- Email: [email protected]
The Pathologic Physiology of Carcinoma of the Thyroid
The Pathologic Physiology of Carcinoma of the Thyroid ROBERT C. HORN, JR., M.D.*
Two briefly cited case histories will serve to illustrate the extreme variability of the clinical behavior of carcinoma of the thyroid gland. The first is that of a boy who, at the age of three, had a lateral cervical mass excised. The diagnosis of "lateral aberrant thyroid" was made at the time but, upon review many years later, it was recognized as a follicular and papillary carcinoma. At the age of 15 the patient, now a strapping youth of 193 pounds, was again hospitalized, this time because of the findings in a roentgenogram of the chest, made as part of a medical examination he had to pass before being allowed to play school football. At this time he had a frank carcinoma of the thyroid with multiple cervical and pulmonary metastases. Thyroidectomy and neck dissection were undertaken but, because of its extensive infiltration, removal of the tumor was incomplete. However, the tumor in the neck and in the lungs was found to take up appreciable amounts of radioactive iodine, and in the succeeding two years the patient was given four therapeutic doses. The shadows in the lung fields cleared strikingly. Today, at the age of 22, seven years after thyroidectomy and 19 years after the diagnosis might have been established, the patient is, for practical purposes, asymptomatic. His chest films are virtually negative. He has a small cervical tumor mass which all observers agree is residual carcinoma. The second patient was a 60 year old woman who had been aware of a goiter for eight years. In the four months before admission there had been rapid growth with the development of hoarseness and dysphagia and a 20 pound weight loss. A massive tumor (265 grams) extending from the clavicle to the angle of the jaw was removed surgically-incompletely because of extensive invasion. Although part of the tumor preFrom the Laboratory of Surgical Pathology and the Penn Mutual Life Insurance Company Foundation for the Study of Neoplastic Disease, Hospital of the University of Pennsylvania, Philadelphia. * Formerly Professor of Surgical Pathology, School of Medicine, University of Pennsylvania, an-t Surgical Pathologist, Hospital of the University of Pennsylvania. Now Pathologist-in-Chief, Henry Ford Hospital, Detroit, Michigan. 1669
1670
Robert C. Horn, Jr.
sented a pleomorphic Hiirthle cell pattern, possibly representing the remnant of the long-standing goiter, most of it was a characteristic giant cell carcinoma. The tumor could not be demonstrated to take up significant amounts of radioactive iodine and deep x-ray therapy was resorted to with little benefit. Four months after operation the patient died with extensive local disease and pulmonary metastases. The primary diagnosis in the two cases is the same-carcinoma of the thyroid; yet the differences in morphology and clinical behavior are extreme. The first case is that of a morphologically and functionally differentiated tumor, growing and evolving slowly in a young individual and responsive to therapy. The second is a highly undifferentiated carcinoma, scarcely recognizable as an epithelial tumor, incapable of function, growing and spreading rapidly in an elderly patient and uninfluenced by therapeutic measures. Occasional thyroid carcinomas may present even more extreme pictures than the two cited but the majority will fall in the broad area between these two extremes. INCIDENCE AND ASSOCIATED THYROID DISEASE
The real incidence of carcinoma of the thyroid has no doubt been obscured in the past because of the failure to realize how many examples might pursue courses approaching or surpassing the slowness of that of the first case cited. The accumulation of careful pathologic studies and follow-up data in recent years has led to more frequent recognition of this disease, but, even so, it is not to be considered one of the more commonly encountered human neoplasms. It has been estimated that there are about two thousand new cases each year in the United Statesan incidence of approximately 0.5 per cent of all carcinomas. 23 The incidence of thyroid carcinoma relative to that of nodular goiter is more striking and has been the source of much of the recently aroused interest in this subject. In a series of 3856 goiters treated surgically over a 19Y2 year period at the Hospital of the University of Pennsylvania, the author found a total of 236 carcinomas (6.1 per cent).15 Subtracting 1198 diffuse goiters from the total of surgically treated thyroids, the percentage of carcinomas becomes 8.9 per cent of 2658 nodular lesions. It is recognized that many of these carcinomas were diagnosed as such, or at least as probably such, preoperatively. If we subtract these, we find that unsuspected carcinoma was found in 5.3 per cent of surgically treated nodular goiters (Table 1). In considering the relative frequency of clinically undiagnosed thyroid carcinoma it must be remembered that many of the thyroidectomies were performed because the possibility of carcinoma was realized although it was not listed as one of the most likely differential diagnostic possibilities. Figures agreeing in import with these in suggesting that clinically unrecognized thyroid carcinoma is a frequent finding in nodular thyroids
The Pathologic Physiology of Carcinoma of the Thyroid
1671
have been presented by other authors.2, 18 Still other investigators,3.4 while they agree that "solitary" nodules frequently (in 19 to 25 per cent of instances) prove to be cancers, doubt a high incidence of carcinoma in multinodular goiters. Unfortunately, it is virtually impossible to define the term "solitary nodule" precisely. Crile and Dempsey4 have properly emphasized that most of the available statistics have been based on surgically treated goiters and that the material has been selected in the process of referral to the surgeon. They question the applicability of the figures to the population in general. Here it might be remarked also that the situation may well be different in endemic goiter areas from elsewhere. In any case, it is generally agreed that the so-called "solitary" nodule is frequently a carcinoma and that, at the very least, the possibility of a multinodular goiter harboring a carcinoma must be given serious consideration. Table 1 RELATIVE INCIDENCE OF NODULAR GOITER AND THYROID CARCINOMA
Including clinically susppcted carcinoma ..... . Excluding clinically suspected carcinoma ..... . Excluding clinically suspected carcinoma and toxic nodular goiters ..................... .
NODULAR THYROID LESIONS
CARCINOMA
2,658 2,557
236 (8.9%) 135 (5.3%)
2,135
131 (6.1%)
From Horn and Dull.'5
A good deal of confusion exists in the literature regarding the nature of the relationship of nodular goiter to carcinoma. The figures cited above indicate the frequency with which a nodule in a thyroid gland is a carcinoma but do not imply that the carcinoma arose in a nodular goiter. In less than half (48 per cent) of a recent series of 174 thyroid carcinomas studied by the author15 was there a history of goiter of more than one year's duration, in contrast to 74 per cent of an earlier series,17 Sloan21 has indicated no greater incidence of nodular goiter in thyroid glands the seat of carcinoma than in the population at large of comparable age and sex. On the other hand, the association of adenomas (true benign neoplasms) with cancer was high in his series (15 per cent). However, the evidence for believing that many thyroid carcinomas arise in adenomas is far from conclusive and the once commonly held belief to that effect is now challenged. 29 . 30 The very common slow evolution of many thyroid cancers indicates that many thyroid "nodules" may actually exist al> malignant tumors over long periods of time and need not be interpreted as malignant change supervening in a pre-existing benign lesion. It is a matter of general agreement that toxic goiter is infrequently associated with cancer. In the series of Majarakis and associates 18 the
Robert C. Horn, Jr.
