World j. Surg. 16, 583--588, 1992
World Journal of Surgery @ 1992 by the Soci~.t~ lnteraationale ~le Chirurgie
Outcome of Long Standing Solitary Thyroid Nodules Kanji K u m a , M . D . , F u m i o M a t s u z u k a , M . D . , A k i r a K o b a y a s h i , M . D . , K e i s u k e Hirai, M . D . , Sinji Morita, M , D . , A k i r a M i y a u c h i , M . D . , Shoichi K a t a y a m a , M . D . , and M a s a h i r o S u g a w a r a , M . D . Kuma Hospital, Second Department of Surgery, Kagawa Medical School, and Kure National Hospital, Kobe, Japan and Division of Metabolism and Endocrinology, University of California, Los Angeles, School of Medicine, Los Angeles, California, U.S.A. We investigated the outcome of long standing palpable solitary thyroid nodules by surveying 441 patients and examining 140 patients who had Untreated thyroid nodules for 15 -+ 4.5 years. In our clinical survey, the nlost COmmon outcome was disappearance of the thyroid nodule (38.3%). AnIso a significant number of patients (36.3%) underwent surgery in other spita|s. Five (1.1%) patients died of thyroid cancer. When thyroid nodules were re-examined, most nodules indeed decreased in size or ~SapPeared; however, 13% of nodules increased in size. Ultrasound of ac nodules showed that most solitary nodules were multiple and partially cYStic and solid. There was an increased incidence of calcification in Ioug standing nod~es. Thyroid cancer was found by fine needle aspiration biopsy in 26.3% of enlarging nodules and 6.4% of nodules without changing size. The risk of cancer decreased when the size of the nudule decreased. A total of 15 patients with suspicion of malignancy underwent surgery. Surgical procedures were Iobectomy, near total thyroidectomy, Or resection of nodules with or without modified neck dissection. Seven Patients had papillary carcinoma and 2 patients with benign cytology had croscopieally evident papillary carcinoma. In our study, the majority nf lPable solitary thyroid nodules tended to decrease in size; these nodules not require treatment. Enlarging solid nodules are a definite risk for aYroid cancer If the size of the nodule remains the same judicious aPProach with fine needle aspiration biopsy is needed.
i
The natural history of thyroid nodules after a prolonged period is Unknown. Vander and coworkers [I] surveyed 5,127 people in the town of Framingham, Massachusetts, and found nontoxic thyroid nodules in 6.4% of the population. In their study, none of the subjects were reported to have thyroid cancer after observation for 15 years. However, their study was done before the technique of fine needle aspiration biopsy was available and tissue diagnosis was therefore lacking. In a recent study of 8,219 patients with thyroid nodules, 4% were positive and I1% VCere SUspicious of malignancy by fine needle aspiration biopsy [2]. Therefore, cancer is the definite risk in patients with a solitary thyroid nodule [3]. Thus, it is important to know the clinical as well as the pathological aspects of solitary thyroid nOdUles. We had an opportunity to examine the outcome of long at the internat,ona, Assoc,a,,o. ot Endocrine Surgeons in
un, Sweden August 1991. v S Shimo ~male r,&.'print requests: l)r. K. K'uma, Kuma Hospital. 8-,-3y~ ' u°rh Chuo-ku, Kobe, 650, Japan.
standing solitary thyroid nodules diagnosed 10 to 30 years ago. We were interested in the change in size, clinical course, and the incidence of malignancy in these nodules after diagnosis. This type of investigation should disclose the behavior of solitary thyroid nodules and shed light on the management of patients with this disorder. First, we mailed questionnaires to 2,609 patients regarding the changes in thyroid nodules. Second, we asked them to visit us for examination of thyroid nodules by ultrasound and fine needle aspiration biopsy. Four hundred forty-one patients responded to our questionnaire and 140 patients came lbr re-examination. We present the results of these investigations. Materials and M e t h o d s
CHnical Survey fiwm Patients with Previously Diagnosed Solitao, Thyroid Nodule We mailed questionnaires to 2,609 patients who were diagnosed with solitary thyroid nodules fi-om 1955 to 1979 at Kuma Hospital, Kobe, Japan, and who did not have lbllow-up care with us thereafter. The diagnosis of a solitary thyroid nodule was made by palpation and all patients underwent needle aspiration with 22 to 23 gauge needles to classify nodules as either cyst or solid nodule (fine needle aspiration biopsy and ultrasound were unavailable at that time). If no fluid was obtained, the lesion was considered solid. The size of the nodule was recorded by measurement of its diameter. These patients did not return to our clinic either because they refused any therapeutic approach or did not consider it as a life threatening condition. Multinodular goiters, Graves' disease, or nodules suggesting thyroid cancer were excluded from this study. We asked 4 questions: I) Were the patients dead or alive? 2) Had the nodule been removed surgically in any other hospital? 3) If surgery was not done, was the nodule still present? and 4) If present, was there any noticeable change in size?
Re-Examination of Thyroid Nodules 10 to 30 Years Later One hundred forty patients came for re-examination of thyroid nodules. Re-examination included palpation, thyroid function
584
World J. Surg. Vol. 16, No. 4, July/Aug. 1992
Table 2. Changes in thyroid nodules in 140 patients with previously diagnosed solitary thyroid nodules.
Table 1. Results of clinical survey. No. of pls. Result Questionnaire sent Responded Nodule no longer present Nodule removed in other hospitals Nodule still present Death No response
Total 2609 441 169" 160" 82"
30" 2168
Re-examined 140 7I 32" -39"
-69
"Result of the patients who responded to the questionnaire.
tests (measurement of serum thyroid hormone and thyrotropin), ultrasound, and fine needle aspiration biopsy. The change in nodular size was determined by comparing the present size with the size of the previously recorded nodule. The same two physicians ( K K and FM) examined all patients.
Thyroid Function Tests Serum free thyroxine (T4) and triiodothyronine (T 3) levels were measured using Amerlex-M kit (Amersham International plc, Buckinghamshire, England). Serum thyrotropin (TSH) level was measured by a highly sensitive radioimmunoassay kit (Dainobot Inc., Tokyo, Japan) which can detect up to 0.05 p,U/ml of TSH.
Ultrasound Study Thyroid ultrasound was obtained using a real-time linear scanner with a 7.5 MHZ transducer housed in a water bath (Aloka USI-82c, ASU-46, Tokyo, Japan).
