Prognosis of Undifferentiated Carcinoma and Lymphoma of the

Thyroid

Ricardo Rossi, MD,’ Boston, Massachusetts

Blake Cady, MD, Boston, Massachusetts

William A. Meissner, MD, Boston, Massachusetts

Cornelius E. Sedgwick, MD, Boston, Massachusetts

Joan Werber, AB, Boston, Massachusetts

Undifferentiated thyroid carcinomas are uncommon and have a reputation for such a poor prognosis that they have elicited little interest among surgeons. However, their management illustrates several sur- gical principles; their etiology, differentiation, and pathology are of contemporary interest; and surgical therapy can contribute to reasonable cure rates in selected patients. Recent reports suggest improve- ments in survival rates with the use of combined modality therapy. Therefore, a review of the biology, incidence, and current therapeutic achievements seems in order.

Material and Methods

Of 964 patients with thyroid cancer treated at the Lahey Clinic between 1931 and 1970 and whose records were re- viewed in 1975 [I], 147 were originally classified as having undifferentiated forms of disease. In a further intensive review by one of us (WAM) of these 147 patients, 21 were reclassified: 10 were found to have medullary carcinoma and 11 could not be substantiated as having primary un- differentiated thyroid carcinoma. The remaining 126 pa- tients with thoroughly documented undifferentiated thyroid cancers form the basis of the present report.

The classification of the Armed Forces Institute of Pa- thology Atlas of Tumor Pathology [2], which closely re- sembles that of the World Health Organization [3], is used. Briefly, the histologic criteria of the major types are as follows:

Giant cell carcinoma is composed of mixtures of bizarre giant cells and spindle cells, either of which may predom- inate. Mitoses, often atypical, are numerous. Invasion of soft tissues and blood vessels is extensive. Follicular ele-

From the Department of Surgery, Lahey Clinic Foundation, and Laboratory of Pathology, New England Deaconess Hospital, Boston, Massachusetts.

Reprint requests should be addressed to Blake Cady, MD, Department of Surgery, Lahey Cllnlc Foundation. 605 Commonwealth Avenue. Boston, Massachusetts 02215.

Presented at the Flfty4ghth Annual h4eetlng of tha New England Surgical Society, Portsmouth, New Hampshire, September 30-October 2, 1977.

* Present address: New England Deaconess Hospital, Harvard Surgical Service, Boston, Massachusetts.

ments formed by the tumor may be difficult to find. Other terms used are spindle cell carcinoma and anaplastic car- cinoma.

Small cell compact carcinoma is made up of clusters and strands of epithelial cells often lying in a fibrous hyaline stroma. The tumor resembles medullary carcinoma but lacks the usual microscopic pattern and the amyloid stro- ma.

In small cell diffuse carcinoma the cells grow in a diffuse arrangement and show numerous mitoses and often ex- tensive vascular invasion. Because the cells are relatively small, there is a resemblance to lymphoma. The tumor can only be recognized as carcinoma by identification of abortive follicles formed by tumor cells best demonstrated in extrathyroidal extensions. Other terms used are poorly differentiated follicular carcinoma and trabecular car- cinoma. Because of the impossibility of distinguishing histologically between small cell diffuse carcinoma and lymphoma, some cancers were diagnosed as small cell tumor, probably carcinoma or small cell tumor, probably lymphoma.

Lymphomas are included in the survey of undifferen- tiated carcinomas because of the frequent difficulty in distinguishing them from small cell diffuse carcinomas. Not only the diagnosis but also classification of the type of lymphoma of the thyroid is a problem without identifying lymphoma elsewhere. Rappaport’s classification [4] is used.

Accurate follow-up information was achieved for a minimum of five years in all patients, and 111 patients were seen for a minimum of fifteen years. Absolute survival and death rates were therefore utilized. No patient who lived for five years free of disease later died of thyroid carcinoma; therefore, five year disease-free survival was tantamount to cure. Patients were considered dead of disease if they died or were last seen with active disease present (including the one patient who died postoperatively). All other pa- tients were documented as living and free of disease or dead of other causes disease-free more than five years after therapy.

At operation, surgical estimation of extent of disease was classified as occult if thyroid carcinoma was not suspected, intrathyroid if carcinoma was suspected but confined within the thyroid gland, or extrathyroid if gross extension

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-

Figure 1. Incidence and sex ratio of the five groups of un- dlfferentlated carcinomas and lymphoma of the thyroid g/and.

of carcinoma was observed to tissues outside the confines of the thyroid gland.

