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Hürthle cell carcinoma of the thyroid gland: Prognostic factors and results of surgical treatment
Hfirthle cell carcinoma of the thyroid gland: Prognostic factors and results of surgical treatment Marian Passaro McDonald, MD, Laura E. Sanders, MD, Mark L. Silveranan, MD, Hsiang-Sui Chan, MD, andJo Buyske, MD, Burlington, Mass.
Background. Hiirthle cell carcinomas of the thyroid are unusual variants of well-differentiated thyroid cancers. Considered more aggressive tumors, their optimal treatment is controversial. Our institution's half century of experience, the largest series to date, includes 40 patients with Hiirthle cell carcinomas of 1000 well-differentiated thyroid cancers. Methods. A retrospective study was carried out on 40 patients. Results. Seventy-two percent were female, with a median age of 53 years, Median follow-up was 9 years. With the AMES risk stratification (age, distant metastasis, capsular extent, tumor size), arr~ong the 21 high-risk patients, 10 (48%) had a recmrence or died, with median time to recurrence 3 years (range, 0.5 to 14 years). Of these 10, 5 died of disease, one died of unrelated causes with disease, and 4 are alive with disease. Five recurrences presented as distant metastases. Extent at operation was the strongest predictor of recurrence, occurring in 66 % of those with gross extraglandular involvement. Conclusions. The A M E S criteria are useful in predicting recurrence and death. Although more aggressive surgery is appropriate for high-risk patients, in general their outlook remains grim. (Surgery 1996;120:1000-5.) From the Department of General SurgeU and the Department of Pathology, 7"heLahey Hatchcock Clinic, B'urlington, Mass.
HI3RTHLE CELLCARCINOMAS(HCCs) of the thyroid gland are u n u s u a l tumors comprising u p to 6% of all differentiated thyroid cancers. 1 They are considered a variant of follicular carcinoma of the thyroid by the World Health Organization a n d are referred to as follicular carcinoma, oxyphilic cell type. ~ Controversy still exists a r o u n d the optimal surgical treatment for this disease. Very little is known about the natural history of Hfirthle cell tumors, and an u n d e r s t a n d i n g of them continues to evolve. Much of the controversy revolves a r o u n d tile ability to differentiate correctly between an a d e n o m a a n d a carcinoma because the behavior of each is quite different, with drastically different outcomes for patients. Some authors 3 believe that all Hfirthle cell tumors should be treated as malignant a n d that aggressive surgical treatment is advocated. 3 Others believe that pathologic evaluation can be accurate in experienced hands a n d that different treatments are warranted for different diagnoses. < 5 However, very few studies contain many cases of Hfirthle cell carcinoma because the Presented at tile SeventeenthAnnual Meetingof the AmericanAssociation of Endocrine Surgeons,Napa, Calif.,April 21-23, 1996. Reprint requests: Laura E. Sanders, MD, Department of General Sn> gery, The LaheyHitchcoekClinic,41 MallRd,, Burlington,MA01805. Copyright 9 1996 by Mosby-YearBook, lnc. 0039-6060/96/$5.00 + 0 11/6/75772 1000 SURGERY
a d e n o m a type is m u c h more predominant. Litde is known about the presentation a n d natural history of HCC, and even less is known about the appropriate m a n a g e m e n t of the disease. This report reviews a half century of experience (1946 to 1996) with HCC a n d thus represents one of the largest series to date.
PATIENTS A N D M E T H O D S A t u m o r registry has b e e n kept at the Lahey Clinic since at least 1946. The older registry data were transferred to a formal database in 1990. Approximately 1000 cases of thyroid cancers have been registered; of these, 40 (4.0%) are reported as HCCs. The pathologic diagnosis was confirmed in each case by using accepted criteria: unequivocal vessel invasion or capsular invasion.3 All charts were reviewed and updated to the present, Each patient was evaluated for his or t~er risk factors by using the AMES criteria (A, age [men older than 41 years or women older than 51 years]; M, presentation with distant metastasis; E, extent of disease at operation; S, size of tumor greater than 4 cm). Operative reports were reviewed and patients were divided into groups according to the operation performed. Extent of disease at operation and the final pathologic reportwere noted. There were eight patients whose inclusion criterion was that o f " m i n o r capsular invasion." None of these eight had Mood vessel invasion. All other patients had major
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capsular invasion or b l o o d vessel invasion, or both. All patients h a d a primary diagnosis of malignancy at the time of the first t r e a t m e n t for HCC. Any history o f radiation before operation was noted. Any postoperative therapy was also noted, as were complications, recm~ fences, or deaths. T h e m e d i a n follow-up was 8.5 years (range, 0.5 to 38 years). T h e fortieth patient was operated on recently, with less than 1 m o n t h follow-up. She is not i n c l u d e d in the statistical analysis for recurrence because o f inadequate time o f follow-up. T h e m e d i a n age at operation was 53 years (range, 24 to 85 years). T h e r e were 28 women a n d 12 men, in keeping with past descriptions of a disease p r e d o m i n a n t l y f o u n d in women. 6 RESULTS Patient presentation varied. Fifteen patients were symptomatic from a thyroid mass. A solitary thyroid n o d u l e was f o u n d in 31 patients. No patient p r e s e n t e d with only neck adenopathy; two patients presented with both a neck and a thyroid mass. O n e patient p r e s e n t e d with distant metastasis, axillary a n d inguinal adenopathy, and liver metastasis. Only one patient h a d undergone previous thyroid operation; that patient had h a d a Benign a d e n o m a r e m o v e d approximately 20 years earlier. Preoperative fine-needle aspiration was perf o r m e d in only 12 patients, which reflects the long time span of this study. Of the 40 patients, only 11 and 5 were o p e r a t e d on in the 1980s a n d 1990s, respectively. Consistent with the difficulties of defining carcinoma on the basis of fine-needle cytology alone, only 5 of the 12 patients who h a d fine-needle aspirations done were thought to have carcinoma before operation. However, four additional patients h a d "suspicious" fine-needle aspirations. T h e earliest operation was p e r f o r m e d in 1946. Since then, 38 patients have u n d e r g o n e operation on the thyroid alone. O n e patient h a d a radical neck dissection. O n e patient h a d a biopsy only (the one presenting with distant metastasis), a n d five had an excision only o f the tumor. Twelve patients u n d e r w e n t a unilateral subtotal or total thyroidectomy, 17 u n d e r w e n t a bilateral subtotal thyroidectomy, two u n d e r w e n t an ipsilateral total a n d a contralateral subtotal thyroidectomy, and two underwent a bilateral total thyroidectomy. All gross t u m o r was t h o u g h t to be removed in 33 patients. T h e r e were two r e c u r r e n t laryngeal nerve injuries in the 40 primary operations, b o t h causing t e m p o r a r y hoarseness. O n e occurred in a patient in 1956 after a unilateral total thyroid lobectomy a n d the o t h e r in a patient in 1990 after an ipsilateral total, contralateral subtotal thyroidectomy. T h e r e was one case of m y x e d e m a in 1962 after the patient u n d e r w e n t a bilateral subtotal thyroidectomy. Extent o f disease at o p e r a t i o n was evaluated. Twentyeight of the 40 patients were t h o u g h t to have intraglan-
