geographic pathology of thyroid carcinoma

GEOGRAPHIC PATHOLOGY OF THYROID CARCINOMA

CARLOS CUELLO, MD, PELAYO CORREA, MD," AND HENRY EISENBERG,~ MD, MPH

Pathologic and epidemiologic studies of carcinoma of the thyroid were carried out in an endemic and a nonendemic goiter area. Two hundred twenty- nine cases from the State of Connecticut, USA, and 217 from Cali, Colombia, were histologically reviewed and classified using a single nomenclature and previously agreed criteria. Tumors were classified in five categories: papillary, follicular, anaplastic, medullary, and others. A detailed pathologic descrip- tion for papillary and follicular varieties was made, since most of the confusion in nomenclature seems to be due to the absence of well-defined criteria for these two types of tumor. Incidence of specific histologic types in the two localities were also studied. A statistically significant excess of follicular carcinoma was found in Cali in comparison with Connecticut. An excess of anaplastic carcinoma in Cali was also seen, but the number of cases was too small to be significant. No differences were found in the incidence of papillary carcinoma in the two localities. Anaplastic and follicular carcinoma were more often associated with nodular goiter than papillary carcinoma.

HE NATURAL HISTORY OF CARCINOMA OF T the thyroid in different patients varies so much that it has been suspected that the different histologic types represent independent biologic entities. After the proposal of many histologic classifications, there is a growing consensus in favor of defining four main types: papillary, follicular, medullary (solid amyloid), and anaplastic.11, 12 , 16 Other types constitute rarities. The medullary carcinoma displays distinctive clinical, pathologic and epidemiologic characteristics, which have been well described in other publications whose authors are in favor of its being considered an independent entity. The other three types are less well characterized epidemiologically. It is the purpose of this study to present pathologic and epidemiologic observations for these histologic types of tumor which may Serve as a basis for judging its hiologic individuality.

MATERIAL AND METHODS

The observations presented are based on

1. Pathologic studies of 217 consecutive cases of primary thyroid malignancies

material obtained from three sources:

From the Department of Pathology, Facultnd dc Medicina, Universidad del Valle, Cali, Colombia,* and the Connecticut Cancer Registry, Hartford, Conn.

Supported by Contract PH-43-66-907, National Can- cer Institute, USPHS.

t Deceased, November 2, 1968. Received for publication July 16, 1968.

diagnosed at the Departments of Pathol- ogy of the Universidad del Valle and of the San Juan de Dios Hospital of Cali, Colombia, during a 15-year period (Janu- ary 1953-December 1967).

2. Pathologic studies of 229 cases from Connecticut. These represent the cases in which slides were available for review at the Connecticut Cancer Registry from 1955 to 1959 for females and from 1950 to 1962 for males. Of the total cases regis- tered, only 70% were available for review.

3. Annual incidence rates by histologic types of cancer of the thyroid based on data from the tumor registry of Cali, Colombia, and Connecticut, USA. In the latter registry, data on survival by histologic type were also available.

The coexistence of cancer and nodular goiter was evaluated in 184 specimens obtained by thyroidectomy or autopsy in the Cali material. The evaluation of chronic lymphocytic thyroiditis was done in 148 cases from Cali and 61 cases from Connecticut in which adequate amounts of tissue from the nontumorous parenchyma could be microscopi- cally studied.

HISTOPATHOLOGIC CRITERIA FOR CLASSIFICATION

The terms papillary and follicular cannot be taken literally in considering thyroid car-

230

No. 1 GEOGRAPHIC PATHOLOGY OF THYROID CARCINOMA - Cuello et al. 23 1

cinoma. They are by no means synonymous with papillae and follicles. Since this is a frequent source of confusion, it seems important to define them accurately in pathologic terms.

P a p i Z h y cn~cinorna: These tumors have a distinct architecture which allows their ready identification and delimitation from the surrounding thyroid structures which may be atrophic or normal. The most typical feature of its structure is the type of invasion of the neighboring tissues, consisting of the presence of small clusters of tumor cells surrounded by 1 ather thick collagenous bundles. This fibrous deposition occasionally forms thick bands but does not usually form a capsule around the tumor. Another outstanding feature of the histology is the nuclei of the tumor cells; they are larger than those of the follicular carcinomas and generally have the chromatin distributed diffusely in very fine grains (“dust”) which gives to them the appearance of ground glass (Fig. 1). The above-mentioned features are more constant than the presence of

papillae. The tumor cells organize themselves in several patterns which give rise to the following varieties:

1. Gyriform variety, composed of abundant trabeculae and papillae mixed with irregularly shaped follicles. No fibrosis is observed in the central portion of the tumor, but in the invasion sites typical desmoplasia is notorious, usually surrounded by mononuclear infiltrate (Fig. 2).