Surgical therapy consisted of biopsy only when thyroid carcinoma was unresectable. This tissue was frequently obtained in the process of performing a tracheotomy for relief of a compromised trachea from direct extension of carcinoma. Unilateral thyroid resection implied excision of a nodule or subtotal or total thyroid lobectomy. Thy- roidectomy implied bilateral thyroid gland removal per- formed tc ensure adequate removal of cancer.

Results

The 126 patients with undifferentiated thyroid cancer represented 13 per cent of all thyroid cancers encountered at the Lahey Clinic. However, during the four consecutive decades between 1931 and 1970 of this study, the number of undifferentiated cancers and percentage of total cases were 29 (19 per cent), 47 (18 per cent), 35 (10 per cent), and 15 (8 per cent). A similar proportion of giant cell and small cell va- rieties existed in all four decades. Thus, undifferen- tiated forms of thyroid carcinoma are becoming less frequent, and this shift is a statistically significant one (p <O.OOl).

The distribution according to number, cell type, and sex is demonstrated in Figure 1. The overall fe- male to male ratio was 2.6 to 1 but was 8 to 1 in small cell difuse carcinomas and 1.3 to 1 in giant cell car- cinomas. The most frequent tumor among women was the small cell diffuse type, but among men it was the giant cell type. Of 126 patients, 51 patients (41 per cent) had giant cell carconomas, 36 patients (29 per cent) had small cell diffuse carcinomas (of which 24 were definite and 12 were probable), 17 patients (14 per cent) had lymphomas (of which 9 were defi- nite and 8 were probable), 9 patients (7 per cent) had small cell compact carcinomas, and 13 patients (10

per cent) had a variety of rare malignant tumors of the thyroid, such as fibrosarcomas (4), unclassifiable carcinomas (3), epidermoid carcinomas (2), ade- noacanthoma (l), adenosarcoma (l), clear cell car- cinoma (l), and columnar cell carcinoma (1).

Most of the present report concerns the first four major groupings-giant cell, small cell diffuse, lym- phoma, and small cell compact. The median age at diagnosis was sixty-three years (range, 41 to 75 years) for patients with giant cell carcinoma, sixty-five years (38 to 83) for patients with small cell diffuse carci- noma, sixty-two years (20 to 78) for patients with lymphoma, fifty years (35 to 67) for patients with small cell compact carcinoma, and fifty-eight years (16 to 85) for patients with the remaining rare car- cinomas.

A history of long-standing goiter with recent sud- den enlargement was reported by 21 per cent of all patients and 33 per cent of those having giant cell carcinomas. Only four patients gave a history of prior radiation to the head and neck area. Hoarseness and dyspnea were common symptoms.

Clinical findings at presentation consisted of a thyroid mass in 70 per cent, masses in both thyroid and cervical lymph nodes in 15 per cent, distant metastases in 10 per cent, and enlarged cervical nodes only in 2 per cent. Disease was clinically occult in 3 per cent of patients because findings were not even suspected of being carcinoma by the examiner. Pa- tients with lymphoma all presented with a thyroid mass, and a few also had adjacent cervical nodal metastases. Of the patients who presented with dis- tant metastases, the commonest site was the lung, followed in incidence by bone, liver, and brain.

Only 22 per cent of patients had primary cancer limited to an intraglandular location at operation (Table I), a few of which (6 per cent) were actually occult lesions. All patients with extraglandular dis- ease had involvement of muscles and soft tissue. Extraglandular extension involved the trachea in 48 per cent of patients and recurrent nerve in 25 per cent of patients, and 7 per cent also had lymph node metastases. Many patients had esophageal involve- ment also. At pathologic examination, 35 per cent of patients had invasion of blood vessels.

TABLE I Surgical Evaluatlon

Giant cell Small cell diffuse Lymphoma Small cell compact Others

No. lntraglandular Extraglandular

51 11(22%) 40 (78%) 36 7 (19%) 29 (81%) 17 3 (18%) 14 (82%) 9 3 (33%) 6 (67%)

13 4 (30%) 9 (70%)

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TABLE II Surgical Therapy of Thyroid

No.

Giant cell :: Small cell diffuse Lymphoma 17 Small cell compact 9 Others 13

Biopsy Only

14 (27%) 7 (19%) 4 (24%) 3 (33%) 1(6%)

Unilateral Thyroidectomy

5 (10%) 5 (14%) 4 (24%)

2 (15%)

Bilateral Thyroidectomy

32 (63%) 24 (67%)

9 (53%) 6 (67%)

10 (77%)

TABLE Ill Tumor Extent, Surgical Therapy, and Survival

Extent at Surgery lntraglandular Extraglandular

No. survwed No. Survived

Giant cell 11 2 (16%) 40 2 (5%) Small cell diffuse Lymphoma ;

4 (57%) 29 8 (28%) 3 (100%) 14 2 (14%)