1672
incidence of cancer was 0.1 per cent in toxic diffuse goiter and 1 per cent in toxic nodular goiter as contrasted with 15.6 per cent in nontoxic nodular goiter. Sloan21 emphasized the point that usually (60 per cent of a series of 106 cases in which total thyroidectomy was done) the gland harboring a cancer is otherwise normal. AGE AND SEX
The peak incidence of thyroid cancer in the Hospital of the University of Pennsylvania series occurred in the fifth decade and approximately two-thirds of the cases were first recognized when the patients were between 41 and 70 years of age. IS, 17 In the more recent series 21 per cent of the cases were diagnosed in patients 30 years of age or younger and 7 per cent were twenty years of age or less at the time of diagnosis.1 5 It should be emphasized that, particularly in these young age groups, thyroid carcinoma may be of long duration before diagnosis and that many patients diagnosed as having thyroid cancer in the second or third decade of life actually had thyroid cancers when they were in their first or second decade. 16 Since nodular goiter is uncommon in these younger age groups, the incidence of carcinoma in nodular thyroid enlargements is extremely high-30.6 per cent in one small series of patients 25 years of age or less.1 6 It is striking that the carcinomas of children, adolescents and young adults are commonly of the types here classified as of a low degree of malignancy and are associated with prolonged and slowly progressive clinical courses. In contrast, the highly malignant tumors, as judged either pathologically or clinically, are tumors of the older age groups. 5, 21 Whereas surgical thyroid disease in general predominates in women in a ratio in the neighborhood of ten to one, the relative predominance of thyroid carcinoma in the female is between two and four to one.15 , 21 However, Winship27 points out a ratio of two females to one male among children and Sloan21 gives female to male ratios of three to one in the elderly and of eight to one in the age group 26 to 40. The latter approaches the female to male ratio of thyroid disease in general. CLASSIFICATION
Many of the more useful pathologic classifications of thyroid cancer differ only in relatively unimportant detail. The classification used at the Hospital of the University of Pennsylvania, based essentially on the earlier one of Warren, 24 is given in Table 2. The percentage figures indicate the proportion of cases in our material falling into each category.15 The more recent classification of Warren and Meissner 26 recognizes two broad groups-differentiated and undifferentiated. Hazard and his collaborators12 likewise list two groups but theirs are papillary and non-
The Pathologic Physiology of Carcinoma of the Thyroid
1673
papillary. Their nonpapillary carcinomas include most of the types listed above. It must be emphasized that many thyroid carcinomas are not pure types, but mixtures of two or more morphologic variants. Such mixtures are particularly common with regard to the papillary and follicular carcinomas. We have based classification on the predominant pattern and Table 2 PATHOLOGIC CLASSIFICATION OF
189
CASES OF THYROID CARCINOMA
I. Low degree of malignancy .......................................... 72% A. Malignant adenoma ........................ 13% B. Follicular .................................. 19% C. Papillary .................................. 33% D. Mixed papillary and follicular. . . . . . . . . . . . . . .. 7% II. Intermediate degree of malignancy-"adenocarcinoma" ................ 19% III. High degree of malignancy-undifferentiated. . . . . . . . . . . . . . . . . . . . . . . . .. 8% IV. Miscella.neous maligna.nt tumors Epidermoid carcinoma Sarcoma After Horn and Dull.15
tumors have been called mixed only when it becomes impossible to determine the predominant type with any degree of assurance. I. CarcinOIna of Low Degree of Malignancy
A. The so-called "malignant adenoma" is the tumor classified as "en_ capsulated angio-invasive carcinoma" by Hazard and his associates,12 "adenoma with invasion" by Warren and Meissner,26 and "adenocarcinoma in adenoma" by others.19 This is the tumor that in the past has given rise to the term "benign metastasizing goiter" because of the difficulty of distinguishing it from simple adenoma. Warren and Meissner26 emphasize the point that the pathologic diagnosis of cancer of the thyroid is made according to the same general criteria for malignant change as are used for cancers of other tissues of the body, although admittedly the recognition of some of the better differentiated thyroid carcinomas may be extremely difficult. Hazard's group12 relies heavily on the demonstration of blood vessel invasion in lesions showing atypical features. That the finding of such vessel invasion may be of great help in the diagnosis of thyroid carcinoma has become widely appreciated since it was first pointed out some 30 years ago by Graham. 1o The malignant adenomas differ from the more common benign adenomas in certain histologic features, often of minor degree. They tend to be more solidly cellular, at times demonstrating growth in solid cords, broad sheets or complex undulating, ribbon-like bands (Fig. 450). There may not be good follicle formation, and when follicles are present, often little colloid is found. The demonstration of blood vessel invasion may
1674
Robert C. Horn, Jr.
be of great help but at times it may be very difficult to differentiate between true invasion and artifact. The malignant adenomas, as might be expected from the frequency with which they are seen to invade blood vessels, tend to metastasize by that route rather than by direct local growth or by the lymphatics. The late recognition of bone or lung metastasis is all too common. Although 56 per cent of the 16 patients in our series with this tumor type survived without clinical evidence of disease for five years, only two (25 per cent) of eight patients who were followed for 12 years survived. The six who died all did so with active carcinoma. These figures indicate the slow
Fig. 450. Malignant adenoma of thyroid. This pattern is characterized by intertwining ribbon-like bands with follicles often sharing walls. (Reproduced from Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: A Re-evaluation; Ann. Surg., Vol. 139, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
evolution of this type of thyroid carcinoma and the necessity of very long follow-up to vindicate the pathologist's diagnostic judgment. B. The follicular carcinoma may bear an even closer resemblance to non-neoplastic thyroid tissue than the malignant adenoma, and colloid is frequently present. Although this tumor has a tendency for the follicles to be irregular and for the lining cells to have unusually abundant, pale or clear, raggedly outlined cytoplasm, there are all too numerous examples in which its malignant nature can be recognized only by the invasive manner of its growth (Fig. 451). The follicular carcinoma parallels the papillary carcinoma in its clinical evolution and frequently occurs in mixtures with it. It will be discussed further with the papillary tumors. C. The papillary carcinoma is the most common of the thyroid carcinomas-33 per cent of the tumors in the Hospital of the University of
The Pathologic Physiology of Carcinoma of the Thyroid
1675
Pennsylvania series being predominantly of this type and another 7 per cent roughly half papillary. The higher incidence of papillary carcinoma reported by some 9 • 12 is probably, in part at least, the result of classifying as papillary all tumors that show any papillary features at all. The papillary tumors need little histologic description, being readily recognizable. They may vary from complex branching growths (Fig. 452) to more nearly solid ones in which anastomosis of the fronds tends to obscure the papillary pattern. Psammoma bodies or calcospherites may be present. Although sometimes encapsulated, they often grow invasively. They are commonly cystic, especially in lymph node metastases. Encapsulated papillary tumors so well differentiated and orderly that
Fig. 451. Follicular carcinoma of thyroid. The re3emblance to normal thyroid tissue almost approaches identity. (Reproduced from Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: A Re-evaluation; Ann. Surg., Vol. 139, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
they may safely be considered benign, are infrequently encountered. The tumors of childhood and young adults are frequently of this type (as well as follicular or a mixture of both), but when they do occur in older people, they often pursue a course in keeping with the lengthy one characterizing this tumor in youth. Papillary and follicular cancer of the thyroid usually spreads via lymphatic channels and the most frequent site of metastasis is the cervical lymph nodes. Of Frazell and Foote's 139 papillary carcinomas, 58 per cent showed cervical lymph node involvement on admission, bilateral in 13 per cent. 9 It is also the papillary tumor (together with the follicular and mixed follicular and papillary tumors) that tend to be multicentric,15. 21 although it is difficult to establish the exact incidence of multicentricity.