2. Follicular variety, described well by Lindsay.1l The predominant pattern is formed by medium-sized or small follicles usually without colloid. Sometimes, small inconspicuous papillae are present; the morphology of the cytoplasm, nuclei and peripheral desmoplasia are similar to the other \ arieties of papillary tumor (Fig. 3).

3. Cystic variety, with tree-branch-shaped

FIG. 1. Papillary carcinoma. “Ground glass’’ nuclei (I-I and E, X420). FIG. 2. Papillar) carcinoma. Irrcgularl) shaped follicles are mixed with papillary structures

(H and E, x270).

232 ,CANCER January 1969 Vol. 23

FIG. 3. Papillary carcinoma. Small and medium-sized follicles. Note “ground glass” nuclei

FIG. 4. Papillary carcinoma. Cyst containing tree-branched papillae. Thick collagcnous and marked desmoplasia in the periphery of the tumor (H and E, ~ 2 7 0 ) .

pseudocapsule invaded by tumor structures (H and E, ~ 5 0 ) .

papillae floating in fluid and compress- ing the surrounding tissue to form a pseudocapsule, (Fig. 4).

4. Sclerosing variety, composed by apparently empty elongated acini surrounded by thick collagenous bundles (Fig 5) . This rare variety is generally devoid of papillae.

Folliculur cawinornu: Rather than follicles, what characterizes these tumors is their com- pact architecture, which results in nodules surrounded by capsules, their growth by expansion and the size and shape of the tumor cells. These are smaller than those of papillary carcinoma and have dens: nuclei with one or two small chromatin clusters which can be differentiated from nucleoli by their basophilic staining; the nuclear size and shape is homogeneous and the nuclear membrane neat. The capsules which surround the nodules characteristically have numerous telangiectasias as well as thick-walled small

arteries and arterioles. Also found within the capsule are small nodules of elastic tissue which might correspond to tangential cuts of arterial walls or occlusion of vessels as a result of elastic hyperplasia. Within the vessels one fiequently finds tumoral thrombi, without rupture, scarring or other sequelae in the arterial wall as evidence of the passage of the tumoral cells. The metastases and local extensions of the tumor usually reproduce a nodular architecture, grow by expansion, form a capsule, compress the surrounding tissue instead of penetrating it and easily invade the vessels. In the center of the large nodules, primary and metastatic, large areas of hyalinized or edematous fibrous tissue are observed. Each nodule tends to expand cen- trifugally and large cellular groups break through the capsule to form satellite nodules which for some time seem to remain united to the principal mass. Areas of necrosis are frequent in large nodules. The fibrous stroma occasionally shows amyloid appearance. Within the nodules, the tumor cells might

No. 1 GEOGRAPHIC PATHOI.OCY OF THYROID CARCINOMA - Cuello ct 01. 233

FIG. 5 . Papillary carciuoma. Elongated empty glandular stiuctuies cmbedded in an abundant

FIG. 6. Follicular carcinoma. The tumor exhibits a solid pattern. Traheculae and follicles thick tollagenous stroma (H and E, X50).

werc seen in other fields of the same tumor (H and E, x105).

organize themselves in one or several of the following patterns:

1. .4s solid masses which occasionally form small follicles, often without lumen. This is the most frequent type (Fig. 6).

2. As well-formed follicles which are reminiscent of the normal thyroid gland. Sometimes called malignant or metastasizing adenoma, this type is frequently seen in metastasis to bone but not so frequently within the thyroid gland (Fig. 7).

3. As elongated spaces with pseudopa- pillae oriented perpendicularly to the capsule, with very little colloid (Fig, 8). ‘This type of tumor should be placed in the category of follicular carcinomas in spite of the presence of papillae for the following reason: It grows by expansion, forms a capsule with thick-walled

vessels and displays definitive vein invasion in the form of thrombi (Fig. 9). Desmoplasia and groundglass nuclei are absent.