Small cell compact 3 1(33%) 6 0

Surgical All Cancer Removed Gross Residual Cancer No. Survived 0. survived

16 3 (19%) 35 1(3%) 12 6 (50%) 24 6 (25%) 5 4 (80%) 12 1(8%) 2 1(50%) 7 0

The extent of operation is portrayed in Table II. Only a biopsy, usually with a concomitant tracheos- tomy, was performed in ‘23 per cent of patients. Only 13 per cent of patients had unilateral thyroidec- tomy,whereas 64 per cent had bilateral thyroidec- tomy of a greater or lesser extent. Simultaneous node dissections were performed in 10 per cent of patients. Only 32 per cent of patients had all macroscopic tumor removed as estimated by the operating sur- geon.

Surgical complications encountered were bleeding, wound infection, inadvertent recurrent nerve pa- ralysis, hypoparathyroidism, unrelieved airway ob- struction, tracheocutaneous listula, and chyle fistula. However, these were seldom life-threatening or se- rious.

External radiation therapy was given to 89 per cent of patients, but all patients with lymphoma had ra- diation. Radioactive iodine was used in a few in- stances; only one patient had documented regression of pulmonary metastases from a small cell diffuse carcinoma.

Figure 2 represents the survival curves of the four major pathologic groups. Of our patients, 33 per cent with small cell diffuse carcinoma, 29 per cent with lymphoma, 11 per cent with small cell compact car- cinoma, and 8 per cent with giant cell carcinoma lived five years and were cured of disease. For patients who actually died of disease, the median survival and range in months was three months (range, 1 to 49 months) for patients with giant cell carcinoma, four months (1 to 40) for patients with small cell diffuse carcinoma, eight months (2 to 48) for patients with lymphoma, and twelve months (1 to 34) for patients with small cell compact carcinoma. Thus, all deaths

from disease in these groups had occurred by forty- nine months.

Table III demonstrates that prognosis was mark- edly better for those patients with intrathyroid dis- ease and those in whom all gross disease could be removed. The median survival of patients who eventually died of carcinoma but who had all gross disease removed was prolonged over those who had residual disease at completion of operation and died. These differences in median survival were four months versus two months for patients with giant cell carcinoma, seven months versus four months for patients with small cell diffuse carcinoma, and twenty-five months (1 patient) versus twelve months for patients with small cell compact carcinoma. Only one of five patients with lymphoma who had all dis-

-- Y* SURVIVAL

0' I 2 3 . 4 - 5 YEARS

Figure 2. Survival curves of undifferentiated thyroid car- clnoma and lymphoma. Note the slmirerity of small cell d/ffuse carcinoma and lymphoma.

vohlma 195, April 1978 591

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ease excised died; death occurred promptly at three months. The 11 patients who had incomplete tumor exkision and died survived a median of ten months.

Survival was not apparently affected by the pres- ence of lymph node metastases in this series except in patients with lymphoma where all who had nega- tive nodes survived and all patients with positive nodes died of disease.

Patients cured of disease were younger than those dead of disease: giant cell carcinoma, fifty-five years (range, 53 to 64 years) versus sixty-three years (41 to 75); small cell diffuse carcinoma, sixty-one years (38 to 71) versus sixty-seven years (50 to 83); lymphoma, fifty-eight years (20 to 77) versus sixty-three years (24 to 78); and small cell compact carcinoma, thirty-five years versus fifty- three years (43 to 67). An equivalent proportion of men and women were found in the group cured and group dead of disease for each pathologic variety.

All patients who survived had radiation therapy to the primary cancer and surrounding neck and superior mediastinal area, usually to a dose exceeding 6,000 r, except for patients with lymphoma; they re- ceived about 3,500 to 4,500 r. Patients who died lived longer if they received radiation therapy than if they had not; however, this figure is adversely biased by the patients who died promptly without the oppor- tunity to receive radiation. The value of radiotherapy can be surmised from the fact that 6 of 24 patients with small cell diffuse cancer who had gross residual disease at completion of operation were cured. The survival in these patients can only be attributed to radiotherapy.

When comparisons were made between patients seen before or after 1951 for each major pathologic type, no changes in incidence, sex, age, disease pre- sentation, surgical therapy, survival, or life duration of treatment failures were discernible.

Two of four patients with fibrosarcoma survived ten years after complete removal of intrathyroid disease. The two patients whose disease could not be excised completely died of disease within one year. One patient who was cured did not receive radio- therapy. The two patients with epidermoid carci- noma had extensive local disease that was resectable, but both died of disease. In one of the three patients with unclassified cancer, disease occurred in a com- pletely excised intraglandular nodule and the patient lived free of disease for ten years. The other two pa- tients had extraglandular extension and died of dis- ease within six months. All three patients received radiotherapy.