Fine Needle Asph'ation Biopsy Fine needle aspiration biopsy of the thyroid nodules was performed using a 22 or 23 gauge needle in patients who came for re-examination. Cytological examination was done by an expert in this field (A.M.) and classified into the following categories: Class 1, Class 2, and foamy cells indicated a benign lesion; Class 3 indicated the presence of atypical follicular cells; Class 4 was suspicious for malignancy; and class 5 was malignant.
Thyroid Surgery Seven patients who had lesions of Class 4 to 5 underwent surgery. Also, 8 patients whose cytology findings were benign but who had the presence of calcification or an enlarged nodule underwent thyroid surgery. Results
Results of Clinical Survey Table I summarizes our clinical survey. Among 2,609 patients, 441 (16.9%) patients responded to our questionnaire. In these responders, 160 (36.3%) patients had surgery in other hospitals.
Changes in nodule size
Age (yrs)"
Enlarged Slightly enlarged Unchanged Smaller No palpable nodule but seen by ultrasound Disappeared'
55 60 56 52 57
No. of pts. F
M
-+ 13 10 1 -+ 10 8 0 --- 12 43 4 - 12 31 I +- 10 24 2
57 +_ II
16 0
Cyst b
SolidI'
Total
0 3 7 15 18
I1 5 40 17 8
II (7.8%) 8 (5.7%) 47 (33.6%) 32 (22.9%) 26 (18.6%)
12
4
16 (11.4%)
"Age is the mean +-- SD. bThis is the initial diagnosis based on needle aspiration. The change in nodule size was determined by palpation on the latest visit. 'Nodule was not seen by ultrasound. F: female; M: male.
Surprisingly, 169 (38.3%) patients noted disappearance of the thyroid nodule. Eighty-two (18.6%) patients claimed that the nodule was still present; in 58 patients the nodule was unchanged, in 13 patients it was felt to have decreased in size, and in 12 patients it was noted to have increased in size. Thus, disappearance of the solitary nodule was the most common outcome of a palpable solitary thyroid nodule when patients judged their own thyroid nodule.
Changes in Nodular Size Re-examination of thyroid nodules was undertaken in 140 patients 10 to 30 years after the initial visit; an average interval between the first visit and the last visit was 15 - 4.5 years. The distribution of these patients in response group and nonresponse group to our questionnaire is presented in Table 2. Surprisingly, the most common outcome (52.9%) of thyroid nodules was a decrease in nodular size including disappearance of the nodule. This was more common in patients whose initial diagnosis was a thyroid cyst. The next most common outcome (33.6%) was no cha~nge in size, which was often seen in patients with solid nodules. A small but significant number of patients (13.5%) were found to have enlarged or slightly enlarged thyroid nodules, particularly patients with solid nodules. The change in nodule size described by patients was co~" pared with our physical findings. Patients' statement on the change in nodule size was in agreement with our findings i0 85.9% of cases. Therefore, judgment of nodule size by patients was reliable. All patients who visited for re-examination had normal thyroid function tests.
Analysis of Thyroid Nodule by Ultrasound We analyzed thyroid nodules by ultrasound in 122 patients from our study group. A significant number of patients (68%) were found to have multiple nodules (Table 3). To examine our technical accuracy of palpating solitary thyroid nodule, 156 patients who were recently diagnosed with solitary thyroid nodules by palpation were examined by ultrasound. The accU" racy of palpating single nodules in the control group was 65.4~ when nodules were judged by ultrasound (Table 3). Thus, our technique of distinguishing solitary nodule from multiple nod"
K. Kuma et al.: Solitary Thyroid Nodules
585
Table 3, Examination of solitary thyroid nodules by ultrasound.
Finding ingle or multiple Single Multiple Calcification Solid or cystic Solid Cystic Mixed tip
Re-examined patients (n = 122)
Control patients" (n = 156)
32% 68% 47.5%
65.4% 34.6% 12.2%
30.3% 14.8% 54.9%
27.6% 17.3% 55. I%
Table 5. Results of fine needle aspiration biopsy.
Classification of cytology
No. of pts.
No. of operations performed
Class 2 Class 2 or 3 Class 3 Class 4 or 5 Class 5 Foamy cells Degenerative change Inadequate
73 1 I 1 6 9 I l
6 0 I 1 6 I 0 0
.
ahents in the control group were diagnosed to have solitary thyroid nodules from 1990 to 1991; these patients were used for comparison.
Ta..._ble4. Comparison of initial diagnosis with ultrasound findings. Initial diagnosis
Ultrasound findings Solid Cystic
Mixed
Solid (n = 79) C.~Ystic(n = 43)
30 (38%) 7 (16.3%)
45 (57%) 22 (51.2%)
4 (5%) 14 (32.5%)
tales Was fairly reliable. Based on the data shown in Table 3, the Change from a solitary nodule to mutiple nodules seems to OCCur in long standing solitary nodules. Another characteristic feature in patients with long standing solitary thyroid nodules Was the presence of calcification in 47.5% of cases (Table 3). The character of the nodules in 122 patients showed 14.8% to be cystic, 54.9% to be mixed cystic and solid nodules, and 30.3% to be solid nodules. These values were similar to those found in the control group (Table 3). We also compared our initial clinical diagnosis with ultraSound findings at the last visit. More than 50% of patients with a diagnosis of either a cystic or solid nodule had mixed cystic Solid nodules (Table 4). Five percent of the solid nodule group and 16.3% of the cystic group were misdiagnosed.
Results of Fine Needle Aspiration Biopsy Ninety-three patients had needle aspiration biopsy and the results are shown in Table 5. A total of 7 (7.5%) patients had findings suggestive of malignancy. One patient showed Class 3 and the rest of the patients were benign by fine needle aspiration biopsy.
Results of Surgery Patients who underwent surgery are listed in Table 6. Surgical Procedures were lobectomy, total thyroidectomy, or resection of nodules with or without modified neck dissection. All patients having Class 4 to 5 cytology were proven to have Papillary carcinoma and 3 of them had cervical lymph node metastases. Eight patients with benign cytology by fine needle aspiration biopsy underwent surgery because of the presence of enlarging nodules, calcification, or extraordinarily hard nodUles. All 8 patients had adenomatous goiter; 2 of them were found to have microscopic cancer (papillary carcinoma) in addition to benign adenomatous nodules.