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d u l a r disease alone. In the others, five involved the trachea, two involved the muscles, two involved the soft tissue and fat, and two were described as extraglandular b u t o f " u n k n o w n extent." O n e patient h a d grossly positive nodes in the neck a n d o n e had grossly positive nodes in the mediastinum. In looking at the final pathologic specimens, all tumors d e m o n s t r a t e d significant Hfirthle cell changes. Twenty-one patients exhibited b l o o d vessel invasion, 15 h a d major capsular involvement, and 15 h a d m i n o r capsular involvement. All patients h a d to exhibit at least one of the a f o r e m e n t i o n e d properties to qualify as having a carcinoma. Minor capsular involvement was defined as definitive invasion o f the capsule of the t u m o r but no extension past the capsule. Major capsular involvement was defined as transcapsular invasion, invasion of adjacent tissues, or both. Six of the nine recurrences h a d b l o o d vessel involvement, a n d five h a d major capsular invasion. Eight patients had only m i n o r capsular involvement as the qualifying criterion. None of the patients with only m i n o r capsular involvement h a d a recurrence. The follow-up on the patients with m i n o r capsular involvement r a n g e d ti-orr, 5 to 40 years. Lymph n o d e involvement was u n c o m m o n , with only two patients having any local lymph n o d e metastasis. T h e relationship of lymph n o d e involvement to recurr e n c e is uncertain, with the one patient having recurrence in one positive lymph node, whereas the patient with six positive nodes d i d not have a recurrence. Five o f the recurrences did n o t involve the lymph nodes. The size o f the tumors r a n g e d from 1 to 10 cm, with most at 4 to 5 cm. O f the 16 patients whose tumors were larger than 5 cm, 4 e x p e r i e n c e d a recurrence. O f all patients with recurrences, five of the nine presented with distant disease at the time of recurrence. After operation only n i n e patients u n d e r w e n t radioactive i o d i n e adjuvant therapy. Four of the nine had a recurrence, supporting the belief that these tumors are n o t responsive to radioactive iodine. No patient had initial postoperative c h e m o t h e r a p y or external radiation therapy. Twenty-two patients remain on thyroid medication after operation. Evaluation of the c u r r e n t status o f the patients reveals that 16 are still alive with n o evidence of disease, eight have d i e d with no evidence o f disease, four are alive with disease, five are d e a d from disease, one d i e d with disease, and 3 were lost to follow-up. However, o f the latter three, two were followed for 6 and 8 years, respectively, with no evidence o f disease. The last "lost" patient r e t u r n e d to her missionary post in Africa and could n o t be reached further. T h e r e were nine recurrences; four patients had m o r e than one recurrence. O f tile nine recurrences (23% o f our population), four p r e s e n t e d with local r e c u r r e n c e and five p r e s e n t e d with distant metastasis. T h e m e d i a n interval to recur-
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T a b l e I. Differentiated thyroid carcinoma risk group definitions: AMES criteria Low-risk group All younger patients without distant metastases (men <41 yr, women <51 yr) All older patients with Intrathyroidal papillary cancer or minor tumor capsular involvement follicular carcinoma and Primary cancers <5 cm in diameter and No distant metastases High-risk group All patients with distant metastases All older patients with Extrathyroidal papillary cancer or major tumor capsular involvement follicular carcinoma and Primary cancers < 5 cm in diameter or larger regardless of extent of disease From Cady B, Rossi R. Surgery 1988;104:947-53.
rence was 4 years, ranging from 0.5 to 14 years. Five patients with recurrences are dead; the m e d i a n time to d e a t h from original operation was 5 years. Four of the five died of their disease, a n d one died with h e r disease. T h e four patients with recurrences who are alive still have disease, b u t all have h a d r e c m l e n c e s within the last year; all of these patients have significant symptoms from the recurrences. T r e a t m e n t for recurrences inc l u d e d surgery in two, radioactive iodine in four, external radiotherapy in two, a n d c h e m o t h e r a p y in one. Four patients all had a second recurrence (one h a d a third recurrence), all within 2 years of the first recurrence. No patient with a known r e c u r r e n c e was cured of the disease. Risk factors in each patient were analyzed. T h e AMES criteria is a well-established scoring system to evaluate a patient's risk of recurrence. 7 T h e value of the system is that it can be used by the surgeon at the time of operation, with clinical criteria a n d frozen section, and thus the surgeon can tailor the o p e r a t i o n on the basis of that particular patient's risk o f recurrence. T h e criteria for its use are listed in Table I. W h e n the low-risk patients were considered by age (part A), no patient h a d a recurrence, whether male or female. W h e n part B was considered (extent, size, metastasis, regardless of age), again, no patien t ever h a d a recurrence. In looking at the high-risk criteria, there seems to be a c o r r e s p o n d i n g risk o f recurrence. T h e one patient who presented with distant metastasis a n d u n d e r w e n t a confirmatory biopsy d i e d within 2 months of presentation. H e h a d presented with axillary and inguinal l y m p h a d e n o p a t h y and liver metastasis a n d was n o t c o u n t e d a m o n g the recurrences. A m o n g the o t h e r high-risk criteria (age older than 41 years in m e n a n d o l d e r than 51 years in women, major capsular involve-
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ment; a n d / o r size greater than 5 cm), there was a high recurrence rate. O f the eight patients with all three of the high-risk criteria, there were four recurrences (50%). O f tile r e m a i n i n g five recurrences, all h a d at least one of the high-risk criteria (age). Four h a d two of the three high-risk criteria (age and size). In addition, four h a d at least major capsular invasion or b l o o d vessel invasion. If all the patients with only two o f the three risk criteria (any c o m b i n a t i o n of age, capsule, or size) are examined, 44% h a d recurrences in our series (Fig. 1). O f all the recurrences a n d deaths from disease, four have died of their disease and one died with disease, giving a death rate with disease o f 63 %. T h e o n e patient who had a recurrence a n d h a d only one of the high-risk criteria (age) also did n o t have extraglandular disease n o t e d at the time o f operation. She is one o f the four who died o f her disease. T h e r e d i d seem to be a correlation between the type of o p e r a t i o n and recurrence, with most recurrences occurring with excision of less than in a bilateral procedure. T h e distribution of percentage of r e c u r r e n c e seems fairly equal a m o n g the "unilateral" p r o c e d u r e s (Fig. 2). No recurrences were r e p o r t e d in the two patients who u n d e r w e n t an ipsilateral total a n d a contralateral subtotal thyroidectomy. The two patients who undei~vent bilateral total thyroidectomies a n d h a d recurrences require some explanation. O n e elderly woman h a d the original operation at a n o t h e r major institution a n d had u n d e r g o n e a two-stage removal after the release of h e r final pathology report. T h e first procedure was a unilateral lobectomy, and the second was a c o m p l e t i o n thyroidectomy. She originally h a d a 14 cm goiter that h a d grown for many years. No extraglandular disease was n o t e d on the pathology specimen, b u t the patient h a d major capsular invasion. T h e second patient was also in h e r eighties with extensive extraglandular disease. H e r pathology r e p o r t n o t e d giant and spindle cell c o m p o n e n t s of a p r e d o m inantly HCC. The t u m o r was 4.5 cm in diameter, with extensive b l o o d vessel a n d capsular involvement. Both of these patients were at extremely high risk for a recurrence a n d seemed to have extensive disease at the time of initial resection.