4. As oxiphilic Hurtle cell tumors form- ing alveolar spaces or cords. I n this type, the nuclei are not so uniform and frequently contain nucleoli.

0 ther types: Medullary and anaplastic carcinomas are adequately described in the litera- ture. 6-16

RESULTS

Tables 1 and 2 show the age distribution of the cases studied in both localities for each sex. In general, papillary carcinoma predominates from 15 to 54 years of age, follicular carcinoma from 35 to 64 and anaplastic carcinoma after 45 years of age.

Association with goiter: The results ob-

234 CANCER January 1969 Vol. 23

FIG. 7. Follicular carcinoma. Metastasis hone. Tumor architectuie similar to that of benign

FIG. 8. Follicular carcinoma. Elongated spaces oriented peipendicularlJ to the capsule. Kote a nodule (H and E, ~ 1 0 5 ) .

thich-walled t r in in the tumor capsule (H and E, ~ 5 0 ) .

tained in the two departments of pathology of Cali, in which this study was carried out, were considered separately because this association has been more thoroughly studied in the department of pathology of the Univer- sidad del Valle where many sections are taken in cases of thyroid cancer, looking for benign nodules. The material from Connecticut was not evaluated for this association because in most cases only slides of the tumor proper were reviewed. As it is shown in Table 3, anaplastic and follicular carcinoma are more frequently associated with benign thyroid nodules than papillary tumors. Such an association is very striking in anaplastic tumors. Most of the goiters associated with cancer were of the parenchymatous variety, also called multiple adenomas, which is the prev- alent type in Cali.1 The proportion of goiter in specimens of papillary carcinoma is similar to that found in the general adult population

Association with thyroiditis: Table 4 shows the results of this evaluation in Connecticut

(45%)-

and Cali. Thirty-three per cent of papillary tumors in Cali and 44.2% in Connecticut were associated with lymphocytic infiltration of the nontumorous parenchyma. This incidence is fairly close to the incidence reported by other authors.* In most cases, such a thyroiditis was of the focal type. In only three cases was the infiltration diffuse and severe, but none of them fulfilled the criteria for classic Hashimoto’s disease. Fully developed Hashi- moto’s disease with goiter, hypothyroidism and oxiphilic changes of the epithelium is a very rare entity in Cali. Lymphocytic thyroiditis associated with follicular and anaplastic carcinoma was not so frequent.

Other yemarks on pathology: Included in the cases of anaplastic tumors are five cases of carcinosarcoma of the thyroid (four with osteocartilagenous and one with fibrosarcoma- tous components. No case of lymphosarcoma of the thyroid gland was found in Cali. In contrast, in Connecticut, four cases of lymphosarcoma but no cases of carcinosarcoma were found.

No. 1 GEOGRAPHIC PATHOLOGY OF THYROID CARCINOMA Cuello et a l . 235 Incidence of specific histologic types: His-

tologic-specific incidence rates for each sex and age group from two cancer registries are compared in Fig. 10. Papillary carcinoma in Connecticut exemplifies the usual pattern observed in most registries. After the thircl decade, the incidence rate for females shows no substantial further elevations, indicating that in spite of the natural aging of the population, the risk of this disease does not in- crease. This could actually be interpreted as a gradual diminution of the effect of car- cinogenic factors related to this tumor. In males, there is a very moderate elevation of the incidence rates from the third to the seventh decades. Papillary carcinoma in Cali females shows a rising excess over the incidence observed in Connecticut after the t h i i d decade.

Follicular carcinoma is a much more frequent disease in Cali than in Connecticut in both sexes after around age 40.

Anaplastic carcinoma reaches its main level of incidence only around the sixth decade of life, and it appears excessive in Cali compared with Connecticut. Whether this excess is somehow related to the endemic goiter, as suggested by the above-mentioned findings in thyroiclectomy specimens, can only be suspected at this time; we must await further epidemiologic studies.

The crude incidence rate of Connecticut with the expected rate iiom Cali, adjusted for age to the population of Connecticut, is compared in Table 5. It is clearly seen that the excess of follicular carcinoma in Cali is statistically significant in both sexes. The rate for papillary tumors is similar in both localities. ‘The differences in anaplastic tumors would need a larger number of cases to prole significance.