We examined whether thyroid cancer occurs in any particular group of thyroid nodules. As shown in Table 7, thyroid cancer was seen in 36,4% of patients whose thyroid nodules clearly enlarged. The incidence of thyroid cancer was 6.4% in patients whose nodules did not change for a prolonged period. One patient, despite descreasing size of the nodule, was found to have a microscopic cancer. Our study indicates a clear-cut increase in thyroid cancer in an enlarging nodule. Discussion
There has been no comprehensive study investigating the clinical course of solitary thyroid nodules since 1968 when Vander and associates [1] reported their 15 year observation of thyroid nodules. Our study is different from the study of Vander and associates [1], since we focused on solitary thyroid nodules and investigated these nodules by combined ultrasound and fine needle aspiration biopsy approximately 15 years after the initial diagnosis. From 1955 to 1979 when our patients in this study were first seen, the technique of fine needle aspiration biopsy was unavailable. Therefore, we had to judge thyroid nodules clinically. We recommended surgery when solitary nodules were hard, large, growing, or calcified. Nearly 6,000 patients had surgery during this period in our hospital. Patients with solitary thyroid nodules who did not have surgery or refused surgery were subjects in this study. Surgery was not done in patients having soft nodules, relatively small nodules, or cysts; these patients were enrolled for the clinical survey. In analyzing thyroid nodules in 140 patients who visited for re-examination, 63% of patients had nodules of 3 cm. Thus, most patients enrolled in our survey had small thyroid nodules. In our clinical survey 441 patients responded to our questionnaire. The most common answer to our questionnaire was disappearance of the nodule (38.3%). Indeed, disappearance of the thyroid nodule was supported by our actual examination (Table 2) and most of these nodules that disappeared were thyroid cysts. In the 441 responders, a significant number of patients (36.3%) had surgery in other hospitals. We were unable to obtain information regarding reasons for surgery and the final diagnosis. At least, there were a certain number of patients who required surgery in a long clinical course with a solitary thyroid nodule. Among 30 (6.8%) deaths, thyroid cancer appeared to be the cause of death in 5 patients. When patients with long standing solitary nodules were examined, the decrease in size, an increased incidence of
586
World J. Surg. Vul. 16, No. 4, July/Aug. 1992
Table 6. Patients who underwent surgery.
Age (yrs)
Sex
Years after first visit
1
62
M
1I
Class 5
Solid + calcification
2
59
F
II
Class 5
Solid + calcification
3
33
F
14
Class 5
Solid + calcification
4
61
F
12
Class 5
Solid ~ calcification
5
40
F
I1
Class 4-5
Solid + calcification
6
37
M
14
Class 5
Solid + calcification
7
56
F
14
Class 5
Solid ~ calcificalion
8 9 10
57 53 49
F F F
16 2t) 16
Class 2 Class 3 Class 2
Resection of nodule Lobectomy Lobectomy
I1 12 13 14
44 66 73 41
F F F F
15 25 19 13
Class 2 Foamy cell Class 2 Class 2
Calcification Calcification Solid + cyst + calcification Solid + cyst Calcification Calcification Solid + cyst
15
47
F
14
Class 2
Solid + cyst
[x~bectomy
Pt. no.
Cytology by FNAB
Ultrasound findings
Operation
Pathological diagnosis
Left Iobectomy and isthmectomy with modified neck dissection Total thyroideclomy with modified neck dissection Sub-total thyroidectomy with modified neck dissection Lobectomy with modified neck dissection I.obectomy with modified neck dissection Total thyroidectomy with modified neck dissection Lobectomy with modified neck dissection
Papillary carcinoma (well encapsulated)
Lobectomy Resection of nodule Lobectomy I.obectomy
Papillary carcinoma Papillary carcinoma with lymph node metastasis Papillary carcinoma Papillary carcinoma (well encapsulated) Papillary carcinoma with lymph node metastasis Papillary carcinoma (well encapsulated) with lymph node metastasis Adenomatous nodule Adenomatous nodule Microscopic cancer + adenomatous nodule Adenomatous nodule Adenomatous nodule Adenomatous nodule Microscopic cancer + adenomatous nodt, le Adenomatous nodule + Hashimoto's thyroiditis
M: male; F: female; FNAB: fine needle aspiration biopsy.
Table 7. Incidence of thyroid cancer and changes in the thyroid nodule. Changes in nodular size
Thyroid cancer
Enlarged (n = I 1) Slightly enlarged (n = 8) Unchanged (n = 47) Smaller (n = 32) No palpable nodule or disappeared (n = 42)
4 (36.4%) I (12.5%) 3 (6.4%) 1 (3.1%) 0
calcifcation, and d e v e l o p m e n t of multiple nodules were common. It is also worth noting that about 13% of solitary nodules enlarged and that papillary c a r c i n o m a was found in 36.4% of clearly enlarging nodules (Table 7). Thus, an enlarging nodule is a definite risk for thyroid cancer. E v e n though nodular size did not change for a prolonged period in some patients, thyroid c a n c e r was found in 6.4% of this group. T h e r e l b r e , careful o b s e r v a t i o n and judicious decision are needed in this group. In contrast, thyroid nodules decreasing in size have a negligiblc risk for cancer (Table 7). Surgery was done in all patients with c y t o l o g y suggesting malignancy. Indeed, all of these patients had well differentiated papillary c a r c i n o m a < 5 cm in diameter; one of them had an extrathyroidal local invasion requiring sacrifice of the recurrent laryngeal nerve. We found 3 patients with cervical lymph node
metastases and 3 patients with well encapsulated papillary carcinoma. Clinical and pathological findings suggest that all patients with papillary c a r c i n o m a belong to a low risk group [4-6]. TheSe papillary carcinomas, h o w e v e r , do not represent all aspects of papillary carcinoma, since we have e x p e r i e n c e d more progressive, invasive, and fatal cases due to papillary c a r c i n o m a (poOr risk group). Indeed, 5 patients w h o died o f thyroid c a n c e r might belong to this category, or they may have had an invasive follicular carcinoma. Also, 8 patients with benign findings bY fine needle aspiration biopsy u n d e r w e n t surgery b e c a u s e malig" nancy was suspected clinically. All these patients had adenOmatous goiters and two of them were found to have coexistent microscopic cancer. It is u n k n o w n w h e t h e r m i c r o s c o p i c cancer was of recent onset or had been present for a long time. H o w e v e r , microscopic c a n c e r may not affect the clinical course significantly, since an occult thyroid c a n c e r has a negligible mortality or morbidity [7]. Fine needle aspiration biopsy is useful for the cytologic diagnosis of solitary thyroid nodules. H o w e v e r , follicular carc i n o m a has been difficult to diagnose by fine needle aspiration biopsy. We have to wait until i m p r o v e d m e t h o d s of diagnosing tk~llicular c a r c i n o m a are available. In s u m m a r y , the majority o f palpable solitary thyroid nodules were of the mixed cystic-solid type and tended to d e c r e a s e in size spontaneously. During the prolonged course, multiple or
K. Kuma et al.: Solitary Thyroid Nodules Calcified nodules may develop. Nodules decreasing in size have a negligible risk of cancer and no treament is required. However, enlarging solid nodules have a definite risk for thyroid Cancer. Nodules remaining the same size have to be judged JUdiciously with fine needle aspiration biopsy.