DISCUSSION HCC is a difficult diagnosis to make, requiring a Skilled a n d diligent pathologist b o t h at the time o f frozen section and in the final pathologic specimen. Most reports regarding this disease focus on the difficulty in distinguishing the a d e n o m a from the carcinoma. 8'9 This series represents one of the largest single-institution populations of confirmed HCC. The incidence of carcinoma is consistent with those in o t h e r series of 4.0%. i0 HCC is thought to be a m o r e aggressive variant o f fol-
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total recur.
NN
10 8 number of patients
6 4
)%
2 0
3/3 risks
[% 2/3 risks
Fig. 1. A comparison of the recurrence rate of patients with their numbers of AMES risk factors. Fifty percent of patients with three risk factors will have a recurrence; 44% of those with only two risk factors will still have a recurrence.
20
I ~ Total Recur
n u m b e r 15
of p a t i e n t s 10
17%
5 0
0%
biopsy excis, uni.lobe bilat. Ipsi.tot. bilat.tot. sub. contr.sub.
Fig. 2. Recurrence rates after various operations for HCC. Bilateral procedures seemed to have a lower recurrence rate than did unilateral procedures. Differences were not statistically significant. Excis, Excision only; uni.lobe, unilateral lobectomy; bilat sub, bilateral subtotal thyroidectomy; ipsi.tot, contr.sub., ipsilateral total, contralateral subtotal thyroidectomy; bilat.tot., bilateral total thyroidectomy. licular thyroid carcinoma. In looking at our series of 182 patients with follicular carcinoma, the m e d i a n age o f presentation was 46 years, c o m p a r e d with 53 years for the Hflrthle cell population. Whereas 43% o f follicular cell cancers h a d b l o o d vessel invasion and 31% h a d maj o r capsular invasion, the Hfirthle cell cancers h a d a 53% b l o o d vessel invasion a n d a 38% major capsular invasion rate. Thus m o r e Hfirthle cell tumors had a h i g h e r n u m b e r o f AMES risk criteria. Perhaps as a result, only 16% o f patients with follicular carcinomas died with the disease or h a d recurrences, whereas 26% of patients with HCC d i e d with the disease or h a d recurrences (Fig. 3). T h e r e is a definite t r e n d in the aggressive invasion of HCCs, a n d they p o r t e n d a p o o r prognosis. Patient presentation varied, but most presented with a mass. Fine-needle aspiration, although helpful in papillary cancers, c a n n o t distinguish the c a r c i n o m a criteria in HCC. All lesions suspected to h a r b o r a H t r t h l e cell t u m o r should be o p e r a t e d on for a definitive diagnosis.
Several series present patients in whom a " b e n i g n " H/irthle cell t u m o r later recurs 3' 9; thus even seemingly b e n i g n tumors should be excised. Because benign tumors were n o t evaluated in this series, no comparison can be m a d e regarding correlation between b e n i g n tum o r s a n d the likelihood o f the d e v e l o p m e n t o f carcinoma. It can be stated that only one patient h a d any previous thyroid disease; the fortieth of our patients had a b e n i g n thyroid n o d u l e excised some 20 years previously. H e r 1-month follow-up is too short to reach any conclusions. Postoperative therapy did n o t seem to help our patients. Forty-four p e r c e n t of those receiving post-operative radioactive iodine therapy had a recurrence anyway. With a recurrence, chemotherapy, radiation, or radioactive iodine did not stop further recurrences in four patients who had a second or third recurrence. Sttrge~y seems to be the only possible cure for this disease. The type of operation seemed to influence the recurrence
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I : Hurthle Follicular
60 50 40 number of patients
30 20 10 0
Bid. Ves.
Maj. Cap.
Died Rec.
Fig. 3. A comparison of the aggressiveness of Hfirthle cell and follicular thyroid cancers. No difference was statistically significant; however, there was a definite trend toward m o r e aggressive behavior with Hfirthle cell cancers. Bid. Ves., Blood vessel invasion; Maj. Cap., major capsular invasion; Died Rec., died with recurrence.
rate, with m o s t r e c u r r e n c e s o c c u r r i n g a m o n g the unilateral p r o c e d u r e s . A l t h o u g h the n u m b e r s in e a c h g r o u p are small, it s e e m e d that an ipsilateral total a n d a c o n t r a l a t e r a l subtotal t h y r o i d e c t o m y has the best c u r e rate. O n e c a n n o t e x c l u d e p e r f o r m i n g a bilateral total t h y r o i d e c t o m y because the two patients w h o u n d e r w e n t such o p e r a t i o n h a d e x t e n u a t i n g circumstances that p u t t h e m i n t o a very high-risk c a t e g o r y a n d thus m a y have skewed the correlation b e t w e e n bilateral total thyroidect o m y a n d r e c u r r e n c e rate. E x t r a g l a n d u l a r i n v o l v e m e n t was also n o t i c e a b l e a m o n g those with r e c u r r e n c e s ; perhaps any suspect soft tissue a r o u n d the thyroid s h o u l d also b e r e s e c t e d to p r o v i d e the best c h a n c e for a primary cure. Careful l o n g - t e r m follow-up o f H C C patients is essential. It s h o u l d be n o t e d that several o f the r e c u r r e n c e s in o u r study o c c u r r e d m o r e t h a n 10 years after the initial o p e r a t i o n . In fact, a l t h o u g h the m e a n interval to rec u r r e n c e was only 3 years, r e c u r r e n c e s w e r e seen for t h e first t i m e at 12 a n d 14 years after o p e r a t i o n . T h e s e patients m u s t be advised that the diagnosis is for a lifetime a n d that they s h o u l d c o n t i n u e l o n g - t e r m evaluation. U s i n g a clinical risk scoring system helps p r e d i c t w h e t h e r a p a t i e n t will have a r e c u r r e n c e . T h e r e was a strong c o r r e l a t i o n b e t w e e n d e g r e e o f risk a n d recurr e n c e . N o low-risk p a t i e n t h a d a r e c u r r e n c e , whereas the high-risk g r o u p h a d a 50% r e c u r r e n c e rate. Eighty perc e n t o f those with at least two o f the t h r e e high-risk criteria h a d a r e c u r r e n c e . Admittedly, o n e p a t i e n t with only o n e o f the high-risk criteria h a d a r e c u r r e n c e ; however, she h a d age as a risk factor. H e r o p e r a t i o n was a bilateral subtotal thyroidectomy. T h e o n e p a t i e n t w h o p r e s e n t e d with metastatic disease d i e d o f his disease within 2 months.