The patient with clear cell carcinoma had intra-

glandular disease that was completely excised and survived for twenty-two years. No radiotherapy was given. At autopsy the kidneys were normal. The three patients with adenoacanthoma, adenosarcoma, and columnar cell carcinoma all died of disease at six, eight, and sixty-four months, respectively. All had undergone thyroidectomy and radiation therapy.

Comments

The exact histologic classification of highly ma- lignant undifferentiated cancers is difficult in all locations, including the thyroid, because these tu- mors have little or no resemblance to their normal tissue prototype. As a result, terminology is confusing and classifications are imprecise, varying from one institution to another. For example, giant cell carci- noma has been called spihdle cell carcinoma, ana- plastic carcinoma, and carcinosarcoma. Small cell carcinomas have been called poorly differentiated follicular carcinomas, trabecular carcinomas, and anaplastic carcinomas. Hedinger [5] has described the difficulties in differentiating spindle cell carci- noma from various sarcomas of the thyroid. Despite the criteria set forth by Walt, Woolner, and Black [6], Hazard [ 71, and Meissner and Phillips [8], the iden- tification of the type of small cell tumor may be very difficult. Rayfield, Nishiyama, and Sisson [9] have insisted that the separation of small cell neoplasms into carcinomas and lymphomas may not be possible at the present time. Burke, Butler, and Fuller [JO] concluded that all small cell tumors without follicle formation are lymphomas. Relatively few undiffer- entiated thyroid carcinomas have as yet been studied by electron microscopy; perhaps this technic will, in the future, help define the classification.

Another aspect of the difficulty in classification of these carcinomas is the differentiation between small cell compact tumors and medullary carcinomas. It is possible that the small cell compact tumors will eventually prove to be medullary carcinoma without one of the usual patterns and without amyloid stro- ma. Indeed, the group of nine patients with small cell compact carcinoma had a median age distinctly dif- ferent from that of patients with other small cell tu- mors or lymphoma (50 years versus 65 and 63 years).

In the 35 patients with medullary carcinoma in the entire Lahey Clinic series of thyroid cancers, the median age was fifty-four years (range, 21 to 76 years) and is similar to the age of patients with lesions classified as small cell compact carcinoma. However, the survival of patients with medullary carcinoma (54 per cent) was distinctly different from that of those

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with small cell compact cancer described here (11 per cent) as was the survival pattern of deaths: twenty- four months median (range, 3 months to 21 years) in contrast to twelve months median (range, 1 to 34 months). Seven of 19 deaths (37 per cent) from me- dullary carcinoma occurred after five years following therapy, a pattern distinctly different from that for undifferentiated thyroid carcinomas generally and for the small cell compact carcinomas specifically when all deaths had occurred by thirty-four months. With more sophisticated histologic technics, electron microscopy, better sampling of contemporary pa- tients, and use of calcitonin assays of the serum, the category of small cell compact carcinoma may lend itself to more precise definition.

The occurrence of these undifferentiated carci- nomas in older patients with female predominance, early invasion of adjacent tissues, and frequent me- tastases has been documented in the literature [1 I-141. Of note is the fact that only in occasional lymphomas, small cell tumors, and rare variations are patients found who are less than forty years of age.

The high incidence of long-standing goiter has been reported [11,12]. Sloan [15] commented on the possible origin of anaplastic cancers in well differ- entiated forms. Ibanez et al [16,17] have supported this conclusion and reported a 10 per cent incidence of follicular carcinoma and a 5 per cent incidence of papillary carcinoma in patients with anaplastic car- cinoma [18]. Frazell and Foote [29] reported 13 pa- tients in whom giant cell and spindle cell metaplasia had occurred in papillary carcinoma. Ueda and Furth [20] have demonstrated experimentally the trans- formation in mice of an epithelial tumor of the thy- roid into a spindle and giant cell tumor. In our study 27 patients (53 per cent) with giant cell carcinoma had adjacent microscopic mixed papillary and fol- licular carcinoma or areas with fibrosis and calcium suggesting such a long-standing differentiated car- cinoma in the thyroid gland.