R6sum6 L'fvolution a long terme des nodules thyroidiens solitaires Palpables a 6t6 6tudi6e en surveillant 441 patients op6r6s et 140 Patients ayant un nodule non trait6 pendant une moyenne de 15 + / - 4.5 ans. Dans notre 6tude clinique, le cas le plus fr6quent 6tait la disparition du nodule (38.3%). De M6me, 36.3% des Patients ont eu une intervention chirurgicale dans un autre 6Stablissement. Cinq patients sont morts d'un cancer de la thyrofde (1.1%). Lorsque les nodules ont 6t6 r6examin6s, la Plupart 6talent soit plus petits, soit non retrouv6s. En revanche, 13% des nodules ont augment6 de volume. L ' e x a m e n 6chographique a montr6 que la plupart des nodules dits solitaires ~taient en fait multiples ou associ6s ~. des kystes. La ponction 1 algullle fine des nodules retrouvait 26.3% de cancer pour les nodules qui avavient augment6 de volume, contre 6.4% pour eeux n'ayant pas chang6 de taille. Le risque de d6velopper un cancer d6croit lorsque la taille du nodule diminue. Quinze Patients ayant un nodule suspect ont 6t6 op6r6s. Les interventions ont consist6 en une lobectomie, une thyroi'dectomie SUbtotale, ou une r6section des.nodules, associ6e ou non ~ un rage ganglionnaire. Sept patients avaient un cancer papillaire. eux patients avaient un microfoyer de cancer papillaire alors que la cytologic par voie percutan6e 6tait rassurante. Dans notre 6tude, la plupart des nodules thyroi'diens solitaires palpables avaient une tendance '~ diminuer de taille; ces nodules ne n6cessitent pas d'autre traitement. Un nodule qui augmente de Volume pr6sente un risque de d6g6n6rescence. Si la taille du nodule reste stable, une ponction ~ l'aiguille est indiqu6e.
~
Resumen Nos propusimos investigar el resultado final de la evoluci6n a largo plazo de los n6dulos tiroideos solitarios, mediante un CUestionario enviado a 441 pacientes y el examen de 140 que 13Oseian n6dulos tiroideos no tratados con una evoluci6n de 15 4.5 (DE) afios. En nuestro cuestionario clinico el hallazgo ~ s comt~n fue la desaparici6n del n6dulo (38.3%). Tambi6n se enCOntr6 que un nt~mero significativo de pacientes (36.3%) fUeron sometidos a cirugia en otros hospitales. Cinco pacientes
Invited Commentary Qlive S. G r a n t , M . D . Department of Surgery, Mayo Clinic, Rochester, Minnesota, U.S.A.
.l~ecause thyroid nodules are increasingly common with advancIng age, identifiable in nearly 50% of patients 50 years of age [1 ], the nature history of these nodules is of interest. Kuma and
587 (I. 1%) murieron de c~icner tiroideo. Cuando los n6dulos fueron reexaminados, la mayoria realmente habfan disminuido de tamafio o habia desaparecido; sin embargo, 13% habian aumentado de tamafio. La ultrasonograffa demostr6 que la mayoria de los n6dulos solitarios eran mtiltiples y quistico-s61idos. Se apreci6 una tasa mayor de calcificaci6n en los n6dulos de larga evoluci6n. Por medio de la aspiraci6n con aguja fina se encontr6 c~incer en 26.3% de los n6dulos que exhibfan crecimiento, y 6.4% en los que no registraban cambio en su tamafio. El riesgo de c~incer fue menor en los n6dulos que mostraron disminuci6n de tamafio. Un total de 15 pacientes con sospecha de malignidad fue sometido a cirugia; la operaci6n consisti6 en iobectomia, tiroidectornfa casi total o resecci6n de los n6dulos con o sin disecci6n cervical modificada. Siete pacientes tuvieron carcinoma papilar y dos, con citologia benigna, ten/an carcinoma micropapilar. En nuestro estudio se encontr6 que la mayorfa de los n6dulos solitarios palpables tendi6 a disminuir de tamafio; tales n6dulos no requieren tratamiento. N6dulos s61idos que aumentan de tamafio definitivamente tienen riesgo de c~incer tiroideo. En los n6dulos de tamafio estacionario esta indicado unjuicioso aproche fundamentado en la aspiraci6n con aguja fina.
Acknowledgments We thank Miss Keiko Tamada, Mr. Hidekazu Toriihara, and Miss Marl Miyabe for their assistance in this study.