DISCUSSION
W h y focus o n r e c u r r e n c e ? R e c u r r e n c e p o r t e n d s a particularly p o o r prognosis in o u r series with n o cure.
Dr. Beth Ann Ditkoff (New York, NY). We recently finished reviewing our 20-year experience with HCC at the Columbia-
Five (56%) o f the n i n e patients with a r e c u r r e n c e d i e d e i t h e r f r o m their disease (four patients) o r with t h e i r disease o f u n k n o w n causes ( o n e patient). R e c u r r e n c e clearly n e e d s to be avoided. In this series p o s t o p e r a t i v e t h e r a p y was unsuccessful in p r e v e n t i n g a r e c u r r e n c e in 44% o f patients. W e advocate m o r e aggressive surgery for those patients w h o p r e s e n t with o n e or m o r e o f the A M E S risk criteria. T h e s e criteria can be e v a l u a t e d by the s u r g e o n at the t i m e o f o p e r a t i o n a n d t h e n u s e d to tailor the o p e r a t i o n o n t h e basis o f the n u m b e r o f risk factors that p a t i e n t m a y have. REFERENCES 1. Cooper D, Schneyer C. Follicular and H(irthle cell carcinoma of the thyroid. Endocrinol Metab Clin North Am 1990;19:577-91. 2. Hedinger C. Histological typing of thyroid tumors. 1st ed. Berlin: Springer-Verlag, 1988:7, 3. Thompson WW, Dunn EL, ButsakisJG, et al. Hfirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555-60. 4. Caplan R, Abellera RM, Kisken WA. H6rthte cell tumors of the thyroid gland. JAMA 1984;251:3114-7. 5. Gosain AK, Clark OH. Hfirthle cell neoplasms. Arch Surg 1984;119:515-9. 6. Arganini M, Behar R, Wu TC. Hfirthle cell tumors: a twenty-five year experience. Surgery 1986;100:1108-14. 7. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:947-53. 8. Heppe H, Attain A, Calandra DB, Lawrence AM, Paloyan E. Hfirthte cell tumors of the thyroid gland. Surgery 1985;98:1162-5. 9. Grant CS, Barr D, GoellnerJR, Hay ID. Benign Hfirthle cell tumors of the thyroid: a diagnosis to be trusted? World J Surg 1988;12:488-95. 10. Watson RG, Brennan ME, Goellner JR, van Heerden JA, McConahey WM, Taylor WF. Invasive Hfirthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc 1984;59:851-5.
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Presbyterian Medical Center. We identified 35 patients with an average follow-up of 8 years. We found that the incidence of multifocality was high; about one third of patients had more than one lesion confined to one lobe. On the other hand, the incidence of bilaterality was quite low; only two patients had bilateral HCCs, and these were easily detected at the time of operation. In addition, we looked at performing bilateral versus unilateral thyroidectomies and found that there was no difference in recurrence, metastatic disease, or survival. What were the incidences of multifocality and bilaterality in your series? Dr. McDonald. We did not specifically address the issue of multifocality in our study. If bilateral disease was obvious at the time of operation, a bilateral procedure was performed. If the pathologic examination revealed positive margins of the carcinoma, a completion bilateral procedure was performed. Dr. Keith Heller (Great Neck, NY). You have shown us in your experience that the ability of fine-needle aspirations to predict HCCs is not good. That is similar to our experience. The other problem we have is that our pathologists are almost never able to give us a definitive diagnosis of HCC on frozen section. What is your experience with that? Because you believe that patients with HCC should have a total or a near-total thyroidectomy, do you wait for the p e r m a n e n t sections or do you r e c o m m e n d doing near-total or total thyroidectomies on all patients with Hfirthle cell neoplasms? Dr. McDonald. I d o n ' t think that our pathologists are any more courageous than any other pathologists throughout the country. They are equally reluctant to make the call of capsular invasion on frozen section. They will give us a reasonable idea about how aggressive the tumor appears. It is not easy to determine capsular invasion on frozen section. If the pathologic findings are equivocal and the patient is classified as a high risk, we will perform a bilateral procedure. I should note that we do a large number of thyroid cases each year and our complication rate is low. Those surgeons who perform only a
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few th~oidectomies in a year might prefer to be more conservative mad await the final pathologic examination. Dr. IanD. Hay (Rochester, MN). We have applied the AMES classification to our 97 patients during a half century, and actually more of our patients are low risk than high risk, in contrast to the experience just described. In our low-risk patients using the AMES category we have a 29% recurrence rate at 20 years and a 9% mortality rate. Overall, our 97 patients enjoy a mortality rate of only 21% during a period of 20 years. The prognosis is not that awesome or ominous for HCC. In temas of DNA ploidy you found the surgical extent of disease at operation to be the most important prognostic factor. We have found DNA ploidy to he the single most important independent factor. All of our deaths are in the DNA aneuploid group. I think this kind of disease should be treated after operation with radioiodine if there is a follicular component present. Dr. McDonald. Our 40 patients met strict criteria for carcinoma, including either blood vessel invasion or capsular invasion. We did have almost equal numbers of high- and low-risk patients. No low-risk patient had a recurrence. The overall recurrence rate was 23%. Of those who experience recurrence, 56% have died. However, of those who did not experience recurrence or present with metastatic disease, there were no deaths from HCC. The prognosis is only ominous for those who experience a recurrence. As far as DNA ploidy goes, I have spoken with our pathologists and they are far from convinced that DNA ploidy is costeffective. I know that there is a lot of controversy on this issue, but we have yet to convince our pathologists to do DNA ploidy on our patients on a routine basis. So we have no significant data to correlate DNA ploidy. The literature states that radioiodine does not help in these tumors, mrd our data support this. Perhaps, as you say, it destroys the follicular element of the tumor, but follicular carcinoma is not what recurs, the HCC does. Radiotherapy, unfortunately, does not help in this disease. Ahnost half of our patients who had radioactive iodine had a recurrence anyway.