1676
Robert C. Horn, Jr.
In the Hospital of the University of Pennsylvania material,15 the papillary carcinomas afforded the highest survival rate (69 per cent at five years and 55 per cent at 12 years). However, three of six patients surviving at the 12 year interval are known to have active disease. If we consider the follicular and papillary tumors together, the five year survival figure becomes 74 per cent (40 of 54 patients) but the 12 year figure drops to 38 per cent (6 of 16 patients) and only 19 per cent (3 of 16) of the patients followed 12 years are without evidence of disease. These figures emphasize the prolonged clinical course of papillary and follicular thyroid cancer.
Fig. 452. Papillary carcinoma of thyroid. (Reproduced from Horn, R. C. Jr. and Ravdin, 1. S.: Carcinoma of the Thyroid Gland in Youth; J. Clin. Endocrinol., Vol. 11, with the permission of Charles C Thomas Co., Springfield, Illinois, publishers.)
D. Mixed papillary and follicular carcinoma. The features of these mixed tumors have been covered in C, above, under papillary carcinoma. Lateral Aberrant Thyroid Carcinoma. It is now generally agreed that the so-called "lateral aberrant thyroid carcinoma" usually, if not always, represents in reality cervical lymph node metastasis from an occult primary carcinoma in the thyroid proper. These tumors are usually papillary or follicular, or a mixture of these two types. They usually occur in the younger age groups and pursue a prolonged course, during which the cervical lymph node metastases may dominate the clinical picture. At times the primary lesion is found only after the most meticulous search by the pathologist. 28 Nonencapsulated Sclerosing Tumor. The tumor given this name by Hazard and his associates ll should be classified with the papillary or papillary and follicular tumors. It is distinguished by its very small size
The Pathologic Physiology of Carcinoma of the Thyroid
1677
and is frequently an incidental finding in a toxic goiter. Although this lesion is apparently of a very low order of malignancy, it appears identical with some of the minute tumors that have given rise to extensive metastases-the so-called "lateral aberrant thyroid carcinomas." II. TunlOrs of an InterIllediate Degree of Malignancy-"AdenocarcinoIlla"
Most of the tumors classified as adenocarcinomas resemble the follicular carcinomas but are less well differentiated in varying degree (Fig. 453). At times the dividing line between the two is not sharp and, similarly, there may not always be sharp distinction between papillary carcinoma and adenocarcinoma. Included in this group also are a num-
Fig. 453. Adenocarcinoma of thyroid. Some follicular differentiation is retained.
ber of poorly differentiated tumors showing an alveolar grouping of more or less spindle-shaped cells 13 (Fig. 454). The malignancy of these latter tumors approaches that of the Group III cancers. The tumors of an intermediate degree of malignancy occur in older age groups than the Group I tumors. They spread by all routes-directly and by both the lymphatic and blood vascular systems. In the Hospital of the University of Pennsylvania material the 12 year survival was 33 per cent (4 of 12 patients). Here, too, the clinical course was often slow, since 14 of 26 patients (54 per cent) could be counted as five year survivors. III. TUIllors of a High Degree of Malignancy-Undifferentiated TUIllors
The best known and most striking of the undifferentiated thyroid carcinomas is the giant cell or spindle cell carcinoma (Fig. 455). It is char-
1678
Robert C. Horn, Jr.
acterized by a mixture of various numbers of cells of these two types. Usually, if extensive search is made, areas of distinct epithelial differentiation can be found with transition to the metaplastic tissues. 22 Occasional undifferentiated tumors are composed of large, rounded, fairly uniform cells or, on the other hand, of small round cells. Warren and Meissner26 subdivide the small cell carcinoma into compact and diffuse types. According to these authors, 20 to 30 per cent of patients with small cell carcinomas may survive for five years. The giant and spindle cell cancers occur in the elderly, frequently becoming manifest by the rapid growth of a previously quiescent goiter of long standing. In addi-
Fig. 454. Adenocarcinoma of thyroid, showing whorled, alveolar pattern. (Reproduced from Horn, R. C. Jr.: Carcinoma of the Thyroid: Description of a Distinctive Morphological Variant and Report of Seven Cases; Cancer, Vol. 4, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
tion to metastasizing early (to the lungs in particular) they frequently invade the neck widely, affecting vital structures. Survival of patients with giant and spindle cell tumors is a rarity. 9, 26 IV. Miscellaneous Malignant TunlOrs
A. Epidermoid Carcinoma. Although areas of squamous metaplasia are occasionally seen in thyroid cancers of various types, pure epidermoid carcinomas are rare. In our experience, they have been highly malignant and have pursued a rapidly fatal course. B. Sarcoma. According to Warren and Meissner,26 fibrosarcoma occurs more often in the thyroid than any other nonepithelial malignant tumor. It may be difficult to distinguish from a spindle cell carcinoma. Lymphosarcoma may occur at times as a disease localized to the thyroid. 6 Other lesions of the "lymphoma" series have been recorded, generally as part of disseminated disease. 26
The Pathologic Physiology of Carcinoma of the Thyroid
1679
HURTHLE CELL TUMORS
The cells of any type of thyroid carcinoma (as well as benign tumors and non-neoplastic lesions) may have the characteristics of Hiirthle cells. The presence of Hiirthle cells, even their predominance, appears to have no prognostic significance. 14 We have not, therefore, placed lesions composed of Hiirthle cells in a separate category.
Fig. 455. Giant and spindle cell carcinoma of thyroid. Two examples. In the upper right-hand corner some epithelial differentiation is apparent. (Reproduced from Horn, R. C. Jr.: Hiirthle Cell Tumors of the Thyroid; Cancer, Vol. 7, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
FUNCTION
Certain thyroid carcinomas can be demonstrated to have the ability to function-that is, to collect radioactive iodine. In general, this ability parallels the differentiation of the tumor, particularly with respect to the amount of colloid present. However, it is noteworthy that histologically identical follicles may differ in their ability to concentrate 1131 as demonstrated by radio-autographs. In none of the 100 cases studied by Fitzgerald and Foote 8 could tumor be shown to take up as much radioactive iodine as did adjacent normal thyroid tissue. Radio-autographic concentration of 1131 was demonstrated in 46 of their cases. It must be emphasized that only a fraction of these cases can be expected to utilize enough radioactive iodine for the latter to be therapeutically useful. 7 Also, as has been pointed out above, the differentiation of any thyroid carcinoma may vary greatly from one area or site to another. Similarly, the demonstrable functional capacity of a given thyroid cancer may not be the same at all times. Many attempts have been made to increase the ability of thyroid neoplasms to concentrate radioactive iodine. It has been demon-
1680
Robert C. Horn, Jr.
strated that the ablation of normal thyroid tissue will enhance a tumor's function in this respect (this may be largely a matter of eliminating an able competitor) and at times other measures, such as administration of certain thiourea compounds or thyroid-stimulating pituitary hormone, may have a similar effect. However, the many thyroid tumors lacking the ability to pick up radioactive iodine initially cannot be made to do so by any presently known procedure. I • 20 CLINICAL COURSE AND END RESULTS
The clinical evolution of thyroid carcinoma has been discussed above in connection with the various histopathologic types. The end results are summarized in Table 3. The frequency with which patients with thyroid Table 3 FIVE AND TWELVE YEAR SURVIVALS OF THYROID CARCINOMA (Hospital of the University of Pennsylvania, 1933-1947) NO. OF PTS. NO. OF PTS. TREATED TREATED 12 YEAR 5 YEAR MORE THAN SURVIVALS MORE THAN SURVIVALS 12 YRS. 5 YRS. AGO AGO Malignant adenoma ... Papillary, follicular or mixed. Adenocarcinoma. . .. Undifferentiated ...... TOTALS ....
