Chem.-Biol. Interactions, 30 (1980) 305--308 305 © Elsevier/North-Holland Scientific Publishers Ltd.

DEVELOPMENT OF A PAPILLARY THYROID CARCINOMA IN A PATIENT WHILE ON HIGH DOSAGE ASCORBIC ACID THERAPY

A. CAMPBELL Department of Medicine, Hairmyres Hospital, East Kilbride (Scotland)

(Received November 13th, 1979) (Accepted February 28th, 1980)

SUMMARY

A case of reticulum cell sarcoma apparently successfully treated with mega ascorbic acid therapy is described briefly. While the patient continued a large maintenance dose of ascorbic acid, a papillary thyroid carcinoma developed clinically. The role of ascorbic acid in the body resistance to cancer and in turnout prevention is discussed.

INTRODUCTION

Cameron et al. [ 1 ] in their comprehensive review of the present position of ascorbic acid in the management of cancer stress, not only its importance in enhancing body resistance to turnout growth and tissue invasion, but also its potential role in turnout prevention. Furthermore, the reported anti- viral activity of ascorbic acid [2] may be important in the prevention of viral induced turnouts.

This article describes the clinical development of a papillary thyroid car- cinoma after successful t rea tment of a reticulum cell sarcoma with mega ascorbic acid therapy and while the patient continued to take a large main- tenance dose of ascorbic acid.

In 1975, Cameron et al. [3] described the case of a 42-year~ld t ruck driver who had been successfully treated for a widespread reticulum cell sarcoma with mega dosage ascorbic acid. Briefly, his first symptoms were noted in July, 1973 and consisted of progressive loss of weight and night sweats. By mid-October he had developed large rubbery lymph glands in the neck and right axilla, with hepato-splenomegaly and radiological evi- dence of hilar adenitis, mediastinal widening and a right pleura] effusion. While awaiting admission to an Oncology Unit, he was started on ascorbic acid, 10 g intravenously per day, with dramatic effect. In a few days there was rapid disappearance of lymph glands and hepato-splenomegaly and a slower resolution of the radiological abnormalities. In January, 1974, he

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was fit in all respects; there was no clinical or radiological evidence of disease. From late January onwards his ascorbic acid was gradually reduced and finally s topped in mid-February. Four weeks later symptoms of lassi- tude and cough returned, with radiological evidence of recurrence. Ascorbic acid was again started with resulting less dramatic, but nevertheless complete, remission. By November, 1974, he was in complete clinical remission and has continued in this state, taking 12.5 g of ascorbic acid orally per day.

In June 1976, he complained of some hoarseness and oto-laryngeal exami- nation showed only catarrhal changes in the vocal cords. By September 1976, a small centrally placed thyroid nodule, about 20 mm diameter, had developed. This was smooth, firm, mobile and non-tender. Removal was carried out in early October 1976, by Mr. D. Miller, Consultant Surgeon. Subsequent histology by Dr. James McKay, Consultant Pathologist, showed the presence of a low grade papillary carcinoma with typical calcospheroles. There was no evidence of lymph gland involvement.

In consultation with Dr. Keith Halnan, Director of the Glasgow Institute of Radiotherapeutics and Oncology, it was decided, in view of the possi- bility of latent metastases, that thyroid ablation with radioactive iodine should be carried out. Repeated doses were given: 80 mCi of Iodine 131 in March 1977, 200 in June 1977 and 200 in January 1978. TRI Iodothyronine (20 mg four times a day) was commenced in June 1977 and during this therapy he continued to take ascorbic acid.

At present, he continues in active employment as a t ruck driver. He is well and has no evidence, clinically or radiologically, of malignant disease. Haemo- globin 15.1 g/l; white cells 4.4; e ry throcyte sedimentation rate 9. Electrolyte biochemical profile normal, including a seromucoid level of 135 gmol/1. Thyroxin level 2 #g/l; t r i iodothronine 4.4 ~g/1. Electrophoresis showed slight diffuse increase in ~- and ~/-globulins, with reduction in the Alpha-2 fraction. IgG 14 g/l; IgA 3 g/l; the IgM at 5.5 g/1 was significantly raised. The plasma ascorbate was 1.9 mg/100 ml and the leucocyte ascorbic was 50.5 pg/10 s white blood cells.

DISCUSSION

The observations of Cameron and Campbell [4] , that some cases of advanced malignancy appeared to benefi t symptomatical ly, and occasionally objectively, while taking daily amounts of ascorbic acid in dosage of 10--20 g, was an encouraging finding. Moreover, Cameron and Pauling [5] have pro- duced evidence based on a retrospective s tudy that supplemental ascorbic therapy tends to prolong survival times in terminal cancer cases. Although Campbell and Jack [6] described three cases in which acute and potentially dangerous symptoms occurred early on in ascorbic acid treatment, in general, apart from mild gastro-intestinal disturbance, mega ascorbic acid therapy presents few side effects.

Papillary carcinoma is the commones t variant of thyroid cancer, consti- tuting from 50--60% of all thyroid neoplasms [7] . It has a wide age distri-

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bution -- from less than ten years to more than eighty years; its most fre- quent distribution lies between the third and fifth decades, with a female to male ratio of 3 : 1. It is characteristically slow growing, and before clinically obvious may have been present for years. Although irradiation to the thymic or cervical region in infancy is etiologically significant in childhood and ado- lescence [ 8] , there is no history in this case of such irradiation at any time.