However, in our previous report [1] of large num- bers of patients with differentiated thyroid carci- noma who were studied for many years, we encoun- tered only four patients who died with significant elements of giant and spindle cell carcinoma in the 94 total deaths. In one of these patients only foci of anaplastic elements were discovered, whereas in another, foci of undifferentiated forms were present at the original resection for differentiated thyroid carcinoma. Thus, only two patients could truly be considered to have conversions from differentiated thyroid carcinoma to undifferentiated giant and spindle thyroid carcinoma with the attendant rapid growth and prompt demise. In addition, no recur-

rences or deaths occurred after twenty-five or thirty years, respectively, after primary therapy of differ- entiated carcinomas; this suggests that despite many presumed residual areas of papillary and mixed carcinomas in lymph node metastases or contralat- era1 thyroid lobes, late conversion to giant cell car- cinoma must be an extremely uncommon event. It is apparent from this study that giant cell carcinomas are perhaps becoming less common in more recent decades despite the generally less aggressive ap- proach to differentiated thyroid carcinomas.

The sex ratio of patients with giant cell carcinomas (1.3 females to 1 male) is distinctly different from that of all patients with other thyroid carcinomas whether differentiated or undifferentiated where the ratio ranges from 3 to 5 or more women to 1 man.

It is most likely when considering all these facts that microscopic and occult differentiated thyroid carcinomas are very common and probably initiated by some agent that is nearly ubiquitous in the envi- ronment (?radiation, both cosmic and iatrogenic). Such occult thyroid carcinomas are not the source of clinical disease even when metastatic to lymph nodes. Separate and distinct promoting factors occur that convert these innocuous occult foci of cancer to clinically significant lesions-either differentiated thyroid carcinomas (generally in younger persons) or giant and spindle cell carcinomas (far less common and generally in older persons). Such a two-step process in development of clinical cancer would be consistent with theoretical and animal models and would be a logical explanation for the many puzzling aspects of thyroid cancer, particularly the relation- ship between differentiated and giant cell types.

The relation between radiation exposure with ra- dioactive iodine or external radiotherapy technics and development of anaplastic thyroid tumors has been noted occasionally [21,22]. Fibrosarcomas have been experimentally induced using radioactive iodine [23]. Only a few patitmts reported here had received radiotherapy in childhood, and late conversion of presumed radiation-induced differentiated thyroid carcinoma has not been reported.

In none of the other varieties of undifferentiated thyroid cancers reported or reviewed herein have any areas of papillary carcinoma or benign residual ade- noma been seen despite a careful search by the pa- thologist for these possible antecedents.

Whether it is currently clinically useful to separate primary lymphoma from small cell diffuse carcinoma is still unclear. In this series the two groups had somewhat similar age, sex ratio, clinical presentation, and survival expectation. While most primary thy- roid lymphomas resemble histiocytic lymphoma

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morphologically, they were frequently difficult to classify as well as to diagnose. In contrast, the lym- phomatous involvement of the thyroid seen at au- topsy in patients dying from disseminated lymphoma was comparatively easy to recognize and classify

181. The best survival is achieved when undifferen-

tiated carcinomas are confined within the thyroid gland or have limited extraglandular spread, which can be totally excised surgically. Thus, every attempt should be made to excise as much bulk tumor as is compatible with safety in those patients without massive disease. However, it is not suggested that the addition of laryngectomy or tracheal resection would add to the therapeutic approach. It is possible that this improvement in survival reflects less extensive disease rather than more effective therapy. Ibanez et al [16] and Kyriakides and Sosin [24] have stressed that surgery is useful in controlling local disease and decreases the percentage of patients dying of local disease. Tracheostomy should be performed in all patients in whom any encroachment of the trachea occurs, for invariably these patients will have a compromised airway requiring tracheostomy at some point because of aggressive local disease despite ra- diation therapy. Such a tracheostomy will obviate fears of tracheal obstruction secondary to the edema accompanying radiotherapy.

Smedal and Meissner [25] reported good results in undifferentiated thyroid carcinoma using radio- therapy alone. Most reports comment on occasional regression or arrest of anaplastic thyroid neoplasm with maximum doses of high voltage radiation [9,11] and indicate that small cell tumors seem more sen- sitive to this mode of therapy. Crile [26] has stated that radiation therapy alone can be as effective as a combination of radiotherapy and surgery in the treatment of lymphomas. In our retrospective ex- perience the value of radiotherapy is clear; several patients with macroscopic residual cancer survived, and significant local palliation frequently occurred in patients with giant cell carcinoma. Our survival figures for patients with lymphoma do not concur with those of Crile [26] in that radiation therapy achieved only one cure in 12 patients with residual tumor while complete surgical removal coupled with radiation of tumor accomplished an 80 per cent five year survival. Thus, in patients with small cell car- cinoma and lymphoma, the most effective therapy is combined surgical resection and postoperative radiotherapy.

Recent studies have reported objective regression using adriamycin 1271, actinomycin D [28}, and methotrexate [29] before or after radiotherapy in

high doses for giant cell carcinoma. In addition, combined chemotherapy in patients with lymphoma has been increasingly effective with many prolonged survivors [30]. Thus, all patients with small cell carcinoma and lymphoma should be considered for such aggressive therapy after completion of radio; therapy.