16 54
26 16 112
9 40 14 3 66
(56%) (74%) (54%) (19%) (59%)
8 16 12 8 44
2 (25%) 6*(38%) 4 (33%) 1 (12.5%) 13*(30%)
* Three patients with papillary carcinoma are living with disease. After Horn and DulJ.15 cancer survive five years only to succumb to the disease subsequently is apparent. Only two of the patients who died after the five year period were not known to have active disease. Neither came to necropsy. Such data as these suggest that the variability of the malignancy of the different types of carcinoma of the thyroid manifests itself, not so much by variation in survival rate as by variation in the speed with which the disease progresses. REFERENCES
1. Black, B. M., Woolner, L. B. and Blackburn, C. M.: The Uptake of Radioactive 2. 3. 4.
5.
Iodine by Carcinoma of the Thyroid Gland: A Study of 128 Cases. J. Clin. Endocrinol. 13: 1378-1390, 1953. Cole, W. H., Majarakis, J. D. and Slaughter, D. P.: Incidence of Carcinoma of the Thyroid in Nodular Goiter. J. Clin. Endocrinol. 9: 1007-1011, 1949. Cope, 0., Dobyns, B. M., Hamlin, E. Jr. and Hopkirk, J.: What Thyroid Nodules Are to be Feared? J. Clin. Endocrinol. 9: 1012-1022, 1949. Crile, G. Jr. and Dempsey, W. S.: Indications for Removal of Nontoxic Nodular Goiters. J.A.M.A. 139: 1247-1251, 1949. Crile, G. Jr. and Hazard, J. B.: Relationship of the Age of the Patient to the Natural History and Prognosis of Carcinoma of the Thyroid. Ann. Surg. 138: 33-38, 1953.
The Pathologic Physiology of Carcinoma of the Thyroid
1681
6. Dinsmore, R. S., Dempsey, W. S. and Hazard, J. B.: Lymphosarcoma of the Thyroid. J. Clin. Endocrinol. 9: 1043-1047, 1949. 7. Dobyns, B. M. and Maloof, F.: The Study and Treatment of 119 Cases of Carcinoma of the Thyroid with Radioactive Iodine. J. Clin. Endocrinol. 11: 1343-1360,1951. 8. Fitzgerald, P. J. and Foote, F. W. Jr.: The Function of Various Types of Thyroid Carcinoma as Revealed by the Radio-autographic Demonstration of Radioactive Iodine (1 131 ). J. Clin. Endocrinol. 9: 1153-1170, 1949. 9. Frazell, E. L. and Foote, F. W. Jr.: The Natural History of Thyroid Cancer. A Review of 301 Cases. J. Clin. Endocrinol. 9: 1023-1030, 1949. 10. Graham, A.: Malignant Epithelial Tumors of the Thyroid with Special Reference to Invasion of Blood Vessels. Surg., Gynec. & Obst. 39: 781-790, 1924. 11. Hazard, J. B., Crile, G. Jr. and Dempsey, W. S.: Nonencapsulated Sclerosing Tumors of the Thyroid. J. Clin. Endocrinol. 9: 1216-1231, 1949. 12. Hazard, J. B. and others: Neoplasms of the Thyroid. Classificat.ion, Morphology 'and Treatment. Arch. Path. 59: 502-513, 1955. 13. Horn, R. C. Jr.: Carcinoma of the Thyroid. Description of a Distinctive Morphological Variant and Report of Seven Cases. Cancer 4: 697-707 (July) 1951. 14. Horp, R. C. Jr.: Hiirthle-Cell Tumors of the Thyroid. Cancer 7: 234-244 (March) 1954. 15. Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: ARe-evaluation. Ann. Surg. 139: 35-43 (Jan.) 1954. 16. Horn, R. C. Jr. and Ravdin, 1. S.: Carcinoma of the Thyroid Gland in Youth. J. Clin. Endocrinol. 11: 1166-1178 (Oct.) 1951. 17. Horn, R. C. Jr. and others: Carcinoma of the Thyroid. Ann. Surg. 126: 140-155 (Aug.) 1947. 18. Majarakis, J. D., Slaughter, D. P. and Cole, W. H.: Carcinoma of the Thyroid Gland. J. Clin. Endocrinol. 13: 1530-1.541,1953. 19. Pemberton, J. deJ.: Malignant Lesions of the Thyroid. A Review of 774 Cases. Surg., Gynec. & Obst. 69: 417-430, 1939. 20. Rail, J. E. and others: The Use of Thiouracil in the Treatment of Metastatic Carcinoma of the Thyroid with Radioiodine. J. Clin. Endocrinol. 11: 12731280, 1951. 21. Sloan, L. W.: Of the Origin, Characteristics and Behavior of Thyroid Cancer. J. Clin. Endocrinol. 14: 1309-1335, 1954. 22. Smith, L. W.: Certain So-called Sarcomas of the Thyroid. Arch. Path. 10: 524530, 1930. 23. Sokal, .J. E.: Surgical Statistics on Malignant Goiter. Surg., Gynec. & Obst. 99: 108-114, 1954. 24. Warren, S.: The Classification of Tumors of the Thyroid. Am. J. Roentgeno!. 40: 447-450, 1941. 25. Warren, S. and Feldman, J. D.: The Nature of Lateral "Aberrant" Thyroid Tumors. Surg., Gynec. & Obst. 88: 31-41, 1949. 26. Warren, S. and Meissner, W. A.: Tumors of the Thyroid Gland. Atlas of Tumor Pathology, Section IV, Fascicle 14, Armed Forces Institute of Pathology, Washington, D. C., 1953. 27. Winship, T.: Carcinoma of the Thyroid in Children. Tr. Am. Goiter A. (1951), pp. 364-389, 1952. 28. Wozencraft, P. and Foote, F. W. Jr.: Occult Carcinomas of the Thyroid; Their Bearing on the Concept of Lateral Aberrant Thyroid Cancer. Cancer 1: 574583 (Nov.) 1948. 29. Young, M. 0.: Carcinoma of the Thyroid Gland: Incidence and Mode of Origin. Surgery 27: 364-367, 1950. 30. Zimmerman, L. M., Wagner, D. H., Perlmutter, H. M. and Amromin, G. D.: Benign and Malignant Epithelial Tumors of the Thyroid Gland. Arch. Surg. 60: 1183-1198, 1950. Henry Ford Hospital Detroit 2, Michigan
Two briefly cited case histories will serve to illustrate the extreme variability of the clinical behavior of carcinoma of the thyroid gland. The first is that of a boy who, at the age of three, had a lateral cervical mass excised. The diagnosis of "lateral aberrant thyroid" was made at the time but, upon review many years later, it was recognized as a follicular and papillary carcinoma. At the age of 15 the patient, now a strapping youth of 193 pounds, was again hospitalized, this time because of the findings in a roentgenogram of the chest, made as part of a medical examination he had to pass before being allowed to play school football. At this time he had a frank carcinoma of the thyroid with multiple cervical and pulmonary metastases. Thyroidectomy and neck dissection were undertaken but, because of its extensive infiltration, removal of the tumor was incomplete. However, the tumor in the neck and in the lungs was found to take up appreciable amounts of radioactive iodine, and in the succeeding two years the patient was given four therapeutic doses. The shadows in the lung fields cleared strikingly. Today, at the age of 22, seven years after thyroidectomy and 19 years after the diagnosis might have been established, the patient is, for practical purposes, asymptomatic. His chest films are virtually negative. He has a small cervical tumor mass which all observers agree is residual carcinoma. The second patient was a 60 year old woman who had been aware of a goiter for eight years. In the four months before admission there had been rapid growth with the development of hoarseness and dysphagia and a 20 pound weight loss. A massive tumor (265 grams) extending from the clavicle to the angle of the jaw was removed surgically-incompletely because of extensive invasion. Although part of the tumor preFrom the Laboratory of Surgical Pathology and the Penn Mutual Life Insurance Company Foundation for the Study of Neoplastic Disease, Hospital of the University of Pennsylvania, Philadelphia. * Formerly Professor of Surgical Pathology, School of Medicine, University of Pennsylvania, an-t Surgical Pathologist, Hospital of the University of Pennsylvania. Now Pathologist-in-Chief, Henry Ford Hospital, Detroit, Michigan. 1669
1670
Robert C. Horn, Jr.