References 1. Vander, J.B., Gaston, E.A., Dawber, T.R.: The significance of nontoxic thyroid nodules. Ann. Intern. Med. 69:537, 1968 2. Grant, C.S., Hay, I.D., Gough, I.R., McCathy, P.M., Goellner, J.R.: Long-term follow-up of patients with benign thyroid fineneedle aspiration cytologic diagnosis. Surgery 106:980, 1989 3. Hoffman, G.L., Thompson, N.W., Heffron, C.: The solitary thyroid nodule: A reassessment. Arch. Surg. 105:379, 1972 4. Cady, B., Rossi, R.: An expanded view of risk group definition in differentiated thyroid cancer. Surgery 104:947, 1988 5. lto, l., Noguchi, S., Murakami, N., Noguchi, A.: Factors affecting the prognOsis of patient with carcinomas of the thyroid. Surg. Gynecol. Obstet. 150:539, 1980 6. Hay, I.D., Grant, C.S., Taylor, W.F., McConahey, W.M.: Ipsilateral Iobectomy versus bilateral lobe resection in papillary carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102:1088, 1987 7. Sampson, R.J.: Prevalence and significance of occult thyroid cancer. in Radiation Associated Thyroid Carcinoma, L. DeGroot, editor, New York, Grune & Stratton, 1977, pp. 137-153
coworkers retrospectively contacted over 2,600 patients who underwent evaluation of solitary thyroid nodules, including fine needle aspiration (FNA). These patients had refused any form of therapy when first seen 10 to 30 years previously. Of this group, 441 patients responded to a brief questionnaire about their status and 140 patients returned for re-examination. Of principal significance were that two-thirds of examined patients had developed multiple nodules, the most common fate of the nodules in general was that they disappeared, and although malignancy was uncommon in nodules that had decreased or
World Journal of Surgery @ 1992 by the Soci~.t~ lnteraationale ~le Chirurgie
Outcome of Long Standing Solitary Thyroid Nodules Kanji K u m a , M . D . , F u m i o M a t s u z u k a , M . D . , A k i r a K o b a y a s h i , M . D . , K e i s u k e Hirai, M . D . , Sinji Morita, M , D . , A k i r a M i y a u c h i , M . D . , Shoichi K a t a y a m a , M . D . , and M a s a h i r o S u g a w a r a , M . D . Kuma Hospital, Second Department of Surgery, Kagawa Medical School, and Kure National Hospital, Kobe, Japan and Division of Metabolism and Endocrinology, University of California, Los Angeles, School of Medicine, Los Angeles, California, U.S.A. We investigated the outcome of long standing palpable solitary thyroid nodules by surveying 441 patients and examining 140 patients who had Untreated thyroid nodules for 15 -+ 4.5 years. In our clinical survey, the nlost COmmon outcome was disappearance of the thyroid nodule (38.3%). AnIso a significant number of patients (36.3%) underwent surgery in other spita|s. Five (1.1%) patients died of thyroid cancer. When thyroid nodules were re-examined, most nodules indeed decreased in size or ~SapPeared; however, 13% of nodules increased in size. Ultrasound of ac nodules showed that most solitary nodules were multiple and partially cYStic and solid. There was an increased incidence of calcification in Ioug standing nod~es. Thyroid cancer was found by fine needle aspiration biopsy in 26.3% of enlarging nodules and 6.4% of nodules without changing size. The risk of cancer decreased when the size of the nudule decreased. A total of 15 patients with suspicion of malignancy underwent surgery. Surgical procedures were Iobectomy, near total thyroidectomy, Or resection of nodules with or without modified neck dissection. Seven Patients had papillary carcinoma and 2 patients with benign cytology had croscopieally evident papillary carcinoma. In our study, the majority nf lPable solitary thyroid nodules tended to decrease in size; these nodules not require treatment. Enlarging solid nodules are a definite risk for aYroid cancer If the size of the nodule remains the same judicious aPProach with fine needle aspiration biopsy is needed.
i
The natural history of thyroid nodules after a prolonged period is Unknown. Vander and coworkers [I] surveyed 5,127 people in the town of Framingham, Massachusetts, and found nontoxic thyroid nodules in 6.4% of the population. In their study, none of the subjects were reported to have thyroid cancer after observation for 15 years. However, their study was done before the technique of fine needle aspiration biopsy was available and tissue diagnosis was therefore lacking. In a recent study of 8,219 patients with thyroid nodules, 4% were positive and I1% VCere SUspicious of malignancy by fine needle aspiration biopsy [2]. Therefore, cancer is the definite risk in patients with a solitary thyroid nodule [3]. Thus, it is important to know the clinical as well as the pathological aspects of solitary thyroid nOdUles. We had an opportunity to examine the outcome of long at the internat,ona, Assoc,a,,o. ot Endocrine Surgeons in
un, Sweden August 1991. v S Shimo ~male r,&.'print requests: l)r. K. K'uma, Kuma Hospital. 8-,-3y~ ' u°rh Chuo-ku, Kobe, 650, Japan.
standing solitary thyroid nodules diagnosed 10 to 30 years ago. We were interested in the change in size, clinical course, and the incidence of malignancy in these nodules after diagnosis. This type of investigation should disclose the behavior of solitary thyroid nodules and shed light on the management of patients with this disorder. First, we mailed questionnaires to 2,609 patients regarding the changes in thyroid nodules. Second, we asked them to visit us for examination of thyroid nodules by ultrasound and fine needle aspiration biopsy. Four hundred forty-one patients responded to our questionnaire and 140 patients came lbr re-examination. We present the results of these investigations. Materials and M e t h o d s
CHnical Survey fiwm Patients with Previously Diagnosed Solitao, Thyroid Nodule We mailed questionnaires to 2,609 patients who were diagnosed with solitary thyroid nodules fi-om 1955 to 1979 at Kuma Hospital, Kobe, Japan, and who did not have lbllow-up care with us thereafter. The diagnosis of a solitary thyroid nodule was made by palpation and all patients underwent needle aspiration with 22 to 23 gauge needles to classify nodules as either cyst or solid nodule (fine needle aspiration biopsy and ultrasound were unavailable at that time). If no fluid was obtained, the lesion was considered solid. The size of the nodule was recorded by measurement of its diameter. These patients did not return to our clinic either because they refused any therapeutic approach or did not consider it as a life threatening condition. Multinodular goiters, Graves' disease, or nodules suggesting thyroid cancer were excluded from this study. We asked 4 questions: I) Were the patients dead or alive? 2) Had the nodule been removed surgically in any other hospital? 3) If surgery was not done, was the nodule still present? and 4) If present, was there any noticeable change in size?
Re-Examination of Thyroid Nodules 10 to 30 Years Later One hundred forty patients came for re-examination of thyroid nodules. Re-examination included palpation, thyroid function
584
World J. Surg. Vol. 16, No. 4, July/Aug. 1992
Table 2. Changes in thyroid nodules in 140 patients with previously diagnosed solitary thyroid nodules.
Table 1. Results of clinical survey. No. of pls. Result Questionnaire sent Responded Nodule no longer present Nodule removed in other hospitals Nodule still present Death No response
Total 2609 441 169" 160" 82"
30" 2168
Re-examined 140 7I 32" -39"
-69
"Result of the patients who responded to the questionnaire.
tests (measurement of serum thyroid hormone and thyrotropin), ultrasound, and fine needle aspiration biopsy. The change in nodular size was determined by comparing the present size with the size of the previously recorded nodule. The same two physicians ( K K and FM) examined all patients.
Thyroid Function Tests Serum free thyroxine (T4) and triiodothyronine (T 3) levels were measured using Amerlex-M kit (Amersham International plc, Buckinghamshire, England). Serum thyrotropin (TSH) level was measured by a highly sensitive radioimmunoassay kit (Dainobot Inc., Tokyo, Japan) which can detect up to 0.05 p,U/ml of TSH.
Ultrasound Study Thyroid ultrasound was obtained using a real-time linear scanner with a 7.5 MHZ transducer housed in a water bath (Aloka USI-82c, ASU-46, Tokyo, Japan).