Summary

The experience with 126 patients with poorly dif- ferentiated thyroid carcinoma or lymphoma treated at the Lahey Clinic between 1931 and 1970 was re- viewed. Undifferentiated thyroid tumors predomi- nate in women and present late in life. While no giant cell tumors were found in patients less than forty years of age, small cell carcinoma and especially lymphoma can be seen earlier in life. Giant cell tu- mors were the most frequently found undifferen- tiated tumors in men while small cell types were commonest in women. These tumors involve ex- traglandular structures early; complete surgical re- moval is possible in only one third of the patients. Clinical course, survival, and biological behavior are closely related to the histologic type of the tumor. While patients who died of giant cell carcinoma had a median survival of three months and a five year survival of 8 per cent, patients with small cell carci- noma and lymphoma have a far better prognosis with a five year survival of 33 and 29 per cent, respectively. Differentiation of small cell carcinoma from lym- phoma is often difficult but may be of no clinical significance at present.

In view of our results we recommend: (1) total excision of tumor whenever possible, including lim- ited neck dissection when this is required; (2) “de- bulking” procedures when feasible to aid in trache- ostomy placement and use of radiotherapy and che- motherapy; (3) tracheostomy placement in the presence of any airway obstruction; (4) high dose external radiotherapy after operation or used as palliation in patients with nonresectable disease; (5) aggressive combination chemotherapy utilizing ei- ther adriamycin or actinomycin when palliation cannot be achieved by surgery and radiotherapy; and (6) thyroid hormone to avoid hypothyroidism, as the thyroid gland is usually functionally destroyed by the effects of invasive tumor and radiotherapy.

References

1. Gady B, Sedgwick CE, Meissner WA, et al: Changing clinical, pathologic, therapeutic and suvival patterns in differentiated thyroid carcinoma. Ann Surg 183: 541, 1976.

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2. Meissner WA, Warren S: Tumors of the thyroid gland. Atlas of Tumor Pathology, 2nd series, fascicle 4. Washington, DC. Armed Forces Institute of Pathology, 1969.

3. International Histological Classification of Tumors. Geneva, World Health Organization, 1967-1976 (15 numbers by various editors).

4. Rappaport H: Tumors of the hematopoietic system. Atlas of Tumor Pathology, Section III. fascicle 6. Washington, DC, Armed Forces Institute of Pathology, 1966.

5. Hedinger CE: Sarcomas of the thyroid gland, p 47. Thyroid Cancer. UICC Monograph Series, vol 12 (Hedinger CE, ed). Berlin, Springer-Verlag, 1969.

6. Walt AJ, Woolner LB, Black BM: Small-cell malignant lesions of the thyroid gland. J C/in Endocrinol Metab 17: 45, 1957. - -

7. Hazard JB: Nomenclature of thyroid tumors, p 3. Thyroid Neo- ~lasia (Youno S. lnman DR. ed). New York, Academic Press, isss.. -

8. Meissner WA, Phillips MI: Diffuse small-cell carcinoma of the thyroid. Arch Pathol74: 291, 1962.

9. Rayfield EJ, Nishiyama RH, Sisson JC: Small cell tumors of the thyroid. A clinicopathologic study. Cancer 28: 1023, 1971.

10. Burke JS, Butler JJ, Fuller LM: Mtllignant lymphomas of the thyroid: a clinical pathologic study of 35 patients including ultrastructural observations. Cancer 39: 1587. 1977.

11. Thomas CG Jr, Buckwalter JA: Poorly differentiated neoplasms of the thyroid gland. Ann Surg 177: 632, 1973.

12. Nishiiama RH, Dunn EL, Thompson NW: Anaplastic spindle-cell and giant-cell tumors of the thyroid gland. Cancer 30: 113, 1972.

13. Granner DK, Buckwalter JA: Poorly differentiated carcinoma of the thyroid gland. Surg Gynecol Obstet 116: 650, 1963.

14. Woolner LB, Beahrs OH, Black BM, et al: Classification and prognosis of thyroid carcinoma. A study of 885 cases ob- served in a thirty-year period. Am J Surg 102: 354, 1961.

15. Sloan LW: Of origin, characteristics and behavior of thyroid cancer. J C/in Endocr/no/ Mefab 14: 1309, 1954.

16. lbanez ML, Russell WO, Albores-Saavedra J, et al: Thyroid carcinoma: biologic behavior and mortality. Postmortem findings in 42 cases, including 27 in which the disease was fatal. Cancer 19: 1039, 1966.

