyer, St Louis)

      )

C-cell Hyperplasia

  • Familial form is invariably accompanied by C-cell hyperplasia in the residual gland
  • C-cell hyperplasia is:
    • the precursor lesion of all familial syndromes
    • preneoplastic
    • typically located in the central part of the lateral lobes
    • may be diffuse or nodular
    • may be seen in an interfollicular or intrafollicular location
    • indicated by an arbitrary figure of more than six cells per thyroid follicle27
    • extremely difficult to establish based on cell count
  • It is probably wise to regard the nodular form as the only definite precursor for the hereditary type of medullary carcinoma
  • Usually, hyperplastic C cells are more immunoreactive for:
    • CEA than normal C cells
    • calcitonin than medullary carcinoma

Metastases

  • Microscopically, tend to resemble the primary tumor
  • Usually contain amyloid
  • Immunohistochemical reactivity tends to resemble that of the primary tumor though discrepancies occur28

Special Stains and Immunohistochemistry

Name+/-% positiveReferences
Calcitonin+951 reference
CEA++1001 reference
Chromogranin+1001 reference
Keratin AE 1/3+1001 reference
TTF-1+901 reference
Thyroglobulin+51 reference

Diagnosis

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Medullary Carcinoma

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C-cell Hyperplasia

  • Early medullary carcinoma (microcarcinoma) is recognized by:
    • the nesting expansile pattern
    • destruction of the follicular basement membrane
    • diminished intensity of calcitonin immunostaining60
  • Patients with thyroid C-cell hyperplasia have elevated serum:
    • calcitonin
    • CEA61
  • Patients with medullary carcinoma also have elevated chromogranin A62

Medullary Adenoma

  • Exceptionally, medullary carcinoma is enveloped by a continuous fibrous capsule
    • this is an encapsulated medullary carcinoma and not medullary adenoma

Hyalinizing Trabecular Carcinoma

  • Must be differentiated from encapsulated medullary carcinoma63

Oncocytic Neoplasms Of Follicular Cell Derivation

  • The oncocytic variety of medullary carcinoma has a microscopic resemblance to oncocytic (Hürthle cell) neoplasms of follicular cell derivation64 (Fig. 9
    Medullary carcinoma of oncocytic type. The appearance closely simulates that of Hürthle cell carcinoma. Clues to the diagnosis are represented by the amphophilic (rather than eosinophilic) staining quality of the cytoplasm and the prominent fibrous septation. This tumor was strongly immunoreactive for calcitonin.

    Fig. 9: Medullary carcinoma of oncocytic type. The appearance closely simulates that of Hürthle cell carcinoma. Clues to the diagnosis are represented by the amphophilic (rather than eosinophilic) staining quality of the cytoplasm and the prominent fibrous septation. This tumor was strongly immunoreactive for calcitonin.

    )
  • Medullary carcinoma should be suspected if:
    • the oncocytic cells are amphophilic rather than brightly eosinophilic
    • the tumor is divided into nests by sharply outlined fibrous bands

Mixed Medullary-Follicular Carcinoma

  • A controversial entity
  • Morphologic features of medullary carcinoma (immunoreactive for calcitonin) coexisting with those of a follicular neoplasm (with immunoreactivity for thyroglobulin)65,66
  • Some cases have been familial67
  • There is evidence to validate the existence of this entity,68 with the observation that the two components are not derived from a single progenitor cell69
  • Most cases considered are in fact:
    • medullary carcinomas with entrapped follicles and/or secondary incorporation of thyroglobulin by carcinoma cells
    • medullary carcinomas with a glandular (tubular and follicular) pattern of growth

Mixed Medullary-Papillary Carcinoma

Paraganglioma

  • Can occur adjacent to or within the thyroid
  • Sometimes in association with carotid body tumor75,76
  • Differential diagnosis from medullary carcinoma can be difficult (Fig. 10
    Thyroid paraganglioma showing well-formed ‘Zellballen’.

    Fig. 10: Thyroid paraganglioma showing well-formed ‘Zellballen’.

    )
  • Reacts immunohistochemically for pan-endocrine markers such as chromogranin and opioid peptides
  • Negative for calcitonin, thyroglobulin, TTF-1, and keratin
  • A useful (but not constant) feature is the presence of S-100 protein-positive sustentacular cells at the periphery of the Zellballen77 (Fig. 11
    S100 protein-positive sustentacular cells at the periphery of the Zellballen in paraganglioma of thyroid.

    Fig. 11: S100 protein-positive sustentacular cells at the periphery of the Zellballen in paraganglioma of thyroid.

    )
  • All but one of the reported cases have been cured by surgical excision78

Small Cell (Neuroendocrine) Carcinoma in the Thyroid

  • Morphologically identical to the homonymous lung tumor
  • Some are calcitonin positive and are therefore regarded as small cell variants of medullary carcinoma
  • Those that are calcitonin negative probably represent the most undifferentiated members of the spectrum and their behavior is extremely aggressive79

Metastatic Neuroendocrine Tumors Of Various Types

  • Can metastasize to the thyroid and simulate a medullary carcinoma80

Genetics

TypeNameComment
geneRETSomatic or germ line mutation
syndromeMEN2Subtypes: MEN 2A, MEN 2B and familial medullary syndrome
chromosome10q11.2Chromosomal location of RET is 10q11.2

Sporadic Medullary Carcinoma

  • RET mutations have been detected, particularly at codon 91881
  • In contrast to familial and MEN-related cases, these mutations are somatic (i.e. found only in the tumor cells)

References

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Last updated: 29 Oct 2005

Medullary Carcinoma

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