Background. Hiirthle cell carcinomas of the thyroid are unusual variants of well-differentiated thyroid cancers. Considered more aggressive tumors, their optimal treatment is controversial. Our institution's half century of experience, the largest series to date, includes 40 patients with Hiirthle cell carcinomas of 1000 well-differentiated thyroid cancers. Methods. A retrospective study was carried out on 40 patients. Results. Seventy-two percent were female, with a median age of 53 years, Median follow-up was 9 years. With the AMES risk stratification (age, distant metastasis, capsular extent, tumor size), arr~ong the 21 high-risk patients, 10 (48%) had a recmrence or died, with median time to recurrence 3 years (range, 0.5 to 14 years). Of these 10, 5 died of disease, one died of unrelated causes with disease, and 4 are alive with disease. Five recurrences presented as distant metastases. Extent at operation was the strongest predictor of recurrence, occurring in 66 % of those with gross extraglandular involvement. Conclusions. The A M E S criteria are useful in predicting recurrence and death. Although more aggressive surgery is appropriate for high-risk patients, in general their outlook remains grim. (Surgery 1996;120:1000-5.) From the Department of General SurgeU and the Department of Pathology, 7"heLahey Hatchcock Clinic, B'urlington, Mass.
HI3RTHLE CELLCARCINOMAS(HCCs) of the thyroid gland are u n u s u a l tumors comprising u p to 6% of all differentiated thyroid cancers. 1 They are considered a variant of follicular carcinoma of the thyroid by the World Health Organization a n d are referred to as follicular carcinoma, oxyphilic cell type. ~ Controversy still exists a r o u n d the optimal surgical treatment for this disease. Very little is known about the natural history of Hfirthle cell tumors, and an u n d e r s t a n d i n g of them continues to evolve. Much of the controversy revolves a r o u n d tile ability to differentiate correctly between an a d e n o m a a n d a carcinoma because the behavior of each is quite different, with drastically different outcomes for patients. Some authors 3 believe that all Hfirthle cell tumors should be treated as malignant a n d that aggressive surgical treatment is advocated. 3 Others believe that pathologic evaluation can be accurate in experienced hands a n d that different treatments are warranted for different diagnoses. < 5 However, very few studies contain many cases of Hfirthle cell carcinoma because the Presented at tile SeventeenthAnnual Meetingof the AmericanAssociation of Endocrine Surgeons,Napa, Calif.,April 21-23, 1996. Reprint requests: Laura E. Sanders, MD, Department of General Sn> gery, The LaheyHitchcoekClinic,41 MallRd,, Burlington,MA01805. Copyright 9 1996 by Mosby-YearBook, lnc. 0039-6060/96/$5.00 + 0 11/6/75772 1000 SURGERY
a d e n o m a type is m u c h more predominant. Litde is known about the presentation a n d natural history of HCC, and even less is known about the appropriate m a n a g e m e n t of the disease. This report reviews a half century of experience (1946 to 1996) with HCC a n d thus represents one of the largest series to date.
PATIENTS A N D M E T H O D S A t u m o r registry has b e e n kept at the Lahey Clinic since at least 1946. The older registry data were transferred to a formal database in 1990. Approximately 1000 cases of thyroid cancers have been registered; of these, 40 (4.0%) are reported as HCCs. The pathologic diagnosis was confirmed in each case by using accepted criteria: unequivocal vessel invasion or capsular invasion.3 All charts were reviewed and updated to the present, Each patient was evaluated for his or t~er risk factors by using the AMES criteria (A, age [men older than 41 years or women older than 51 years]; M, presentation with distant metastasis; E, extent of disease at operation; S, size of tumor greater than 4 cm). Operative reports were reviewed and patients were divided into groups according to the operation performed. Extent of disease at operation and the final pathologic reportwere noted. There were eight patients whose inclusion criterion was that o f " m i n o r capsular invasion." None of these eight had Mood vessel invasion. All other patients had major
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capsular invasion or b l o o d vessel invasion, or both. All patients h a d a primary diagnosis of malignancy at the time of the first t r e a t m e n t for HCC. Any history o f radiation before operation was noted. Any postoperative therapy was also noted, as were complications, recm~ fences, or deaths. T h e m e d i a n follow-up was 8.5 years (range, 0.5 to 38 years). T h e fortieth patient was operated on recently, with less than 1 m o n t h follow-up. She is not i n c l u d e d in the statistical analysis for recurrence because o f inadequate time o f follow-up. T h e m e d i a n age at operation was 53 years (range, 24 to 85 years). T h e r e were 28 women a n d 12 men, in keeping with past descriptions of a disease p r e d o m i n a n t l y f o u n d in women. 6 RESULTS Patient presentation varied. Fifteen patients were symptomatic from a thyroid mass. A solitary thyroid n o d u l e was f o u n d in 31 patients. No patient p r e s e n t e d with only neck adenopathy; two patients presented with both a neck and a thyroid mass. O n e patient p r e s e n t e d with distant metastasis, axillary a n d inguinal adenopathy, and liver metastasis. Only one patient h a d undergone previous thyroid operation; that patient had h a d a Benign a d e n o m a r e m o v e d approximately 20 years earlier. Preoperative fine-needle aspiration was perf o r m e d in only 12 patients, which reflects the long time span of this study. Of the 40 patients, only 11 and 5 were o p e r a t e d on in the 1980s a n d 1990s, respectively. Consistent with the difficulties of defining carcinoma on the basis of fine-needle cytology alone, only 5 of the 12 patients who h a d fine-needle aspirations done were thought to have carcinoma before operation. However, four additional patients h a d "suspicious" fine-needle aspirations. T h e earliest operation was p e r f o r m e d in 1946. Since then, 38 patients have u n d e r g o n e operation on the thyroid alone. O n e patient h a d a radical neck dissection. O n e patient h a d a biopsy only (the one presenting with distant metastasis), a n d five had an excision only o f the tumor. Twelve patients u n d e r w e n t a unilateral subtotal or total thyroidectomy, 17 u n d e r w e n t a bilateral subtotal thyroidectomy, two u n d e r w e n t an ipsilateral total a n d a contralateral subtotal thyroidectomy, and two underwent a bilateral total thyroidectomy. All gross t u m o r was t h o u g h t to be removed in 33 patients. T h e r e were two r e c u r r e n t laryngeal nerve injuries in the 40 primary operations, b o t h causing t e m p o r a r y hoarseness. O n e occurred in a patient in 1956 after a unilateral total thyroid lobectomy a n d the o t h e r in a patient in 1990 after an ipsilateral total, contralateral subtotal thyroidectomy. T h e r e was one case of m y x e d e m a in 1962 after the patient u n d e r w e n t a bilateral subtotal thyroidectomy. Extent o f disease at o p e r a t i o n was evaluated. Twentyeight of the 40 patients were t h o u g h t to have intraglan-