17. Russell WO, lbanez ML, Clark RL, et al: Follicular (organoid) carcinoma of the thyroid gland. Report of 84 cases, p 14. Thyroid Cancer. UICC Monograph Series, vol 12, (Hedinger CE, ed). Berlin, Springer-Verlag. 1969.

18. Russell WO, lbanez ML, Clark RL, et al: Thyroid carcinoma. Classification, intraglandular dissemination, and clini- copathological study based upon whole organ sections of 80 glands. Cancer 16: 1425, 1963.

19. Frazell EL, Foote FW Jr: Papillary cancer of the thyroid; a review of 25 years of experience. Cancer 11: 695, 1958.

20. Ueda G, Furth J: Sarcomatoid transformation of transplanted thyroid carcinoma. Similarity to anaplastic human thyroid carcinomas. Arch Pathol63: 3, 1967.

2 1. Baker HW: Anaplastic thyroid cancer twelve years after ra- dioiodlne therapy. Cancer 23: 885, 1969.

22. Crile G Jr, Wilson OH: Transformation of a low grade papillary carcinoma of the thyroid to an anaplastic carcinoma after treatment with radioiodine. Surg Gynecol Obsfet 108: 357, 1959.

23. Marks S, Gsorge LA Jr, Bustad LK: Fibrosarcoma involving the thyroid gland of sheep given 1131 daily. Cancer 10: 587, 1957.

24. Kyriakiis G, Sosin H: Anaplastic carcinoma of tha thyroid. Ann Surg 179: 295, 1974.

25. Smedal MI, Meissner WA: The results of x-ray treatment in undifferentiated carcinoma of the thyroid. RadMgy 76: 927, 1961.

26. Crile G Jr: Lymphosarcoma and reticulum cell sarcoma of the thyroid. Surg Gynecol Obstet 118: 449, 1983.

27. Gottlieb JA, Hill CS Jr: Chemotherapy of thyroid cancer with

adriamycin: experience with 30 patients. N En@ J Med 290: 193,1974.

28. Rogers JD, Lindberg RD, Hill CS Jr, et al: Spindle and giant cell carcinoma of the thyroid: a different therapeutic approach. Cancer 34: 1328, 1974.

29. Jereb B, Stjernswlrd J, Lowhagen TZ Anaplastic giant-cell carcinoma of the thyroid: a study of treatment and prognosis. Cancer 35: 1293,1975.

30. Schein PS, Chabner BA, Canellos GP, et al: Potential for pro- longed disease-free survival following combination che- motherapy of non-Hodgkin’s lymphoma. Blood 43: 181, 1974.

Discussion

W. Bradford Patterson (Rochester, NY): Other than the Lahey Clinic and the New England Deaconess Hospi- tal, there are very few centers in the country or the world who could collect this large a group of these uncommon cancers. Therefore, I think that this presentation is very important.

My questions are two: It has been suggested by Clark and others that the progenitor of the small cell and the giant cell carcinoma in many or in all cases is the highly differ- entiated carcinoma, either papillary or follicular. This has been used by the group at the M.D. Anderson Hospital and others to say that patients with well differentiated cancer should have a total thyroidectomy, because a significant number will have these undifferentiated cancers later. Perhaps Dr. Cady could comment on whether this policy makes sense. Secondly, it is a syllogism for the authors to say that because those patients who had all their tumor removed fared better, then one should remove all of the tumor. It may be that the patient who had localized cancer that could be removed was destined for a longer survival and that it had nothing to do with the operation. Many believe that these anaplastic tumors of the thyroid are not surgical lesions and that radiotherapy is the most effective available treatment, although it too has limited benefit. I wonder if in many of these patients a needle biopsy alone is indicated and no other surgical procedure. This is one form of thyroid cancer in which patients often come in with symptoms such as pain or dysphagia. With this particular presentation a needle biopsy may establish the diagnosis quite well and be followed only by radiation.

John Brooks (Boston, MA): I enjoyed reading this ex- cellent paper and I find that it agrees in large measure with our experience at the Brigham. Thyroid carcinoma has a wide spectrum of biologic behavior ranging, pathologically speaking, from the almost benign papillary form to the anaplastic histologic type.

The behavior of thyroid cancer, like cancer of the stomach, seems to be changing: anaplastic tumors be- coming less common and papillary more common. Dr. Cady’s incidence of anaplastic malignancy in his series of all thyroid tumors is 13 per cent and this agrees with our experience reported at our 1972 meeting. Incidentally, it is interesting to note that few of his patients had had prior radiation in early life, in contrast to patients with papillary tumors.

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In our experience with over 150 malignancies of the thyroid followed from five to twenty-five years, there were no deaths from pure papillary carcinoma treated with lo- bectomy, isthmectomy, and subtotal contralateral lobec- tomy.