Fine Needle Asph'ation Biopsy Fine needle aspiration biopsy of the thyroid nodules was performed using a 22 or 23 gauge needle in patients who came for re-examination. Cytological examination was done by an expert in this field (A.M.) and classified into the following categories: Class 1, Class 2, and foamy cells indicated a benign lesion; Class 3 indicated the presence of atypical follicular cells; Class 4 was suspicious for malignancy; and class 5 was malignant.
Thyroid Surgery Seven patients who had lesions of Class 4 to 5 underwent surgery. Also, 8 patients whose cytology findings were benign but who had the presence of calcification or an enlarged nodule underwent thyroid surgery. Results
Results of Clinical Survey Table I summarizes our clinical survey. Among 2,609 patients, 441 (16.9%) patients responded to our questionnaire. In these responders, 160 (36.3%) patients had surgery in other hospitals.
Changes in nodule size
Age (yrs)"
Enlarged Slightly enlarged Unchanged Smaller No palpable nodule but seen by ultrasound Disappeared'
55 60 56 52 57
No. of pts. F
M
-+ 13 10 1 -+ 10 8 0 --- 12 43 4 - 12 31 I +- 10 24 2
57 +_ II
16 0
Cyst b
SolidI'
Total
0 3 7 15 18
I1 5 40 17 8
II (7.8%) 8 (5.7%) 47 (33.6%) 32 (22.9%) 26 (18.6%)
12
4
16 (11.4%)
"Age is the mean +-- SD. bThis is the initial diagnosis based on needle aspiration. The change in nodule size was determined by palpation on the latest visit. 'Nodule was not seen by ultrasound. F: female; M: male.
Surprisingly, 169 (38.3%) patients noted disappearance of the thyroid nodule. Eighty-two (18.6%) patients claimed that the nodule was still present; in 58 patients the nodule was unchanged, in 13 patients it was felt to have decreased in size, and in 12 patients it was noted to have increased in size. Thus, disappearance of the solitary nodule was the most common outcome of a palpable solitary thyroid nodule when patients judged their own thyroid nodule.
Changes in Nodular Size Re-examination of thyroid nodules was undertaken in 140 patients 10 to 30 years after the initial visit; an average interval between the first visit and the last visit was 15 - 4.5 years. The distribution of these patients in response group and nonresponse group to our questionnaire is presented in Table 2. Surprisingly, the most common outcome (52.9%) of thyroid nodules was a decrease in nodular size including disappearance of the nodule. This was more common in patients whose initial diagnosis was a thyroid cyst. The next most common outcome (33.6%) was no cha~nge in size, which was often seen in patients with solid nodules. A small but significant number of patients (13.5%) were found to have enlarged or slightly enlarged thyroid nodules, particularly patients with solid nodules. The change in nodule size described by patients was co~" pared with our physical findings. Patients' statement on the change in nodule size was in agreement with our findings i0 85.9% of cases. Therefore, judgment of nodule size by patients was reliable. All patients who visited for re-examination had normal thyroid function tests.
Analysis of Thyroid Nodule by Ultrasound We analyzed thyroid nodules by ultrasound in 122 patients from our study group. A significant number of patients (68%) were found to have multiple nodules (Table 3). To examine our technical accuracy of palpating solitary thyroid nodule, 156 patients who were recently diagnosed with solitary thyroid nodules by palpation were examined by ultrasound. The accU" racy of palpating single nodules in the control group was 65.4~ when nodules were judged by ultrasound (Table 3). Thus, our technique of distinguishing solitary nodule from multiple nod"
K. Kuma et al.: Solitary Thyroid Nodules
585
Table 3, Examination of solitary thyroid nodules by ultrasound.
Finding ingle or multiple Single Multiple Calcification Solid or cystic Solid Cystic Mixed tip
Re-examined patients (n = 122)
Control patients" (n = 156)
32% 68% 47.5%
65.4% 34.6% 12.2%
30.3% 14.8% 54.9%
27.6% 17.3% 55. I%
Table 5. Results of fine needle aspiration biopsy.
Classification of cytology
No. of pts.
No. of operations performed
Class 2 Class 2 or 3 Class 3 Class 4 or 5 Class 5 Foamy cells Degenerative change Inadequate
73 1 I 1 6 9 I l
6 0 I 1 6 I 0 0
.
ahents in the control group were diagnosed to have solitary thyroid nodules from 1990 to 1991; these patients were used for comparison.
Ta..._ble4. Comparison of initial diagnosis with ultrasound findings. Initial diagnosis
Ultrasound findings Solid Cystic
Mixed
Solid (n = 79) C.~Ystic(n = 43)
30 (38%) 7 (16.3%)
45 (57%) 22 (51.2%)
4 (5%) 14 (32.5%)
tales Was fairly reliable. Based on the data shown in Table 3, the Change from a solitary nodule to mutiple nodules seems to OCCur in long standing solitary nodules. Another characteristic feature in patients with long standing solitary thyroid nodules Was the presence of calcification in 47.5% of cases (Table 3). The character of the nodules in 122 patients showed 14.8% to be cystic, 54.9% to be mixed cystic and solid nodules, and 30.3% to be solid nodules. These values were similar to those found in the control group (Table 3). We also compared our initial clinical diagnosis with ultraSound findings at the last visit. More than 50% of patients with a diagnosis of either a cystic or solid nodule had mixed cystic Solid nodules (Table 4). Five percent of the solid nodule group and 16.3% of the cystic group were misdiagnosed.
Results of Fine Needle Aspiration Biopsy Ninety-three patients had needle aspiration biopsy and the results are shown in Table 5. A total of 7 (7.5%) patients had findings suggestive of malignancy. One patient showed Class 3 and the rest of the patients were benign by fine needle aspiration biopsy.
Results of Surgery Patients who underwent surgery are listed in Table 6. Surgical Procedures were lobectomy, total thyroidectomy, or resection of nodules with or without modified neck dissection. All patients having Class 4 to 5 cytology were proven to have Papillary carcinoma and 3 of them had cervical lymph node metastases. Eight patients with benign cytology by fine needle aspiration biopsy underwent surgery because of the presence of enlarging nodules, calcification, or extraordinarily hard nodUles. All 8 patients had adenomatous goiter; 2 of them were found to have microscopic cancer (papillary carcinoma) in addition to benign adenomatous nodules.
