Bone Agent Avidity of Medullary Thyroid Carcinoma Liver Metastasis

Amitabha Banerjee, M.D.

Barbara J. McNeil, M.D.

January 5, 1988

Case Presentation:

A 64 year-old male presented in 1980 with thyroid enlargement and normal thyroid function tests. He was diagnosed to have multinodular goiter. The patient was subsequently lost to follow-up until October 1986, presenting with frequent diarrhea and flushing. An upper GI series and barium enema were normal. Two months later he had fractures of the 5th and 6th ribs. In April 1987 the patient presented with a left neck mass. Past history was unremarkable except for bilateral cataracts. The family history is obscure because the patient became an orphan at age twelve.

On physical exam, he had a 7.8 cm x 7.5 cm left neck mass arising from the thyroid deviating the trachea to the right. His lab data showed a RAI uptake of 15%, elevated serum calcium at 11.6g/dl, parathormone level at 131U/dl, elevated urine calcium at 134 per 24 hours, markedly elevated calcitonin at 81, 750U/dl, and elevated CEA levels. A CT scan showed liver and possibly lung metastasis. A CT scan of the neck demonstrated the mass to arise from the thyroid, showing necrosis centrally with calcification. The mass extended into the thorax. The thyroid scintigram showed a cold nodule in the left lobe of the thyroid. A needle biopsy was positive for medullary carcinoma.

He subsequently began chemotherapy. Palliative debulking of the tumor was performed for his intractable diarrhea and bone pain. He continued to have diarrhea and has radiographic and scintigraphic evidence of bony metastasis. Interestingly the bone scan did not reflect the degree of osteolytic metastasis present on CT and plain films.

Findings:

A Tc-99m MDP bone scintigram showed several regions of increase uptake over the region of the liver. A Tc-99m sulfur colloid liver-spleen scintigram and CT scan show multiple focal defects.

Discussion

Extraosseous accumulation of bone imaging agents has been reported in the literature. Factors such as bone-blood flow, enzyme activity (especially alkaline phosphatase), and active bone mineralization of hydroxyapatite crystals play a part in radionuclide accumulation (2). Normally, many lesions of bones have higher concentrations of amorphous calcium phosphate which has a greater affinity to bone imaging agents, particularly Tc-99m MDP. This is due to the greater surface area of the matrix which facilitates adsorption of the bone agent (9). Specifically, the -OH radicals on the phosphonate group are responsible for this matrix affinity. Mechanisms for extraosseous uptake of bone agent are not well defined, but include the following possibilities: tumor, necrosis, altered cellular calcium metabolism, altered blood flow (controversial because of its non-specificity), abnormal capillary permeability, high concentration of phosphatase enzymes, and ion exchange at the surface of macroscopic calcifications (10). Another suggested mechanism is disruption of the cell membrane with deposition of bone agent on calcium already fixed to mitochondria (10).

Various hepatic neoplasms have demonstrated Tc-99m phosphate uptake. These include hepatoblastoma (calcified osteoid) (1), hemangioendothelioma (increased blood pooling) (3), lymphoma (calcium mobilizing factor and active sequestration may or may not be present; not related to serum calcium) (2), hepatoma (blood flow) (7). Other tumors for which no explanation can be found include: cholangiocarcinoma, metastasis from breast, melanoma, esophageal squamous cell carcinoma (2).

In general, other causes of liver activity on bone scan include faulty radiopharmaceutical preparation from aluminum breakthrough, recent (within 24 hours) liver sulfur colloid scan, massive hepatic necrosis, and amyloid (2,6).

To understand which mechanism is responsible for uptake in medullary thyroid carcinoma one needs to explore the subject further. This type of carcinoma arises from the neoplastic transformation of the C-cells of the thyroid. These cells are derived from the neural crest embryologically rather than the foregut endoderm as is the remainder of the thyroid. The tumor affects the upper third of the lateral lobe of the thyroid since this is where most of the C-cells are concentrated. Medullary carcinoma accounts for 10% of thyroid neoplasms. It occurs sporadically in 80-90% and is familial in 10-20% of cases. The familial type is transmitted as autosomal dominant and is associated with the MEN II or MEN III syndrome.

Thyroid function tests are usually normal. Radiographs may show dense irregular calcification. Metastasis occur to the cervical and mediastinal nodes, soft tissue, lung, liver, trachea, adrenals, esophagus, and bone. Numerous hormones are produced by this neoplasm and these include calcitonin, ketocalcin, L-Dopa decarboxylase, carcinoembryonic antigen, serotonin, prostaglandins, ACTH, histaminase and substance p. It should be noted that the first four hormones are also secreted by normal C cells. Elevated calcitonin is related to the secreted diarrhea which occurs in 30% of cases. This particular hormone is the only sensitive indicator for the presence of tumor because it is the only one showing response to provocative or suppressive stimuli. Elevated histaminase correlates well with metastasis (12).

In conclusion, liver uptake of bone imaging agents in medullary thyroid carcinoma metastasis has never been previously reported. Possible mechanisms for uptake might include adsorption on amorphous calcium since these tumors do calcify. Other unproved possibilities include relationship to calcitonin-calcium metabolism, active sequestration or related to secretion of one of the tumor hormones.

References:

1) Cory DA, et al. Uptake of technetium-99m MDP by hepatoblastoma. Eur J Nucl Med 1987; 12:546-547.

2) Romyn AM, et al. Visualization of metastatic liver disease on technetium-99m bone scintigraphy. Clin Nucl Med 1987; 12:264-267.

3) Noel, AW, et al. Scintigraphic findings in infantile hemangioendothelioma. l Clin Nucl Med 1986; 11:413-416.

4) Stone C K, Sisson JC. What causes uptake of technetium-99m menthylene diphosphonate by tumors? A case where tumor appeared to secrete a hypercalcemia-causing substance. J Nucl Med 1985; 26:250-253.

5) Shih, W-J, et al. Localization of Tc-99m HMDP in hepatic metastasis from colonic carcinoma. AJR 1986; 146:333-335.

6) Shih W-J, et al. Diffuse thoracoabdominal radioactivity seen in bone imaging. Clin Nucl Med 1986;4:254-258.

7) Shin-Hwa Y, et al. Sequential uptake patterns of technetium-99m pyrophosphate in hepatoma.

8) Hansen S, Stadalnik RC. GAMUT:Liver uptake of Tc-99m pyrophosphate. Seminars in Nuclear Medicine. 1982; XII 1:89-91.

9) Francis MD, et al. Comparative evaluation of three diphosphonates in vitro adsorption (c-14 labeled) and in vivo osteogenic uptake (Tc-99m complexed). J Nucl Med 1980; 21:1185-1189.

10) Richards AG. Metastatic calcification detected through scanning with Tc-99m Polyphosphate. J Nucl Med Vol 15, 11:1057-1060.

11) Chaudhuri TK, et al. Extraosseous non-calcified soft tissue uptake of Tc-99m polyphosphate. J Nucl Med Vol 15, 1974;1054-1056.

12) Wilson GD, Foster DW. Medullary carcinoma of the thyroid. Williams Textbook of Endocardinology P. W.B. Saunders 7th edition, 1985;1279-1282.

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J. Anthony Parker, MD PhD, jap@nucmed.bih.harvard.edu