sented a pleomorphic Hiirthle cell pattern, possibly representing the remnant of the long-standing goiter, most of it was a characteristic giant cell carcinoma. The tumor could not be demonstrated to take up significant amounts of radioactive iodine and deep x-ray therapy was resorted to with little benefit. Four months after operation the patient died with extensive local disease and pulmonary metastases. The primary diagnosis in the two cases is the same-carcinoma of the thyroid; yet the differences in morphology and clinical behavior are extreme. The first case is that of a morphologically and functionally differentiated tumor, growing and evolving slowly in a young individual and responsive to therapy. The second is a highly undifferentiated carcinoma, scarcely recognizable as an epithelial tumor, incapable of function, growing and spreading rapidly in an elderly patient and uninfluenced by therapeutic measures. Occasional thyroid carcinomas may present even more extreme pictures than the two cited but the majority will fall in the broad area between these two extremes. INCIDENCE AND ASSOCIATED THYROID DISEASE
The real incidence of carcinoma of the thyroid has no doubt been obscured in the past because of the failure to realize how many examples might pursue courses approaching or surpassing the slowness of that of the first case cited. The accumulation of careful pathologic studies and follow-up data in recent years has led to more frequent recognition of this disease, but, even so, it is not to be considered one of the more commonly encountered human neoplasms. It has been estimated that there are about two thousand new cases each year in the United Statesan incidence of approximately 0.5 per cent of all carcinomas. 23 The incidence of thyroid carcinoma relative to that of nodular goiter is more striking and has been the source of much of the recently aroused interest in this subject. In a series of 3856 goiters treated surgically over a 19Y2 year period at the Hospital of the University of Pennsylvania, the author found a total of 236 carcinomas (6.1 per cent).15 Subtracting 1198 diffuse goiters from the total of surgically treated thyroids, the percentage of carcinomas becomes 8.9 per cent of 2658 nodular lesions. It is recognized that many of these carcinomas were diagnosed as such, or at least as probably such, preoperatively. If we subtract these, we find that unsuspected carcinoma was found in 5.3 per cent of surgically treated nodular goiters (Table 1). In considering the relative frequency of clinically undiagnosed thyroid carcinoma it must be remembered that many of the thyroidectomies were performed because the possibility of carcinoma was realized although it was not listed as one of the most likely differential diagnostic possibilities. Figures agreeing in import with these in suggesting that clinically unrecognized thyroid carcinoma is a frequent finding in nodular thyroids
The Pathologic Physiology of Carcinoma of the Thyroid
1671
have been presented by other authors.2, 18 Still other investigators,3.4 while they agree that "solitary" nodules frequently (in 19 to 25 per cent of instances) prove to be cancers, doubt a high incidence of carcinoma in multinodular goiters. Unfortunately, it is virtually impossible to define the term "solitary nodule" precisely. Crile and Dempsey4 have properly emphasized that most of the available statistics have been based on surgically treated goiters and that the material has been selected in the process of referral to the surgeon. They question the applicability of the figures to the population in general. Here it might be remarked also that the situation may well be different in endemic goiter areas from elsewhere. In any case, it is generally agreed that the so-called "solitary" nodule is frequently a carcinoma and that, at the very least, the possibility of a multinodular goiter harboring a carcinoma must be given serious consideration. Table 1 RELATIVE INCIDENCE OF NODULAR GOITER AND THYROID CARCINOMA
Including clinically susppcted carcinoma ..... . Excluding clinically suspected carcinoma ..... . Excluding clinically suspected carcinoma and toxic nodular goiters ..................... .
NODULAR THYROID LESIONS
CARCINOMA
2,658 2,557
236 (8.9%) 135 (5.3%)
2,135
131 (6.1%)
From Horn and Dull.'5
A good deal of confusion exists in the literature regarding the nature of the relationship of nodular goiter to carcinoma. The figures cited above indicate the frequency with which a nodule in a thyroid gland is a carcinoma but do not imply that the carcinoma arose in a nodular goiter. In less than half (48 per cent) of a recent series of 174 thyroid carcinomas studied by the author15 was there a history of goiter of more than one year's duration, in contrast to 74 per cent of an earlier series,17 Sloan21 has indicated no greater incidence of nodular goiter in thyroid glands the seat of carcinoma than in the population at large of comparable age and sex. On the other hand, the association of adenomas (true benign neoplasms) with cancer was high in his series (15 per cent). However, the evidence for believing that many thyroid carcinomas arise in adenomas is far from conclusive and the once commonly held belief to that effect is now challenged. 29 . 30 The very common slow evolution of many thyroid cancers indicates that many thyroid "nodules" may actually exist al> malignant tumors over long periods of time and need not be interpreted as malignant change supervening in a pre-existing benign lesion. It is a matter of general agreement that toxic goiter is infrequently associated with cancer. In the series of Majarakis and associates 18 the
Robert C. Horn, Jr.