We examined whether thyroid cancer occurs in any particular group of thyroid nodules. As shown in Table 7, thyroid cancer was seen in 36,4% of patients whose thyroid nodules clearly enlarged. The incidence of thyroid cancer was 6.4% in patients whose nodules did not change for a prolonged period. One patient, despite descreasing size of the nodule, was found to have a microscopic cancer. Our study indicates a clear-cut increase in thyroid cancer in an enlarging nodule. Discussion
There has been no comprehensive study investigating the clinical course of solitary thyroid nodules since 1968 when Vander and associates [1] reported their 15 year observation of thyroid nodules. Our study is different from the study of Vander and associates [1], since we focused on solitary thyroid nodules and investigated these nodules by combined ultrasound and fine needle aspiration biopsy approximately 15 years after the initial diagnosis. From 1955 to 1979 when our patients in this study were first seen, the technique of fine needle aspiration biopsy was unavailable. Therefore, we had to judge thyroid nodules clinically. We recommended surgery when solitary nodules were hard, large, growing, or calcified. Nearly 6,000 patients had surgery during this period in our hospital. Patients with solitary thyroid nodules who did not have surgery or refused surgery were subjects in this study. Surgery was not done in patients having soft nodules, relatively small nodules, or cysts; these patients were enrolled for the clinical survey. In analyzing thyroid nodules in 140 patients who visited for re-examination, 63% of patients had nodules of 3 cm. Thus, most patients enrolled in our survey had small thyroid nodules. In our clinical survey 441 patients responded to our questionnaire. The most common answer to our questionnaire was disappearance of the nodule (38.3%). Indeed, disappearance of the thyroid nodule was supported by our actual examination (Table 2) and most of these nodules that disappeared were thyroid cysts. In the 441 responders, a significant number of patients (36.3%) had surgery in other hospitals. We were unable to obtain information regarding reasons for surgery and the final diagnosis. At least, there were a certain number of patients who required surgery in a long clinical course with a solitary thyroid nodule. Among 30 (6.8%) deaths, thyroid cancer appeared to be the cause of death in 5 patients. When patients with long standing solitary nodules were examined, the decrease in size, an increased incidence of
586
World J. Surg. Vul. 16, No. 4, July/Aug. 1992
Table 6. Patients who underwent surgery.
Age (yrs)
Sex
Years after first visit
1
62
M
1I
Class 5
Solid + calcification
2
59
F
II
Class 5
Solid + calcification
3
33
F
14
Class 5
Solid + calcification
4
61
F
12
Class 5
Solid ~ calcification
5
40
F
I1
Class 4-5
Solid + calcification
6
37
M
14
Class 5
Solid + calcification
7
56
F
14
Class 5
Solid ~ calcificalion
8 9 10
57 53 49
F F F
16 2t) 16
Class 2 Class 3 Class 2
Resection of nodule Lobectomy Lobectomy
I1 12 13 14
44 66 73 41
F F F F
15 25 19 13
Class 2 Foamy cell Class 2 Class 2
Calcification Calcification Solid + cyst + calcification Solid + cyst Calcification Calcification Solid + cyst
15
47
F
14
Class 2
Solid + cyst
[x~bectomy
Pt. no.
Cytology by FNAB
Ultrasound findings
Operation
Pathological diagnosis
Left Iobectomy and isthmectomy with modified neck dissection Total thyroideclomy with modified neck dissection Sub-total thyroidectomy with modified neck dissection Lobectomy with modified neck dissection I.obectomy with modified neck dissection Total thyroidectomy with modified neck dissection Lobectomy with modified neck dissection
Papillary carcinoma (well encapsulated)
Lobectomy Resection of nodule Lobectomy I.obectomy
Papillary carcinoma Papillary carcinoma with lymph node metastasis Papillary carcinoma Papillary carcinoma (well encapsulated) Papillary carcinoma with lymph node metastasis Papillary carcinoma (well encapsulated) with lymph node metastasis Adenomatous nodule Adenomatous nodule Microscopic cancer + adenomatous nodule Adenomatous nodule Adenomatous nodule Adenomatous nodule Microscopic cancer + adenomatous nodt, le Adenomatous nodule + Hashimoto's thyroiditis
M: male; F: female; FNAB: fine needle aspiration biopsy.
Table 7. Incidence of thyroid cancer and changes in the thyroid nodule. Changes in nodular size
Thyroid cancer
Enlarged (n = I 1) Slightly enlarged (n = 8) Unchanged (n = 47) Smaller (n = 32) No palpable nodule or disappeared (n = 42)
4 (36.4%) I (12.5%) 3 (6.4%) 1 (3.1%) 0
calcifcation, and d e v e l o p m e n t of multiple nodules were common. It is also worth noting that about 13% of solitary nodules enlarged and that papillary c a r c i n o m a was found in 36.4% of clearly enlarging nodules (Table 7). Thus, an enlarging nodule is a definite risk for thyroid cancer. E v e n though nodular size did not change for a prolonged period in some patients, thyroid c a n c e r was found in 6.4% of this group. T h e r e l b r e , careful o b s e r v a t i o n and judicious decision are needed in this group. In contrast, thyroid nodules decreasing in size have a negligiblc risk for cancer (Table 7). Surgery was done in all patients with c y t o l o g y suggesting malignancy. Indeed, all of these patients had well differentiated papillary c a r c i n o m a < 5 cm in diameter; one of them had an extrathyroidal local invasion requiring sacrifice of the recurrent laryngeal nerve. We found 3 patients with cervical lymph node
metastases and 3 patients with well encapsulated papillary carcinoma. Clinical and pathological findings suggest that all patients with papillary c a r c i n o m a belong to a low risk group [4-6]. TheSe papillary carcinomas, h o w e v e r , do not represent all aspects of papillary carcinoma, since we have e x p e r i e n c e d more progressive, invasive, and fatal cases due to papillary c a r c i n o m a (poOr risk group). Indeed, 5 patients w h o died o f thyroid c a n c e r might belong to this category, or they may have had an invasive follicular carcinoma. Also, 8 patients with benign findings bY fine needle aspiration biopsy u n d e r w e n t surgery b e c a u s e malig" nancy was suspected clinically. All these patients had adenOmatous goiters and two of them were found to have coexistent microscopic cancer. It is u n k n o w n w h e t h e r m i c r o s c o p i c cancer was of recent onset or had been present for a long time. H o w e v e r , microscopic c a n c e r may not affect the clinical course significantly, since an occult thyroid c a n c e r has a negligible mortality or morbidity [7]. Fine needle aspiration biopsy is useful for the cytologic diagnosis of solitary thyroid nodules. H o w e v e r , follicular carc i n o m a has been difficult to diagnose by fine needle aspiration biopsy. We have to wait until i m p r o v e d m e t h o d s of diagnosing tk~llicular c a r c i n o m a are available. In s u m m a r y , the majority o f palpable solitary thyroid nodules were of the mixed cystic-solid type and tended to d e c r e a s e in size spontaneously. During the prolonged course, multiple or
K. Kuma et al.: Solitary Thyroid Nodules Calcified nodules may develop. Nodules decreasing in size have a negligible risk of cancer and no treament is required. However, enlarging solid nodules have a definite risk for thyroid Cancer. Nodules remaining the same size have to be judged JUdiciously with fine needle aspiration biopsy.