Suruiual by histologic type: Data on survival by histologic type in Connecticut are shown in Table 6. The differences in prognosis of each histologic type are obvious.

FIG. 9. Follicular carcinoma. Same as Fig. 5 . Note short papillae and a tumor thrombus in a vein (H and E, x50).

DISCUSSIOX

Published data from different parts of the world show that mortality from thyroid carcinoma is much greater in some communities than others.13 Incidence rates in men4 are about 60 times greater in Hawaiians than in Ugandans. In some places, e.g., Hawaii, it can be observed that the high incidence covers all ethnic groups. There is evidence that the mortality rates are increasing in some countries, eg. , Japan, while they are decreasing in others, e.g., S~i tzer1and. l~ All of these data

TABLE 1. Age Distribution in Patients with Different Histologic Types of Thyroid Carcinoma in Males: ___- Cali 1953-1967; Connecticut 1950-1962

____ Papillary Follicular Xnaplastic Medullary

Age Cali Conn. Cali Conn. Cali Conn. Cali Conn.

n-14 n n n n 0 0 0 0 - _ _ 4 0 0 2 0 1

TOTAL 18 58 24 19 26 25 3 10

2 3 4 24 10 13 13 19 1 6

15-34 9 12 35-54 5 22 10 6 13 4 55 f

236 CANCER Janua?-y 1969 Vol. 23

TABLE 2. Age Distribution in Patients with Different Histologic Types of Thyroid Carcinoma in Females: Cali 1953-1967; Connecticut 1955-1959

__. ~- Papillary Follicular Anaplastic Medullary

Age Cali Conn. Cali Conn. Cali Conn. Cali Conn.

n-i 4 n 1 n n n n n n . _.

15-34 35-54

17 2 0 I2 22 37 27

4 4

2 9

55 + 13 11 16 9 15 15 1 2 TOTAT. 52 69 55 17 26 23 8 5

are in favor of the theory that environmental factors play a decisive role in the production of these tumors.

The age-specific incidence rates for thyroid carcinoma in general show a somewhat different pattern for each sex and for different geographic areas2+ The rates in lemales usually reach a high level in the third decade and have none or minor elevations after that age. This pattern is well exemplified by the data from New York State. Data from Canada and Connecticut show a similar pattern with the addition of elevation of the level of incidence rates around the age of 60 years. This elevation is also clearly seen in other sets of data like those from Israel, Iceland, Co- lombia (Cali), and Yugoslavia (Slovenia). The rates for females are higher than those of males at all ages, with few exceptions after age 70. Data from England and the Scandi- navia show a constant slope for both sexes after age 25. Data from Iceland, Colombia (Cali) and Hawaii stand out for its high level of incidence in both sexes.

It is important to note that these sets of data, although confirming high prevalence of thyroid cancer in some well-known goiter areas, e.g., Colombia (Cali) and Israel,g also point out that high goiter prevalence is not a necessary factor for the presence of high thyroid cancer rates. This is the case of Iceland, Hawaii, and Newfoundland, where factors responsible for thyroid carcinoma seem

TABLE 3 . Frequency of Association with Goiter of Each Histologic Type of Tumor (Number of

Cases in Parentheses)

Hospital Universidad San Juan

del Valle de Dios

Papillary (51) 58.8% (8) 50.0% Follicular (51) 78.4% (25) 7 2 . 0 % Anaplastic (33) 96.9% (8) 87.5% Medullary (9) 33 3% - -

not to be associated with endemic goiter. Our findings may be interpreted as an

epidemiologic test applied to a morphologic observation and resulting in a confirmation of the validity of the pathologic classification. The tumor types considered may be thought of as having biologic individuality, based on the following observations.

Papillary carcinoma apparently arises from the epithelial cells of the follicles; the tumor cells organize themselves in very small clusters which penetrate the surrounding structures and stimulate fibroplasia and inflammation to a considerable extent; the cells have abundant cytoplasm and a rather large nucleus with its chromatin distributed in very small gran- ules and apparently low content of DNA per nuc1eus;lO it may be found in an otherwise normal gland or in a nodular goiter, in which case i t is usually not located inside the nodules. This type of tumor is much more frequent in females at all ages. The age- specific incidence rates for females in most registries rises in the second and third decades of life and then either remains at the same level or shows minimal elevations with age. In a few registries it shows a constant moderate elevation after the second decade of life. The progress of the disease is slow and the tumor is usually controlled by surgery. Therefore, the survival rates are usually excellent. The inflammatory and fi- brotic response to microinvasion might be

T A B L E 4. Frequency of Association of Each Histologic Type of Tumor with Lymphocitic Thyroiditis.