1672
incidence of cancer was 0.1 per cent in toxic diffuse goiter and 1 per cent in toxic nodular goiter as contrasted with 15.6 per cent in nontoxic nodular goiter. Sloan21 emphasized the point that usually (60 per cent of a series of 106 cases in which total thyroidectomy was done) the gland harboring a cancer is otherwise normal. AGE AND SEX
The peak incidence of thyroid cancer in the Hospital of the University of Pennsylvania series occurred in the fifth decade and approximately two-thirds of the cases were first recognized when the patients were between 41 and 70 years of age. IS, 17 In the more recent series 21 per cent of the cases were diagnosed in patients 30 years of age or younger and 7 per cent were twenty years of age or less at the time of diagnosis.1 5 It should be emphasized that, particularly in these young age groups, thyroid carcinoma may be of long duration before diagnosis and that many patients diagnosed as having thyroid cancer in the second or third decade of life actually had thyroid cancers when they were in their first or second decade. 16 Since nodular goiter is uncommon in these younger age groups, the incidence of carcinoma in nodular thyroid enlargements is extremely high-30.6 per cent in one small series of patients 25 years of age or less.1 6 It is striking that the carcinomas of children, adolescents and young adults are commonly of the types here classified as of a low degree of malignancy and are associated with prolonged and slowly progressive clinical courses. In contrast, the highly malignant tumors, as judged either pathologically or clinically, are tumors of the older age groups. 5, 21 Whereas surgical thyroid disease in general predominates in women in a ratio in the neighborhood of ten to one, the relative predominance of thyroid carcinoma in the female is between two and four to one.15 , 21 However, Winship27 points out a ratio of two females to one male among children and Sloan21 gives female to male ratios of three to one in the elderly and of eight to one in the age group 26 to 40. The latter approaches the female to male ratio of thyroid disease in general. CLASSIFICATION
Many of the more useful pathologic classifications of thyroid cancer differ only in relatively unimportant detail. The classification used at the Hospital of the University of Pennsylvania, based essentially on the earlier one of Warren, 24 is given in Table 2. The percentage figures indicate the proportion of cases in our material falling into each category.15 The more recent classification of Warren and Meissner 26 recognizes two broad groups-differentiated and undifferentiated. Hazard and his collaborators12 likewise list two groups but theirs are papillary and non-
The Pathologic Physiology of Carcinoma of the Thyroid
1673
papillary. Their nonpapillary carcinomas include most of the types listed above. It must be emphasized that many thyroid carcinomas are not pure types, but mixtures of two or more morphologic variants. Such mixtures are particularly common with regard to the papillary and follicular carcinomas. We have based classification on the predominant pattern and Table 2 PATHOLOGIC CLASSIFICATION OF
189
CASES OF THYROID CARCINOMA
I. Low degree of malignancy .......................................... 72% A. Malignant adenoma ........................ 13% B. Follicular .................................. 19% C. Papillary .................................. 33% D. Mixed papillary and follicular. . . . . . . . . . . . . . .. 7% II. Intermediate degree of malignancy-"adenocarcinoma" ................ 19% III. High degree of malignancy-undifferentiated. . . . . . . . . . . . . . . . . . . . . . . . .. 8% IV. Miscella.neous maligna.nt tumors Epidermoid carcinoma Sarcoma After Horn and Dull.15
tumors have been called mixed only when it becomes impossible to determine the predominant type with any degree of assurance. I. CarcinOIna of Low Degree of Malignancy
A. The so-called "malignant adenoma" is the tumor classified as "en_ capsulated angio-invasive carcinoma" by Hazard and his associates,12 "adenoma with invasion" by Warren and Meissner,26 and "adenocarcinoma in adenoma" by others.19 This is the tumor that in the past has given rise to the term "benign metastasizing goiter" because of the difficulty of distinguishing it from simple adenoma. Warren and Meissner26 emphasize the point that the pathologic diagnosis of cancer of the thyroid is made according to the same general criteria for malignant change as are used for cancers of other tissues of the body, although admittedly the recognition of some of the better differentiated thyroid carcinomas may be extremely difficult. Hazard's group12 relies heavily on the demonstration of blood vessel invasion in lesions showing atypical features. That the finding of such vessel invasion may be of great help in the diagnosis of thyroid carcinoma has become widely appreciated since it was first pointed out some 30 years ago by Graham. 1o The malignant adenomas differ from the more common benign adenomas in certain histologic features, often of minor degree. They tend to be more solidly cellular, at times demonstrating growth in solid cords, broad sheets or complex undulating, ribbon-like bands (Fig. 450). There may not be good follicle formation, and when follicles are present, often little colloid is found. The demonstration of blood vessel invasion may
1674
Robert C. Horn, Jr.
be of great help but at times it may be very difficult to differentiate between true invasion and artifact. The malignant adenomas, as might be expected from the frequency with which they are seen to invade blood vessels, tend to metastasize by that route rather than by direct local growth or by the lymphatics. The late recognition of bone or lung metastasis is all too common. Although 56 per cent of the 16 patients in our series with this tumor type survived without clinical evidence of disease for five years, only two (25 per cent) of eight patients who were followed for 12 years survived. The six who died all did so with active carcinoma. These figures indicate the slow
Fig. 450. Malignant adenoma of thyroid. This pattern is characterized by intertwining ribbon-like bands with follicles often sharing walls. (Reproduced from Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: A Re-evaluation; Ann. Surg., Vol. 139, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
evolution of this type of thyroid carcinoma and the necessity of very long follow-up to vindicate the pathologist's diagnostic judgment. B. The follicular carcinoma may bear an even closer resemblance to non-neoplastic thyroid tissue than the malignant adenoma, and colloid is frequently present. Although this tumor has a tendency for the follicles to be irregular and for the lining cells to have unusually abundant, pale or clear, raggedly outlined cytoplasm, there are all too numerous examples in which its malignant nature can be recognized only by the invasive manner of its growth (Fig. 451). The follicular carcinoma parallels the papillary carcinoma in its clinical evolution and frequently occurs in mixtures with it. It will be discussed further with the papillary tumors. C. The papillary carcinoma is the most common of the thyroid carcinomas-33 per cent of the tumors in the Hospital of the University of
The Pathologic Physiology of Carcinoma of the Thyroid
1675
Pennsylvania series being predominantly of this type and another 7 per cent roughly half papillary. The higher incidence of papillary carcinoma reported by some 9 • 12 is probably, in part at least, the result of classifying as papillary all tumors that show any papillary features at all. The papillary tumors need little histologic description, being readily recognizable. They may vary from complex branching growths (Fig. 452) to more nearly solid ones in which anastomosis of the fronds tends to obscure the papillary pattern. Psammoma bodies or calcospherites may be present. Although sometimes encapsulated, they often grow invasively. They are commonly cystic, especially in lymph node metastases. Encapsulated papillary tumors so well differentiated and orderly that
Fig. 451. Follicular carcinoma of thyroid. The re3emblance to normal thyroid tissue almost approaches identity. (Reproduced from Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: A Re-evaluation; Ann. Surg., Vol. 139, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
they may safely be considered benign, are infrequently encountered. The tumors of childhood and young adults are frequently of this type (as well as follicular or a mixture of both), but when they do occur in older people, they often pursue a course in keeping with the lengthy one characterizing this tumor in youth. Papillary and follicular cancer of the thyroid usually spreads via lymphatic channels and the most frequent site of metastasis is the cervical lymph nodes. Of Frazell and Foote's 139 papillary carcinomas, 58 per cent showed cervical lymph node involvement on admission, bilateral in 13 per cent. 9 It is also the papillary tumor (together with the follicular and mixed follicular and papillary tumors) that tend to be multicentric,15. 21 although it is difficult to establish the exact incidence of multicentricity.