I am impressed by Dr. Cady’s five year survival rates. Our anaplastic patients have not done as well, although we have had a disproportionately large number of bad-acting extensive giant cell tumors that involved neighboring structures. His patients who did well with surgery and ra- diation had tumors confined to the gland itself.

Finally, allow me to theorize: We have had an anecdotal experience with two cases in our small anaplastic group in which a long-standing low grade papillary tumor in one case and a papillary-follicular tumor in another appear to have converted to anaplastic tumors over a period of years. In the first case, an inadequate excision had been per- formed and in the other only a biopsy had been performed. Both eventually developed incurable giant cell tumors.

In other cases of anaplasia, areas of papillary or follicular histology may be encountered concomitantly in the same specimen. Whatever significance you place on these find- ings, it makes theoretical sense to give oral thyroid extract to patients following excision of a malignant papillary or follicular nodule in the hope of preventing recurrent ma- lignancy or conversion of papillary or follicular cells into anaplastic ones.

Chiu-an Wang (Boston, MA): I want to show a slide of a twenty year did boy who had lymphoma proven by needle biopsy, followed by x-ray therapy and chemotherapy. When I first saw this boy three and a half years ago, he had a large goiter and I did a needle biopsy. It was lympho- ma.

I resisted operating on this child since I believed that surgery would not be effective. So I had him irradiated with 4,500 r and the mass disappeared. Four months later he developed a lump in the lung. I was worried that we were losing out. I got him treated by Dr. S. Kaufman of our Department of Oncology, with a combination of four drugs (cyclophosphamide, vincristine, procarbazine, and pred- nisone). In the course of time the nodule in the lung dis- appeared as is evidenced in the chest film taken subse- quently. He has been free of disease for at least three and a half years since the diagnosis WBS made. The point I want to stress is that there is a place for needle biopsy in the care of these patients.

The second point I want to mention is that we surgeons have to be more selective in choosing our patients for sur- gery-which one should have surgery and which one should have x-ray and chemotherapy.

William A. Meissner (Boston, MA): Thyroid cancers have an extremely wide range of behavior. In no other

organ or tissue is the precise histologic classification more important in determining prognosis and in selecting ap- propriate treatment. The recent classification proposed by the World Health Organization is very satisfactory and was used in our study.

The growth habits of the differentiated (papillary and follicular) thyroid carcinomas are now fairly well appre- ciated and predictable. For the most part, such cancers grow slowly and have a fairly good prognosis. The less common undifferentiated carcinomas on the other hand grow rapidly and usually cause death of the patient.

Although all undifferentiated thyroid carcinomas often are lumped together, it is important, because of their very poor prognosis, to search for variations in histologic pat- terns which might aid in defining subgroups with pre- dictable clinical behavior. This poses several problems for the pathologist, however. In the first place, all poorly dif- ferentiated cancers are difficult to classify with precision and to differentiate from other neoplasms. Furthermore, the follicular thyroid cells are capable of growing not only in a follicular and a papillary pattern but may manifest themselves in tumors as spindle cells, giant cells, small cells, or squamous cells, frequently with a mixture of types. Recognition of a poorly differentiated tumor as thyroid carcinoma may require searching many sections for abor- tive follicles formed by the tumor. Lastly, due to tumor inoperability, only a small biopsy may be submitted making an adequate pathologic study impossible.

Despite problems of evaluation both clinically and pathologically, the undifferentiated thyroid cancers should be continually reviewed in the hopes that more effective therapy might be developed for this highly lethal tumor.

Blake Cady (closing): The relationship between well differentiated papillary and giant cell carcinomas of the thyroid is frequently questioned. Of 99 patients who died after differentiated thyroid cancer in our entire experience, only 2 patients converted to giant cell carcinomas; yet, in patients with giant cell carcinoma who die, adjacent mi- croscopic papillary carcinomas are frequently seen. The sex ratio of giant cell carcinoma is 1 to 1, women to men; yet, in differentiated cancers it is 4 to 1. It is difficult to conceive of a theory to accommodate these facts. I think there is a two-step process in clinical thyroid cancer in- duction. First is the very common, perhaps even universal, development of microscopic foci of differentiated thyroid cancer. They are common because the harder pathologists look for such lesions and the more sections they make, the more frequently such lesions are seen. Second, such mi- croscopic foci may convert either to clinical papillary car- cinoma or to giant cell carcinoma. The pathway from mi- croscopic foci to macroscopic differentiated cancer to giant cell carcinoma must be very unusual. The factors that in- duce these two steps are unclear but may include radia- tion.

596 Tha American Journal cl Surgary