MEDULLARY THYROID CANCER

• Medullary thyroid carcinoma (MTC) constitutes 6% to 8% of thyroid cancers.

• It represents a malignant transformation of the neuroectodermally derived parafollicular C cells

• S. Calcitonin is the most specific circulating and immunohistochemical (IHC) marker.

• MTC does not concentrate RI and therefore has no role in its management

• Surgery is the mainstay of management of these cancers

Types
• 75-80%- sporadic
• 20-25%- familial

Clinical differences between sporadic and familial MTCs

Presentation:
• Painless thyroid swelling or nodule (STN)
• Lymph node metastasis - 50% - 75% at presentation.
• Signs of local infiltration i.e. dyspnoea, dysphagia, and hoarsness may be present.
• Distant metastasis 10%-15% at presentation (lung, liver, bone)
• Rarely patients may present with symptoms of ectopic hormone production such as diarrhea, facial flushing and Cushings syndrome.

Principles of Management

1) Detection
• Fine needle aspiration cytology/biopsy with IHC for calcitonin if necessary
• Serum calcitonin – Most specific marker
                            – increased in all cases of clinically palpable MTC.

2) Staging
• Chest Xray.
• Imaging
       – Ultrasonography/ CT scan of the neck – To assess the extent of cervical disease.
       – CT scan of the mediastinum and abdomen – To assess the extent of mediastinal lymphadenopathy, pulmonary metastasis, liver metastasis and the adrenal glands.
• Laparoscopy – More sensitive in detecting liver metastasis than routine imaging, however not recommended as routine

3) Evaluation of heritable disease
• Genetic screening
            – All patients should ideally undergo screening for RET proto oncogene mutations
            – Approximately 5-10% of patients with a negative family history have germline mutations
• Screening for pheochromocytoma

4) Other Investigations
• S. Calcium
• X ray neck if large goiter
• Indirect laryngoscopy

Staging TNM UICC 2005

Primary tumour T

Tx- Primary tumour cannot be assessed
T0- No evidence of primary tumour

All histological types except undifferentiated carcinoma
T1- Tumour 2 cm or less in largest dimension, limited to the thyroid
T2- Tumour more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid
T3- Tumour more than 4 cm in greatest dimension, limited to the thyroid or any tumour with minimal extrathyroidal extension (e.g.: extension into sternothyroid muscle or perithyroid soft tissues)
T4a- Tumour extends beyond the thyroid capsule and invades any of the following, subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve.
T4b- Tumour invades prevertebral fascia, mediastinal vessels or encases the carotid artery.

Regional Nodes- N
Nx- Regional lymph nodes cannot be assessed.
N0- No regional lymph node metastases
N1a- Metastasis in Level VI (pretracheal, paratracheal, including prelaryngeal and Delphian lymph node)
N1b- Metastasis in other unilateral, bilateral, or contralateral cervical or upper/superior mediastinal lymph nodes

Distant Metastasis M
Mx- distant metastasis cannot be assessed
M0- No distant metastasis
M1- Distant metastasis

Medullary carcinoma

TREATMENT

Role of EBRT in MTCs

Indications
• Unresectable tumours
• Microscopic or macroscopic residual disease
• High risk patients (older age, ETS or lymph node metastasis)
• T4 tumours
• Recurrent disease in the neck not amenable to surgery
• Palliation of recurrent or metastatic disease in bone, cerebrum, spine and other areas

Familial MTCs (FMTC)
Familial Medullary Thyroid Carcinomas constitute 16 to 20% of medullary thyroid carcinomas (MTC). There are 4 types of Familial MTC.

• MEN II A
• MEN II B
• Non MEN FMTC
• Other FMTC

MEN II A:
MEN II A has 3 components
• MTC
• Pheochromocytoma (40-60% lifetime incidence)
• Hyperparathyroidism (10-20% incidence)

Three types of MEN II A are described
MEN II A (1): MTC + Pheochromocytoma + Hyperparathyoidism
MEN II A (2): MTC + Pheochromocytoma
MEN II A (3): MTC + Hyperparathyoidism (rare)

MEN II B:
MEN II B has 4 components
• MTC
• Pheochromocytoma
• Multiple mucosal ganglioneuromatosis (Lips, tongue, eye lids etc)
• Marphanoid features (long extremities, hyper flexible joints and epiphyseal abnormalities)

Non MEN FMTC:
Four or more patients in a family, without other features of MEN II.

Other Non MEN FMTC:
Two or 3 patients in a family, without other features of MEN II.

Indications for investigations for Familial MTC:
Younger age group (less than 30 years)
Bilateral / Multi-focal disease
Family history of MTC and / or other features of MEN II
Clinical features of MEN II

Investigations in suspected c/o FMTC
For pheochromocytoma
Urinary Catacholamines (Epinephrine, norepinephrine & dopamine)
24 hr Urinary Vanillyl Mandelic Acid (VMA)
USG abdomen
I131 MIBG scan if above are doubtful.

For hyperparathyroidism
Serum calcium / phosphates
Serum PTH

RET Proto-oncogene
MEN IIA, MEN IIB and FMTC are autosomal dominant disorders. RET proto-oncogene is located on long arm of chromosome 10, band q11.2. Germline mutations in RET proto-oncogene are associated with Familial MTCs.

Table shows various mutations seen in MTC.

Mutations in RET proto-oncogene are studied by PCR (polymerase chain reaction) on blood samples. Specific mutations are investigated with Restriction endonuclease analysis. Ideally, all patients of MTC (sporadic and familial) should be investigated for mutations in RET proto-oncogene.

*10- 25% of these patients have hyperparathyroidism in the MEN II B syndrome, making a case in point for parathyroid autotransplantation in the forearm at the time of total thyroidectomy.

MANAGEMENT OF FAMILIAL MTC

Role of Prophylactic total thyroidectomy

• Prophylactic total thyroidectomy is advocated in all patients with germline mutations in RET proto-oncogene.
• Controversy exists regarding the age of prophylactic thyroidectomy. In MEN IIB, it should be done as early as possible. In MEN IIA and Non MEN FMTC, some advocate surgery between 5 to 10 years while others advocate early surgery.
• In MEN IIA, if early thyroidectomy is not done, patients should be monitored with periodic serum calcitonin + pentagastrin stimulated calcitonin levels. Any rise in calcitonin warrants total thyroidectomy.