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d u l a r disease alone. In the others, five involved the trachea, two involved the muscles, two involved the soft tissue and fat, and two were described as extraglandular b u t o f " u n k n o w n extent." O n e patient h a d grossly positive nodes in the neck a n d o n e had grossly positive nodes in the mediastinum. In looking at the final pathologic specimens, all tumors d e m o n s t r a t e d significant Hfirthle cell changes. Twenty-one patients exhibited b l o o d vessel invasion, 15 h a d major capsular involvement, and 15 h a d m i n o r capsular involvement. All patients h a d to exhibit at least one of the a f o r e m e n t i o n e d properties to qualify as having a carcinoma. Minor capsular involvement was defined as definitive invasion o f the capsule of the t u m o r but no extension past the capsule. Major capsular involvement was defined as transcapsular invasion, invasion of adjacent tissues, or both. Six of the nine recurrences h a d b l o o d vessel involvement, a n d five h a d major capsular invasion. Eight patients had only m i n o r capsular involvement as the qualifying criterion. None of the patients with only m i n o r capsular involvement h a d a recurrence. The follow-up on the patients with m i n o r capsular involvement r a n g e d ti-orr, 5 to 40 years. Lymph n o d e involvement was u n c o m m o n , with only two patients having any local lymph n o d e metastasis. T h e relationship of lymph n o d e involvement to recurr e n c e is uncertain, with the one patient having recurrence in one positive lymph node, whereas the patient with six positive nodes d i d not have a recurrence. Five o f the recurrences did n o t involve the lymph nodes. The size o f the tumors r a n g e d from 1 to 10 cm, with most at 4 to 5 cm. O f the 16 patients whose tumors were larger than 5 cm, 4 e x p e r i e n c e d a recurrence. O f all patients with recurrences, five of the nine presented with distant disease at the time of recurrence. After operation only n i n e patients u n d e r w e n t radioactive i o d i n e adjuvant therapy. Four of the nine had a recurrence, supporting the belief that these tumors are n o t responsive to radioactive iodine. No patient had initial postoperative c h e m o t h e r a p y or external radiation therapy. Twenty-two patients remain on thyroid medication after operation. Evaluation of the c u r r e n t status o f the patients reveals that 16 are still alive with n o evidence of disease, eight have d i e d with no evidence o f disease, four are alive with disease, five are d e a d from disease, one d i e d with disease, and 3 were lost to follow-up. However, o f the latter three, two were followed for 6 and 8 years, respectively, with no evidence o f disease. The last "lost" patient r e t u r n e d to her missionary post in Africa and could n o t be reached further. T h e r e were nine recurrences; four patients had m o r e than one recurrence. O f tile nine recurrences (23% o f our population), four p r e s e n t e d with local r e c u r r e n c e and five p r e s e n t e d with distant metastasis. T h e m e d i a n interval to recur-
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T a b l e I. Differentiated thyroid carcinoma risk group definitions: AMES criteria Low-risk group All younger patients without distant metastases (men <41 yr, women <51 yr) All older patients with Intrathyroidal papillary cancer or minor tumor capsular involvement follicular carcinoma and Primary cancers <5 cm in diameter and No distant metastases High-risk group All patients with distant metastases All older patients with Extrathyroidal papillary cancer or major tumor capsular involvement follicular carcinoma and Primary cancers < 5 cm in diameter or larger regardless of extent of disease From Cady B, Rossi R. Surgery 1988;104:947-53.
rence was 4 years, ranging from 0.5 to 14 years. Five patients with recurrences are dead; the m e d i a n time to d e a t h from original operation was 5 years. Four of the five died of their disease, a n d one died with h e r disease. T h e four patients with recurrences who are alive still have disease, b u t all have h a d r e c m l e n c e s within the last year; all of these patients have significant symptoms from the recurrences. T r e a t m e n t for recurrences inc l u d e d surgery in two, radioactive iodine in four, external radiotherapy in two, a n d c h e m o t h e r a p y in one. Four patients all had a second recurrence (one h a d a third recurrence), all within 2 years of the first recurrence. No patient with a known r e c u r r e n c e was cured of the disease. Risk factors in each patient were analyzed. T h e AMES criteria is a well-established scoring system to evaluate a patient's risk of recurrence. 7 T h e value of the system is that it can be used by the surgeon at the time of operation, with clinical criteria a n d frozen section, and thus the surgeon can tailor the o p e r a t i o n on the basis of that particular patient's risk o f recurrence. T h e criteria for its use are listed in Table I. W h e n the low-risk patients were considered by age (part A), no patient h a d a recurrence, whether male or female. W h e n part B was considered (extent, size, metastasis, regardless of age), again, no patien t ever h a d a recurrence. In looking at the high-risk criteria, there seems to be a c o r r e s p o n d i n g risk o f recurrence. T h e one patient who presented with distant metastasis a n d u n d e r w e n t a confirmatory biopsy d i e d within 2 months of presentation. H e h a d presented with axillary and inguinal l y m p h a d e n o p a t h y and liver metastasis a n d was n o t c o u n t e d a m o n g the recurrences. A m o n g the o t h e r high-risk criteria (age older than 41 years in m e n a n d o l d e r than 51 years in women, major capsular involve-
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ment; a n d / o r size greater than 5 cm), there was a high recurrence rate. O f the eight patients with all three of the high-risk criteria, there were four recurrences (50%). O f tile r e m a i n i n g five recurrences, all h a d at least one of the high-risk criteria (age). Four h a d two of the three high-risk criteria (age and size). In addition, four h a d at least major capsular invasion or b l o o d vessel invasion. If all the patients with only two o f the three risk criteria (any c o m b i n a t i o n of age, capsule, or size) are examined, 44% h a d recurrences in our series (Fig. 1). O f all the recurrences a n d deaths from disease, four have died of their disease and one died with disease, giving a death rate with disease o f 63 %. T h e o n e patient who had a recurrence a n d h a d only one of the high-risk criteria (age) also did n o t have extraglandular disease n o t e d at the time o f operation. She is one o f the four who died o f her disease. T h e r e d i d seem to be a correlation between the type of o p e r a t i o n and recurrence, with most recurrences occurring with excision of less than in a bilateral procedure. T h e distribution of percentage of r e c u r r e n c e seems fairly equal a m o n g the "unilateral" p r o c e d u r e s (Fig. 2). No recurrences were r e p o r t e d in the two patients who u n d e r w e n t an ipsilateral total a n d a contralateral subtotal thyroidectomy. The two patients who undei~vent bilateral total thyroidectomies a n d h a d recurrences require some explanation. O n e elderly woman h a d the original operation at a n o t h e r major institution a n d had u n d e r g o n e a two-stage removal after the release of h e r final pathology report. T h e first procedure was a unilateral lobectomy, and the second was a c o m p l e t i o n thyroidectomy. She originally h a d a 14 cm goiter that h a d grown for many years. No extraglandular disease was n o t e d on the pathology specimen, b u t the patient h a d major capsular invasion. T h e second patient was also in h e r eighties with extensive extraglandular disease. H e r pathology r e p o r t n o t e d giant and spindle cell c o m p o n e n t s of a p r e d o m inantly HCC. The t u m o r was 4.5 cm in diameter, with extensive b l o o d vessel a n d capsular involvement. Both of these patients were at extremely high risk for a recurrence a n d seemed to have extensive disease at the time of initial resection.