(Number of Cases in Parentheses)

Cali Connecticut

Papillary (53) 33.9% (61) 44.2% Follicular (63) 6 .3% Not studied Anaplastic (22 ) 9.1% Not studied Medullary (10) 0 .0% Not studied

No. 1

0.1 :

GEOGRAPHIC PATHOLOGY OF THYROID CARCINOMA - CueZZo et aZ. 237

l 1 1 1 1 1 1 1 ,

ANAPLASTIC 10: 107 ,@--a

1: / , : @A’ -

0.1: 0.11

I 1

1

I I I I I I I ,

/ ? a,’

a----a CALI M CONNECTICUT

FIG. 10. Age-specific incidence rates per 100, 000 by sex in both localities.

I 0.1

related to this prognosis. Experimental production is achieved mainly with ionizing radiation and is enhanced by iodine deficiency.5 It has been reported in excess in persons expo\ed to ionizing radiation in infancy.7-lS

Follicular carcinoma is characterized mor- phologically by the fact that it grows in the

foim of large cell masses. The tumor cells, although apparently also originating from the follicular epithelium, maintain their cohesive- ness to some extent and therefore invade by pressing the surrounding tissues instead of penetrating them. This may be one reason why they do not stimulate fibroplasia or inflammation to any considerable extent. In

238 CANCER January 1969

TABLE 5 . Comparison of Observed Incidence Rate for Each Histologic Type of Thyroid Carcinoma in Connecticut and the Expected Rate for Cali (9573 Confidence

Limits Rascd on Total Number of Observcd Cascs in Each Locality)

VOl. 23

~~ ~ ~ ~~ ~ ~~~ ~~ ~

Z’Iales Females

Connecticut Cali (expected) Connecticut Cali (expected)

Confidcncc Confidencc Confidence Confidence I b t c limits Rate limits Rate 1 imi t s Rate limits

1 45 (” l8 1 4 9 {l 85 0 91 1 19

0 40 {’ O2 0 11

P,ipillar\ 0 54

1 . 7 7 i‘,” 1.09

0.62 f ’ 8 4 0.44

1.48 f ’” 0.64

Follicular 0 .2 1

0 43 (“ 63 0 28

0 46 (,’87 0 21

.Inaplastic 0 18

the process of growth they result in the production of numerous telangiectasias and this apparently facilitates their spread via vas- cular channels. It might be that the telangiectasias are the result of the expansive growth and its blocking effects on blood and lymph vessels. Blocking of fine branches of the carotid arteries might facilitate the travel of tumor emboli back to that arterial origin in the external carotid artery. This might explain the metastasis in the frontal bone, a frequent first sign of thyroid follicular carcinoma.

Epidemiologically, follicular carcinoma age- specific incidence rates usually have a constant rise after the third decade of life, reach- ing a peak around the sixth decade. It predominates in females to a less marked degree than papillary carcinoma. It is apparently frequently associated with endemic goiter14 and seems to start from nodules, which might be called “adenomas” or “parenchymatous nodules” in different nomencla- tures. These processes can be seen experi- mentally with iodine deficiency and “goitro- gens” which usually result in excessive TSH effect on the thyroid gland. Nodules have also been reported in human subjects exposed to ionizing radiation to the neck region during infancy, but in such cases their incidence would suggest that they appear later than the cases of papillary carcinomas ol such cohorts.7 Even if the rate of growth of such tumors is not very great, their prognosis is worse than that of papillary tumors, due in part to the ease with which they invade blood vessels and the ease with which their metastases grow successfully in certain tissues such as bone marrow. In this case the good “differentiation”

of the tumor cells does not constitute ;I favor- able factor for the patient.

Medullary carcinoma has been clearly sep- arated from the rest of thyroid tumors by its clinical and biologic aspects.6 Its family clus- tering and its association with tumors in other endocrine organs do not favor an ecologic factor as etiologic agent.