R6sum6 L'fvolution a long terme des nodules thyroidiens solitaires Palpables a 6t6 6tudi6e en surveillant 441 patients op6r6s et 140 Patients ayant un nodule non trait6 pendant une moyenne de 15 + / - 4.5 ans. Dans notre 6tude clinique, le cas le plus fr6quent 6tait la disparition du nodule (38.3%). De M6me, 36.3% des Patients ont eu une intervention chirurgicale dans un autre 6Stablissement. Cinq patients sont morts d'un cancer de la thyrofde (1.1%). Lorsque les nodules ont 6t6 r6examin6s, la Plupart 6talent soit plus petits, soit non retrouv6s. En revanche, 13% des nodules ont augment6 de volume. L ' e x a m e n 6chographique a montr6 que la plupart des nodules dits solitaires ~taient en fait multiples ou associ6s ~. des kystes. La ponction 1 algullle fine des nodules retrouvait 26.3% de cancer pour les nodules qui avavient augment6 de volume, contre 6.4% pour eeux n'ayant pas chang6 de taille. Le risque de d6velopper un cancer d6croit lorsque la taille du nodule diminue. Quinze Patients ayant un nodule suspect ont 6t6 op6r6s. Les interventions ont consist6 en une lobectomie, une thyroi'dectomie SUbtotale, ou une r6section des.nodules, associ6e ou non ~ un rage ganglionnaire. Sept patients avaient un cancer papillaire. eux patients avaient un microfoyer de cancer papillaire alors que la cytologic par voie percutan6e 6tait rassurante. Dans notre 6tude, la plupart des nodules thyroi'diens solitaires palpables avaient une tendance '~ diminuer de taille; ces nodules ne n6cessitent pas d'autre traitement. Un nodule qui augmente de Volume pr6sente un risque de d6g6n6rescence. Si la taille du nodule reste stable, une ponction ~ l'aiguille est indiqu6e.
~
Resumen Nos propusimos investigar el resultado final de la evoluci6n a largo plazo de los n6dulos tiroideos solitarios, mediante un CUestionario enviado a 441 pacientes y el examen de 140 que 13Oseian n6dulos tiroideos no tratados con una evoluci6n de 15 4.5 (DE) afios. En nuestro cuestionario clinico el hallazgo ~ s comt~n fue la desaparici6n del n6dulo (38.3%). Tambi6n se enCOntr6 que un nt~mero significativo de pacientes (36.3%) fUeron sometidos a cirugia en otros hospitales. Cinco pacientes
Invited Commentary Qlive S. G r a n t , M . D . Department of Surgery, Mayo Clinic, Rochester, Minnesota, U.S.A.
.l~ecause thyroid nodules are increasingly common with advancIng age, identifiable in nearly 50% of patients 50 years of age [1 ], the nature history of these nodules is of interest. Kuma and
587 (I. 1%) murieron de c~icner tiroideo. Cuando los n6dulos fueron reexaminados, la mayoria realmente habfan disminuido de tamafio o habia desaparecido; sin embargo, 13% habian aumentado de tamafio. La ultrasonograffa demostr6 que la mayoria de los n6dulos solitarios eran mtiltiples y quistico-s61idos. Se apreci6 una tasa mayor de calcificaci6n en los n6dulos de larga evoluci6n. Por medio de la aspiraci6n con aguja fina se encontr6 c~incer en 26.3% de los n6dulos que exhibfan crecimiento, y 6.4% en los que no registraban cambio en su tamafio. El riesgo de c~incer fue menor en los n6dulos que mostraron disminuci6n de tamafio. Un total de 15 pacientes con sospecha de malignidad fue sometido a cirugia; la operaci6n consisti6 en iobectomia, tiroidectornfa casi total o resecci6n de los n6dulos con o sin disecci6n cervical modificada. Siete pacientes tuvieron carcinoma papilar y dos, con citologia benigna, ten/an carcinoma micropapilar. En nuestro estudio se encontr6 que la mayorfa de los n6dulos solitarios palpables tendi6 a disminuir de tamafio; tales n6dulos no requieren tratamiento. N6dulos s61idos que aumentan de tamafio definitivamente tienen riesgo de c~incer tiroideo. En los n6dulos de tamafio estacionario esta indicado unjuicioso aproche fundamentado en la aspiraci6n con aguja fina.
Acknowledgments We thank Miss Keiko Tamada, Mr. Hidekazu Toriihara, and Miss Marl Miyabe for their assistance in this study.
References 1. Vander, J.B., Gaston, E.A., Dawber, T.R.: The significance of nontoxic thyroid nodules. Ann. Intern. Med. 69:537, 1968 2. Grant, C.S., Hay, I.D., Gough, I.R., McCathy, P.M., Goellner, J.R.: Long-term follow-up of patients with benign thyroid fineneedle aspiration cytologic diagnosis. Surgery 106:980, 1989 3. Hoffman, G.L., Thompson, N.W., Heffron, C.: The solitary thyroid nodule: A reassessment. Arch. Surg. 105:379, 1972 4. Cady, B., Rossi, R.: An expanded view of risk group definition in differentiated thyroid cancer. Surgery 104:947, 1988 5. lto, l., Noguchi, S., Murakami, N., Noguchi, A.: Factors affecting the prognOsis of patient with carcinomas of the thyroid. Surg. Gynecol. Obstet. 150:539, 1980 6. Hay, I.D., Grant, C.S., Taylor, W.F., McConahey, W.M.: Ipsilateral Iobectomy versus bilateral lobe resection in papillary carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 102:1088, 1987 7. Sampson, R.J.: Prevalence and significance of occult thyroid cancer. in Radiation Associated Thyroid Carcinoma, L. DeGroot, editor, New York, Grune & Stratton, 1977, pp. 137-153
coworkers retrospectively contacted over 2,600 patients who underwent evaluation of solitary thyroid nodules, including fine needle aspiration (FNA). These patients had refused any form of therapy when first seen 10 to 30 years previously. Of this group, 441 patients responded to a brief questionnaire about their status and 140 patients returned for re-examination. Of principal significance were that two-thirds of examined patients had developed multiple nodules, the most common fate of the nodules in general was that they disappeared, and although malignancy was uncommon in nodules that had decreased or