DISCUSSION HCC is a difficult diagnosis to make, requiring a Skilled a n d diligent pathologist b o t h at the time o f frozen section and in the final pathologic specimen. Most reports regarding this disease focus on the difficulty in distinguishing the a d e n o m a from the carcinoma. 8'9 This series represents one of the largest single-institution populations of confirmed HCC. The incidence of carcinoma is consistent with those in o t h e r series of 4.0%. i0 HCC is thought to be a m o r e aggressive variant o f fol-
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total recur.
NN
10 8 number of patients
6 4
)%
2 0
3/3 risks
[% 2/3 risks
Fig. 1. A comparison of the recurrence rate of patients with their numbers of AMES risk factors. Fifty percent of patients with three risk factors will have a recurrence; 44% of those with only two risk factors will still have a recurrence.
20
I ~ Total Recur
n u m b e r 15
of p a t i e n t s 10
17%
5 0
0%
biopsy excis, uni.lobe bilat. Ipsi.tot. bilat.tot. sub. contr.sub.
Fig. 2. Recurrence rates after various operations for HCC. Bilateral procedures seemed to have a lower recurrence rate than did unilateral procedures. Differences were not statistically significant. Excis, Excision only; uni.lobe, unilateral lobectomy; bilat sub, bilateral subtotal thyroidectomy; ipsi.tot, contr.sub., ipsilateral total, contralateral subtotal thyroidectomy; bilat.tot., bilateral total thyroidectomy. licular thyroid carcinoma. In looking at our series of 182 patients with follicular carcinoma, the m e d i a n age o f presentation was 46 years, c o m p a r e d with 53 years for the Hflrthle cell population. Whereas 43% o f follicular cell cancers h a d b l o o d vessel invasion and 31% h a d maj o r capsular invasion, the Hfirthle cell cancers h a d a 53% b l o o d vessel invasion a n d a 38% major capsular invasion rate. Thus m o r e Hfirthle cell tumors had a h i g h e r n u m b e r o f AMES risk criteria. Perhaps as a result, only 16% o f patients with follicular carcinomas died with the disease or h a d recurrences, whereas 26% of patients with HCC d i e d with the disease or h a d recurrences (Fig. 3). T h e r e is a definite t r e n d in the aggressive invasion of HCCs, a n d they p o r t e n d a p o o r prognosis. Patient presentation varied, but most presented with a mass. Fine-needle aspiration, although helpful in papillary cancers, c a n n o t distinguish the c a r c i n o m a criteria in HCC. All lesions suspected to h a r b o r a H t r t h l e cell t u m o r should be o p e r a t e d on for a definitive diagnosis.
Several series present patients in whom a " b e n i g n " H/irthle cell t u m o r later recurs 3' 9; thus even seemingly b e n i g n tumors should be excised. Because benign tumors were n o t evaluated in this series, no comparison can be m a d e regarding correlation between b e n i g n tum o r s a n d the likelihood o f the d e v e l o p m e n t o f carcinoma. It can be stated that only one patient h a d any previous thyroid disease; the fortieth of our patients had a b e n i g n thyroid n o d u l e excised some 20 years previously. H e r 1-month follow-up is too short to reach any conclusions. Postoperative therapy did n o t seem to help our patients. Forty-four p e r c e n t of those receiving post-operative radioactive iodine therapy had a recurrence anyway. With a recurrence, chemotherapy, radiation, or radioactive iodine did not stop further recurrences in four patients who had a second or third recurrence. Sttrge~y seems to be the only possible cure for this disease. The type of operation seemed to influence the recurrence
1004
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I : Hurthle Follicular
60 50 40 number of patients
30 20 10 0
Bid. Ves.
Maj. Cap.
Died Rec.
Fig. 3. A comparison of the aggressiveness of Hfirthle cell and follicular thyroid cancers. No difference was statistically significant; however, there was a definite trend toward m o r e aggressive behavior with Hfirthle cell cancers. Bid. Ves., Blood vessel invasion; Maj. Cap., major capsular invasion; Died Rec., died with recurrence.
rate, with m o s t r e c u r r e n c e s o c c u r r i n g a m o n g the unilateral p r o c e d u r e s . A l t h o u g h the n u m b e r s in e a c h g r o u p are small, it s e e m e d that an ipsilateral total a n d a c o n t r a l a t e r a l subtotal t h y r o i d e c t o m y has the best c u r e rate. O n e c a n n o t e x c l u d e p e r f o r m i n g a bilateral total t h y r o i d e c t o m y because the two patients w h o u n d e r w e n t such o p e r a t i o n h a d e x t e n u a t i n g circumstances that p u t t h e m i n t o a very high-risk c a t e g o r y a n d thus m a y have skewed the correlation b e t w e e n bilateral total thyroidect o m y a n d r e c u r r e n c e rate. E x t r a g l a n d u l a r i n v o l v e m e n t was also n o t i c e a b l e a m o n g those with r e c u r r e n c e s ; perhaps any suspect soft tissue a r o u n d the thyroid s h o u l d also b e r e s e c t e d to p r o v i d e the best c h a n c e for a primary cure. Careful l o n g - t e r m follow-up o f H C C patients is essential. It s h o u l d be n o t e d that several o f the r e c u r r e n c e s in o u r study o c c u r r e d m o r e t h a n 10 years after the initial o p e r a t i o n . In fact, a l t h o u g h the m e a n interval to rec u r r e n c e was only 3 years, r e c u r r e n c e s w e r e seen for t h e first t i m e at 12 a n d 14 years after o p e r a t i o n . T h e s e patients m u s t be advised that the diagnosis is for a lifetime a n d that they s h o u l d c o n t i n u e l o n g - t e r m evaluation. U s i n g a clinical risk scoring system helps p r e d i c t w h e t h e r a p a t i e n t will have a r e c u r r e n c e . T h e r e was a strong c o r r e l a t i o n b e t w e e n d e g r e e o f risk a n d recurr e n c e . N o low-risk p a t i e n t h a d a r e c u r r e n c e , whereas the high-risk g r o u p h a d a 50% r e c u r r e n c e rate. Eighty perc e n t o f those with at least two o f the t h r e e high-risk criteria h a d a r e c u r r e n c e . Admittedly, o n e p a t i e n t with only o n e o f the high-risk criteria h a d a r e c u r r e n c e ; however, she h a d age as a risk factor. H e r o p e r a t i o n was a bilateral subtotal thyroidectomy. T h e o n e p a t i e n t w h o p r e s e n t e d with metastatic disease d i e d o f his disease within 2 months.