The anti- tumour effect of ascorbic acid may be related to more than one action. Depolymerizat ion of matrix in the immediate proximity of prolifera- ting invasive malignant cells is a striking feature, as pointed ou t by Cameron (1966). This action appears to be brought abou t by the action of glycosidases and neutral proteases, probably released from cellular lysomes during cell division. It has been suggested by Cameron and Pauling [9] that ascorbic acid plays an important role in limiting their activity, tending to protect pre- existing collagen barriers and improving focal tissue resistance to the erosive action of the neoplastic cell.

There is fairly general acceptance that host resistance to cancer depends to some extent on immune system activity. Horrobin et al. [10] have stressed the key role of ascorbic acid in converting Dihomo Gamma Linolenic Acid (DGLA) to prostaglandin El , the latter substance enhancing T lymphocyte activity through its action on thymus T cells.

In the case described above, the initial response of the reticulum cell sarcoma was so rapid that it suggested either (a) a cy to toxic reaction in a very sensitive turnout or (b) a very rapidly established and powerful immune reaction. Could this have been mediated by ascorbic acid through the DGLA- prostaglandin E1 thymus pathway? [ 11 ].

Why, therefore, did the thyroid carcinoma continue to develop while the patient was taking ascorbic acid in a dosage similar to that which brought about the apparent cure of a widespread reticulosis? There is no reason to believe that the patient at any time failed to take his therapy regularly. In fact, it is probable that his raised IgM, reported in August, 1979, was the result of this continuous ascorbic acid therapy [12] , since clinically he was not suffering from any infective process and his W.B.C. and E.S.R. were normal. The explanation may lie in the fact that papillary carcinoma, being such a slow growing turnout, is minimally invasive and poorly antigenic. Ashley [13] stresses 'the morphological difficulty or impossibility in many cases of distinguishing a benign papillary tumour of the thyroid from a malignant one'. Cameron et al. [1] have advanced the idea that while all dividing cells by cell membrane change elicit a feeble 'not self' sequence as part of the homeostasis of the body, this would be normally too weak to elicit a recognisable antigenic response. Only if a very large number of similar clonal cells were dividing, as, for example, in a rapidly-growing cancer, would an antigenic response of any significance be elicited and call into activity immuno-competence and focal resistance mechanisms in which ascorbic acid plays an important and essential part.

Stone [ 14] reviewed the evidence that most animals are able to produce several grammes of ascorbic acid per 70 kg body weight per day and, of

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course, in this they differ from man, who is unable to synthesise the ascorbic acid. Animals have no immunity to cancer, in spite of their ability to pro- duce endogenous ascorbic acid. If, therefore, ascorbic acid has any role in the prevention of the development of turnouts in man, the dose would presumably have to be very large and taken on a regular basis. The failure of ascorbic acid to prevent the growth of a papillary carcinoma in this case should not , however, discourage further examination of its possible preven- tative action.

ACKNOWLEDGEMENTS

I wish to acknowledge financial support obtained from the National Foundat ion for Cancer Research (U.S.A.}; also, a grant from the Research Fund, Area Health Board, Lanarkshire to Mrs. L. Currie, Research Assistant.

REFERENCES

1 E. Cameron, L. Pauling and B. Leibovitz, Ascorbic acid and cancer: a review, Cancer Res., 39 (1979) 663.

2 F. Morishiga and A. Murata, Vitamin C for prophylaxis of viral hepatitis B in trans- fused patients, J. Int. Acad. Prey. Med., (1978) in press.

3 E. Cameron, A. Campbell and T. Jack, The orthomolecular t reatment of cancer. III. Reticulum cell sarcoma: double complete regression induced by high-dose ascorhic acid therapy, Chem.-Biol. Interact., 11 (1975) 387.

4 E. Cameron and A. Campbell, The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplement in advanced human cancer, Chem.-Biol. Interact., 9 (1974) 285.

5 E. Cameron and L. Pauling, Supplemental ascorbate in the supportive treatment of cancer: re-evaluation of prolongation of survival times in terminal human cancer, Proc. Natl. Acad. Sci. (U.S.A.), 75 (1978) 4358.

6 A. Campbell and T. Jack, Acute reactions to mega ascorbic acid therapy in malignant disease, Scot. Med. J., 24 (1979) 151.

7 G. Crile, Cancer of the thyroid, J. Clin. Endocrinol., 19 (1950) 1152. 8 A. Winshipt and R.V. Resvoll, Childhood thyroid cancer, Cancer, 14 (1961) 734. 9 E. Cameron, Hyaluronidase and cancer, Pergamon, Oxford and New York, 1966.

10 E. Cameron and L. Pauling, The orthomolecular treatment of cancer. I. The role of ascorbic acid in host resistance, Chem.-Biol. Interact., 9 (1974) 273.

11 D.F. Horrobin, M. Oka and M.S. Manku, The regulation of prostaglandin E1 forma- tion: a candidate for one of the fundamental mechanisms in the actions of Vitamin C, Med. Hypoth., 5 (1979) 849.

12 M.S. Manku, M. Oka and D.F. Horrobin, Differential regulation of the formation of prostaglandins and related substances from arachidonic acid and from dihomo gamma- linolenic acid. II. Effects of Vitamin C, Prostaglandins and Medicine, 3 (1979) 129.

13 S. Vallance, Relationship between ascorbic acid and serum proteins of the immune system, Br. Med. J., 2 (1977) 437.

14 D.J.B. Ashley, Evans Histological Appearances of Tumors, 3rd edn., Churchill Livingstone, Edinburgh, 1978, p. 251.

15 I. Stone, The Healing Factor, Grosset & Dunlop, New York, 1972, p. 51.