1676
Robert C. Horn, Jr.
In the Hospital of the University of Pennsylvania material,15 the papillary carcinomas afforded the highest survival rate (69 per cent at five years and 55 per cent at 12 years). However, three of six patients surviving at the 12 year interval are known to have active disease. If we consider the follicular and papillary tumors together, the five year survival figure becomes 74 per cent (40 of 54 patients) but the 12 year figure drops to 38 per cent (6 of 16 patients) and only 19 per cent (3 of 16) of the patients followed 12 years are without evidence of disease. These figures emphasize the prolonged clinical course of papillary and follicular thyroid cancer.
Fig. 452. Papillary carcinoma of thyroid. (Reproduced from Horn, R. C. Jr. and Ravdin, 1. S.: Carcinoma of the Thyroid Gland in Youth; J. Clin. Endocrinol., Vol. 11, with the permission of Charles C Thomas Co., Springfield, Illinois, publishers.)
D. Mixed papillary and follicular carcinoma. The features of these mixed tumors have been covered in C, above, under papillary carcinoma. Lateral Aberrant Thyroid Carcinoma. It is now generally agreed that the so-called "lateral aberrant thyroid carcinoma" usually, if not always, represents in reality cervical lymph node metastasis from an occult primary carcinoma in the thyroid proper. These tumors are usually papillary or follicular, or a mixture of these two types. They usually occur in the younger age groups and pursue a prolonged course, during which the cervical lymph node metastases may dominate the clinical picture. At times the primary lesion is found only after the most meticulous search by the pathologist. 28 Nonencapsulated Sclerosing Tumor. The tumor given this name by Hazard and his associates ll should be classified with the papillary or papillary and follicular tumors. It is distinguished by its very small size
The Pathologic Physiology of Carcinoma of the Thyroid
1677
and is frequently an incidental finding in a toxic goiter. Although this lesion is apparently of a very low order of malignancy, it appears identical with some of the minute tumors that have given rise to extensive metastases-the so-called "lateral aberrant thyroid carcinomas." II. TunlOrs of an InterIllediate Degree of Malignancy-"AdenocarcinoIlla"
Most of the tumors classified as adenocarcinomas resemble the follicular carcinomas but are less well differentiated in varying degree (Fig. 453). At times the dividing line between the two is not sharp and, similarly, there may not always be sharp distinction between papillary carcinoma and adenocarcinoma. Included in this group also are a num-
Fig. 453. Adenocarcinoma of thyroid. Some follicular differentiation is retained.
ber of poorly differentiated tumors showing an alveolar grouping of more or less spindle-shaped cells 13 (Fig. 454). The malignancy of these latter tumors approaches that of the Group III cancers. The tumors of an intermediate degree of malignancy occur in older age groups than the Group I tumors. They spread by all routes-directly and by both the lymphatic and blood vascular systems. In the Hospital of the University of Pennsylvania material the 12 year survival was 33 per cent (4 of 12 patients). Here, too, the clinical course was often slow, since 14 of 26 patients (54 per cent) could be counted as five year survivors. III. TUIllors of a High Degree of Malignancy-Undifferentiated TUIllors
The best known and most striking of the undifferentiated thyroid carcinomas is the giant cell or spindle cell carcinoma (Fig. 455). It is char-
1678
Robert C. Horn, Jr.
acterized by a mixture of various numbers of cells of these two types. Usually, if extensive search is made, areas of distinct epithelial differentiation can be found with transition to the metaplastic tissues. 22 Occasional undifferentiated tumors are composed of large, rounded, fairly uniform cells or, on the other hand, of small round cells. Warren and Meissner26 subdivide the small cell carcinoma into compact and diffuse types. According to these authors, 20 to 30 per cent of patients with small cell carcinomas may survive for five years. The giant and spindle cell cancers occur in the elderly, frequently becoming manifest by the rapid growth of a previously quiescent goiter of long standing. In addi-
Fig. 454. Adenocarcinoma of thyroid, showing whorled, alveolar pattern. (Reproduced from Horn, R. C. Jr.: Carcinoma of the Thyroid: Description of a Distinctive Morphological Variant and Report of Seven Cases; Cancer, Vol. 4, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
tion to metastasizing early (to the lungs in particular) they frequently invade the neck widely, affecting vital structures. Survival of patients with giant and spindle cell tumors is a rarity. 9, 26 IV. Miscellaneous Malignant TunlOrs
A. Epidermoid Carcinoma. Although areas of squamous metaplasia are occasionally seen in thyroid cancers of various types, pure epidermoid carcinomas are rare. In our experience, they have been highly malignant and have pursued a rapidly fatal course. B. Sarcoma. According to Warren and Meissner,26 fibrosarcoma occurs more often in the thyroid than any other nonepithelial malignant tumor. It may be difficult to distinguish from a spindle cell carcinoma. Lymphosarcoma may occur at times as a disease localized to the thyroid. 6 Other lesions of the "lymphoma" series have been recorded, generally as part of disseminated disease. 26
The Pathologic Physiology of Carcinoma of the Thyroid
1679
HURTHLE CELL TUMORS
The cells of any type of thyroid carcinoma (as well as benign tumors and non-neoplastic lesions) may have the characteristics of Hiirthle cells. The presence of Hiirthle cells, even their predominance, appears to have no prognostic significance. 14 We have not, therefore, placed lesions composed of Hiirthle cells in a separate category.
Fig. 455. Giant and spindle cell carcinoma of thyroid. Two examples. In the upper right-hand corner some epithelial differentiation is apparent. (Reproduced from Horn, R. C. Jr.: Hiirthle Cell Tumors of the Thyroid; Cancer, Vol. 7, with the permission of J. B. Lippincott Co., Philadelphia, publishers.)
FUNCTION
Certain thyroid carcinomas can be demonstrated to have the ability to function-that is, to collect radioactive iodine. In general, this ability parallels the differentiation of the tumor, particularly with respect to the amount of colloid present. However, it is noteworthy that histologically identical follicles may differ in their ability to concentrate 1131 as demonstrated by radio-autographs. In none of the 100 cases studied by Fitzgerald and Foote 8 could tumor be shown to take up as much radioactive iodine as did adjacent normal thyroid tissue. Radio-autographic concentration of 1131 was demonstrated in 46 of their cases. It must be emphasized that only a fraction of these cases can be expected to utilize enough radioactive iodine for the latter to be therapeutically useful. 7 Also, as has been pointed out above, the differentiation of any thyroid carcinoma may vary greatly from one area or site to another. Similarly, the demonstrable functional capacity of a given thyroid cancer may not be the same at all times. Many attempts have been made to increase the ability of thyroid neoplasms to concentrate radioactive iodine. It has been demon-
1680
Robert C. Horn, Jr.
strated that the ablation of normal thyroid tissue will enhance a tumor's function in this respect (this may be largely a matter of eliminating an able competitor) and at times other measures, such as administration of certain thiourea compounds or thyroid-stimulating pituitary hormone, may have a similar effect. However, the many thyroid tumors lacking the ability to pick up radioactive iodine initially cannot be made to do so by any presently known procedure. I • 20 CLINICAL COURSE AND END RESULTS
The clinical evolution of thyroid carcinoma has been discussed above in connection with the various histopathologic types. The end results are summarized in Table 3. The frequency with which patients with thyroid Table 3 FIVE AND TWELVE YEAR SURVIVALS OF THYROID CARCINOMA (Hospital of the University of Pennsylvania, 1933-1947) NO. OF PTS. NO. OF PTS. TREATED TREATED 12 YEAR 5 YEAR MORE THAN SURVIVALS MORE THAN SURVIVALS 12 YRS. 5 YRS. AGO AGO Malignant adenoma ... Papillary, follicular or mixed. Adenocarcinoma. . .. Undifferentiated ...... TOTALS ....