DISCUSSION
W h y focus o n r e c u r r e n c e ? R e c u r r e n c e p o r t e n d s a particularly p o o r prognosis in o u r series with n o cure.
Dr. Beth Ann Ditkoff (New York, NY). We recently finished reviewing our 20-year experience with HCC at the Columbia-
Five (56%) o f the n i n e patients with a r e c u r r e n c e d i e d e i t h e r f r o m their disease (four patients) o r with t h e i r disease o f u n k n o w n causes ( o n e patient). R e c u r r e n c e clearly n e e d s to be avoided. In this series p o s t o p e r a t i v e t h e r a p y was unsuccessful in p r e v e n t i n g a r e c u r r e n c e in 44% o f patients. W e advocate m o r e aggressive surgery for those patients w h o p r e s e n t with o n e or m o r e o f the A M E S risk criteria. T h e s e criteria can be e v a l u a t e d by the s u r g e o n at the t i m e o f o p e r a t i o n a n d t h e n u s e d to tailor the o p e r a t i o n o n t h e basis o f the n u m b e r o f risk factors that p a t i e n t m a y have. REFERENCES 1. Cooper D, Schneyer C. Follicular and H(irthle cell carcinoma of the thyroid. Endocrinol Metab Clin North Am 1990;19:577-91. 2. Hedinger C. Histological typing of thyroid tumors. 1st ed. Berlin: Springer-Verlag, 1988:7, 3. Thompson WW, Dunn EL, ButsakisJG, et al. Hfirthle cell lesions of the thyroid gland. Surg Gynecol Obstet 1974;139:555-60. 4. Caplan R, Abellera RM, Kisken WA. H6rthte cell tumors of the thyroid gland. JAMA 1984;251:3114-7. 5. Gosain AK, Clark OH. Hfirthle cell neoplasms. Arch Surg 1984;119:515-9. 6. Arganini M, Behar R, Wu TC. Hfirthle cell tumors: a twenty-five year experience. Surgery 1986;100:1108-14. 7. Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104:947-53. 8. Heppe H, Attain A, Calandra DB, Lawrence AM, Paloyan E. Hfirthte cell tumors of the thyroid gland. Surgery 1985;98:1162-5. 9. Grant CS, Barr D, GoellnerJR, Hay ID. Benign Hfirthle cell tumors of the thyroid: a diagnosis to be trusted? World J Surg 1988;12:488-95. 10. Watson RG, Brennan ME, Goellner JR, van Heerden JA, McConahey WM, Taylor WF. Invasive Hfirthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc 1984;59:851-5.
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Presbyterian Medical Center. We identified 35 patients with an average follow-up of 8 years. We found that the incidence of multifocality was high; about one third of patients had more than one lesion confined to one lobe. On the other hand, the incidence of bilaterality was quite low; only two patients had bilateral HCCs, and these were easily detected at the time of operation. In addition, we looked at performing bilateral versus unilateral thyroidectomies and found that there was no difference in recurrence, metastatic disease, or survival. What were the incidences of multifocality and bilaterality in your series? Dr. McDonald. We did not specifically address the issue of multifocality in our study. If bilateral disease was obvious at the time of operation, a bilateral procedure was performed. If the pathologic examination revealed positive margins of the carcinoma, a completion bilateral procedure was performed. Dr. Keith Heller (Great Neck, NY). You have shown us in your experience that the ability of fine-needle aspirations to predict HCCs is not good. That is similar to our experience. The other problem we have is that our pathologists are almost never able to give us a definitive diagnosis of HCC on frozen section. What is your experience with that? Because you believe that patients with HCC should have a total or a near-total thyroidectomy, do you wait for the p e r m a n e n t sections or do you r e c o m m e n d doing near-total or total thyroidectomies on all patients with Hfirthle cell neoplasms? Dr. McDonald. I d o n ' t think that our pathologists are any more courageous than any other pathologists throughout the country. They are equally reluctant to make the call of capsular invasion on frozen section. They will give us a reasonable idea about how aggressive the tumor appears. It is not easy to determine capsular invasion on frozen section. If the pathologic findings are equivocal and the patient is classified as a high risk, we will perform a bilateral procedure. I should note that we do a large number of thyroid cases each year and our complication rate is low. Those surgeons who perform only a
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few th~oidectomies in a year might prefer to be more conservative mad await the final pathologic examination. Dr. IanD. Hay (Rochester, MN). We have applied the AMES classification to our 97 patients during a half century, and actually more of our patients are low risk than high risk, in contrast to the experience just described. In our low-risk patients using the AMES category we have a 29% recurrence rate at 20 years and a 9% mortality rate. Overall, our 97 patients enjoy a mortality rate of only 21% during a period of 20 years. The prognosis is not that awesome or ominous for HCC. In temas of DNA ploidy you found the surgical extent of disease at operation to be the most important prognostic factor. We have found DNA ploidy to he the single most important independent factor. All of our deaths are in the DNA aneuploid group. I think this kind of disease should be treated after operation with radioiodine if there is a follicular component present. Dr. McDonald. Our 40 patients met strict criteria for carcinoma, including either blood vessel invasion or capsular invasion. We did have almost equal numbers of high- and low-risk patients. No low-risk patient had a recurrence. The overall recurrence rate was 23%. Of those who experience recurrence, 56% have died. However, of those who did not experience recurrence or present with metastatic disease, there were no deaths from HCC. The prognosis is only ominous for those who experience a recurrence. As far as DNA ploidy goes, I have spoken with our pathologists and they are far from convinced that DNA ploidy is costeffective. I know that there is a lot of controversy on this issue, but we have yet to convince our pathologists to do DNA ploidy on our patients on a routine basis. So we have no significant data to correlate DNA ploidy. The literature states that radioiodine does not help in these tumors, mrd our data support this. Perhaps, as you say, it destroys the follicular element of the tumor, but follicular carcinoma is not what recurs, the HCC does. Radiotherapy, unfortunately, does not help in this disease. Ahnost half of our patients who had radioactive iodine had a recurrence anyway.