Anaplastic carcinomas seem to be a rather heterogeneous group. They all have in com- mon their bad prognosis, their incidence in the later decades of life and their aggressive- ness. However, they display a large variety of histologic patterns. In countries with a history of severe goiter endemia, past or present, there iq an excess of these tumors. In the same countries an unusually high frequency of carcinosarcomas is found.3 It would seem that some histologic varieties of anaplastic tumors might be associated with long-standing goiter. T h e number of cases in any given community is usually too small for the adequate epidemiologic study of them.

TABLE 6. Studies on 5-year Survival in 218 Cases from Connecticut (Three Patients with Papillary

Carcinoma and the Same Number of Anaplastic Carcinoma were lost to Follow-up)

Total Tumor type cases 5-Year follow-up ..

Dead of Dead of other cancer causes

Papillary 120 6 12 Follicular 3 5 10 5 Xnaplastic 43 38 2 Medullary 14 3 3

so. 1 GEOGRAPHIC PATHOLOGY OF THYROID CARCINOMA - Citello et al.

REFERENCES

239

1. Correa, P., and Castro, S.: Survey of the pathology of thyroid glands. From Cali, Colombia; a goiter area.

2. ---, Cuello, C., and Eiscnberg, H.: Epidemi- ology of different types of thyroid cancer. Monograph of the UICC Conference on Thyroid Cancer, Lausanne, Switzerland. To be published.

3. Cuello, C., and Coirea, P.: Carcinosarcoma of the thyroid. To be published.

4. Doll, R., Payne, P., and Waterhouse, J.: Cancer Incidence in Five Continents. UICC Monograph, Switzerland, Springer Verlag, 1966.

5. Doniach, I.: Effects including carcinogenesis of 1131 and x-rays on the thyroid of experimental animals -A review. Health Phys. 91357-1362, 1963.

6. Hazard, J. B., Hawk, W. A,, and Crile, G., Jr.: Medullary (solid) carcinoma of the thyroid-A clinico- pathologic entity. J. Clin. Endocr. 19:152-161, 1959.

7. Hempelmann, L. H., Pifer, J. W., Burke, G. J., Terry, R., and Ames, W. R.: Neoplasms in persons trcuted with x-rays in infancy for thymic enlargement. J. Nut. Cancer Inst. 38:317-341, 1967.

8. Hirabayashi, R. N., and Lindsay, S.: Thyroid rarcinorna and chronic thyroiditis of the Hashimoto type-A statistical study of their relationship. In T u - mors of the Thyroid Gland. New York, Karger, 1966;

Lab . I W X S ~ . 10:39-50, 1961.

pp. 272..291.

9. Kelly, F. C., and Snedden, W. W.: Prevalence and Geographic Distribution of Endemic Goiter. In En- demic Goiter. Geneva, WHO Monograph No. 44, 1960.

10. Laumonier, R., Laquerrierc, R., and Nassif, N.: Histological and histochcmical criteria of malignancy in thyroid epitheliomas. I n Tumors of the Thyroid Gland. New York, Karger, 1966; pp. 85-105.

11. Lindsay, S.: Carcinoma of the thyroid gland. Springfield, Charles C Thomas, 1960.

12. Russell, W. O., Ibanez, M. L., Clark, K. L., and White, E. C.: Thyroid carcinoma-classification, intra- glandular dissemination and clinicopathological study based upon whole organ sections of 80 glands. Cancer 16:1425-1460, 1963.

13. Segi, M., and Kurihara, M.: Cancer Mortality for Selected Sites in 24 countries. No. 4 (1962-1963). Sendai, Japan, Tohoku University School of Medicine, 1966.

14. Saxh , E.: Carcinoma thyroideae and its incidence in Finland. Acta Chir. Scand. Suppl. 156:l-GO, 1950.

15. Winship, T., and Rosvoll, R. \ I . : Cancer of thc thyroid gland in children. I n Tumors of thc Thyroid Gland. New York, Karger, 1966; pp. 320-329.

16. Woolner, L. B., Beahrs, 0. H., Black, B. M., hkConahay, W. M., and Keating, F. R., Jr.: Classifica- tion and prognosis of thyroid carcinoma. A m . J . S w g . 102:354-387, 1961.

geographic pathology of thyroid carcinoma

Documents