16 54
26 16 112
9 40 14 3 66
(56%) (74%) (54%) (19%) (59%)
8 16 12 8 44
2 (25%) 6*(38%) 4 (33%) 1 (12.5%) 13*(30%)
* Three patients with papillary carcinoma are living with disease. After Horn and DulJ.15 cancer survive five years only to succumb to the disease subsequently is apparent. Only two of the patients who died after the five year period were not known to have active disease. Neither came to necropsy. Such data as these suggest that the variability of the malignancy of the different types of carcinoma of the thyroid manifests itself, not so much by variation in survival rate as by variation in the speed with which the disease progresses. REFERENCES
1. Black, B. M., Woolner, L. B. and Blackburn, C. M.: The Uptake of Radioactive 2. 3. 4.
5.
Iodine by Carcinoma of the Thyroid Gland: A Study of 128 Cases. J. Clin. Endocrinol. 13: 1378-1390, 1953. Cole, W. H., Majarakis, J. D. and Slaughter, D. P.: Incidence of Carcinoma of the Thyroid in Nodular Goiter. J. Clin. Endocrinol. 9: 1007-1011, 1949. Cope, 0., Dobyns, B. M., Hamlin, E. Jr. and Hopkirk, J.: What Thyroid Nodules Are to be Feared? J. Clin. Endocrinol. 9: 1012-1022, 1949. Crile, G. Jr. and Dempsey, W. S.: Indications for Removal of Nontoxic Nodular Goiters. J.A.M.A. 139: 1247-1251, 1949. Crile, G. Jr. and Hazard, J. B.: Relationship of the Age of the Patient to the Natural History and Prognosis of Carcinoma of the Thyroid. Ann. Surg. 138: 33-38, 1953.
The Pathologic Physiology of Carcinoma of the Thyroid
1681
6. Dinsmore, R. S., Dempsey, W. S. and Hazard, J. B.: Lymphosarcoma of the Thyroid. J. Clin. Endocrinol. 9: 1043-1047, 1949. 7. Dobyns, B. M. and Maloof, F.: The Study and Treatment of 119 Cases of Carcinoma of the Thyroid with Radioactive Iodine. J. Clin. Endocrinol. 11: 1343-1360,1951. 8. Fitzgerald, P. J. and Foote, F. W. Jr.: The Function of Various Types of Thyroid Carcinoma as Revealed by the Radio-autographic Demonstration of Radioactive Iodine (1 131 ). J. Clin. Endocrinol. 9: 1153-1170, 1949. 9. Frazell, E. L. and Foote, F. W. Jr.: The Natural History of Thyroid Cancer. A Review of 301 Cases. J. Clin. Endocrinol. 9: 1023-1030, 1949. 10. Graham, A.: Malignant Epithelial Tumors of the Thyroid with Special Reference to Invasion of Blood Vessels. Surg., Gynec. & Obst. 39: 781-790, 1924. 11. Hazard, J. B., Crile, G. Jr. and Dempsey, W. S.: Nonencapsulated Sclerosing Tumors of the Thyroid. J. Clin. Endocrinol. 9: 1216-1231, 1949. 12. Hazard, J. B. and others: Neoplasms of the Thyroid. Classificat.ion, Morphology 'and Treatment. Arch. Path. 59: 502-513, 1955. 13. Horn, R. C. Jr.: Carcinoma of the Thyroid. Description of a Distinctive Morphological Variant and Report of Seven Cases. Cancer 4: 697-707 (July) 1951. 14. Horp, R. C. Jr.: Hiirthle-Cell Tumors of the Thyroid. Cancer 7: 234-244 (March) 1954. 15. Horn, R. C. Jr. and Dull, J. A.: Carcinoma of the Thyroid: ARe-evaluation. Ann. Surg. 139: 35-43 (Jan.) 1954. 16. Horn, R. C. Jr. and Ravdin, 1. S.: Carcinoma of the Thyroid Gland in Youth. J. Clin. Endocrinol. 11: 1166-1178 (Oct.) 1951. 17. Horn, R. C. Jr. and others: Carcinoma of the Thyroid. Ann. Surg. 126: 140-155 (Aug.) 1947. 18. Majarakis, J. D., Slaughter, D. P. and Cole, W. H.: Carcinoma of the Thyroid Gland. J. Clin. Endocrinol. 13: 1530-1.541,1953. 19. Pemberton, J. deJ.: Malignant Lesions of the Thyroid. A Review of 774 Cases. Surg., Gynec. & Obst. 69: 417-430, 1939. 20. Rail, J. E. and others: The Use of Thiouracil in the Treatment of Metastatic Carcinoma of the Thyroid with Radioiodine. J. Clin. Endocrinol. 11: 12731280, 1951. 21. Sloan, L. W.: Of the Origin, Characteristics and Behavior of Thyroid Cancer. J. Clin. Endocrinol. 14: 1309-1335, 1954. 22. Smith, L. W.: Certain So-called Sarcomas of the Thyroid. Arch. Path. 10: 524530, 1930. 23. Sokal, .J. E.: Surgical Statistics on Malignant Goiter. Surg., Gynec. & Obst. 99: 108-114, 1954. 24. Warren, S.: The Classification of Tumors of the Thyroid. Am. J. Roentgeno!. 40: 447-450, 1941. 25. Warren, S. and Feldman, J. D.: The Nature of Lateral "Aberrant" Thyroid Tumors. Surg., Gynec. & Obst. 88: 31-41, 1949. 26. Warren, S. and Meissner, W. A.: Tumors of the Thyroid Gland. Atlas of Tumor Pathology, Section IV, Fascicle 14, Armed Forces Institute of Pathology, Washington, D. C., 1953. 27. Winship, T.: Carcinoma of the Thyroid in Children. Tr. Am. Goiter A. (1951), pp. 364-389, 1952. 28. Wozencraft, P. and Foote, F. W. Jr.: Occult Carcinomas of the Thyroid; Their Bearing on the Concept of Lateral Aberrant Thyroid Cancer. Cancer 1: 574583 (Nov.) 1948. 29. Young, M. 0.: Carcinoma of the Thyroid Gland: Incidence and Mode of Origin. Surgery 27: 364-367, 1950. 30. Zimmerman, L. M., Wagner, D. H., Perlmutter, H. M. and Amromin, G. D.: Benign and Malignant Epithelial Tumors of the Thyroid Gland. Arch. Surg. 60: 1183-1198, 1950. Henry Ford Hospital Detroit 2, Michigan