Upsala J Med Sci 91: 67-76, 1986 Fine Needle Biopsy and Scintigram in the Preoperative Diagnosis of Thyroid Lesions Sighild Westman-Naeser,' Lars Grimelius,' Henry Johansson3 and Jan Malmaeus3 'Departments o Pathology and 'Surgery, University Hospital, Uppsala, Malmo General Hospital, Malmo, Sweden and f Department of Pathology, University of Lund, ABSTRACT Fine needle biopsies (FNB) of the t h y r o i d were examined from 860 p a t i e n t s . In 703 c a s e s f o l l i c u l a r c e l l s without atypia were found and i n t h i s group of p a t i e n t s the c l i n i c a l diagnosis was nodular goitre. Operations were performed i n 138 p a t i e n t s and i n 97 cases the cytological f i n d i n g could be c o r r e l a t e d t o t h e histopathological diagnosis. In 33 of these patients thyroid carcinoma was h i s t o l o g i c a l l y v e r i f i e d . I n 26 of the carcinoma cases cytologic examination showed grave atypia or changes fndicating carcinoma. The cases i n which the cytological diagnoses were f a l s e l y negative are discussed. Moderate c e l l u l a r atypia occurred i n one case w i t h papillary carcinoma. In two cases the cyto- 1 ogical examination gave a f a l s e positive diagnosis of cancer, both represent- i n g t h y r o i d i t i s of the lymphoid type. Cold nodules were found i n 10/19 p a t i e n t s and a hot nodule i n ,1 p a t i e n t . In 3 p a t i e n t s the scintigrams were normal a n d i n another 5 inconclusive. The results indicate t h a t thyroid scintigrams can only be used as a supplement t o t h e physical examination and a guidance f o r FNB. T h e contribution of FNB i n t h e decision t o operate i s discussed and i t is concluded t h a t FNB i s a valuable adjunct i n preoperative diagnosis of thyroid lesions. The b e s t diagnostic r e s u l t s a r e obtained when there i s a c l o s e cooperation between c l i n i c i a n , r a d i o l o g i s t , c y t o l o g i s t and pathologist. The scintigrams i n patients w i t h thyroid carcinoma a r e a l s o presented. INTRODUCTION Palpable thyroid nodules may present d i f f i c u l t i e s i n the d i f f e r e n t i a l diag- nosis between a malignant tumour and a benign thyroid lesion. The thyroid gland i s readily accessible f o r f i n e needle aspiration biopsy and thus a possi- b i l i t y i s offered t o d i s t i n g u i s h morphologically between non-ma1 ignant and malignant lesions as well as between various types of malignant neoplasms (10,2,6). Scintigraphy is often used t o l o c a l i z e areas suspected of malignancy, i . e . cold nodules. I t i s a valuable aid i n the guidance of the f i n e needle 67 b i o p s y . The frequency o f maiignancy on s c i n t i g r a p h i c a l l y l o c a l i z e d c o l d nod- u l e s has been r e p o r t e d t o v a r y between 3 and 30 %, and i t i n c r e a s e s w i t h age (8,4,). The p r e s e n t study was undertaken t o analyze t o what e x t e n t these two methods have proven u s e f u l t o g u i d e t h e c l i n i c i a n i n t h e t r e a t m e n t o f p a t i e n t s w i t h t h y r o i d l e s i o n s . To e s t i m a t e t h e accuracy o f t h e c y t o l o g i c a l d i a g n o s i s , t h e r e s u l t s o b t a i n e d a f t e r f i n e needle a s p i r a t i o n b i o p s y were compared w i t h t h e h i s t o p a t h o l o g i c a l f i n d i n g s i n those cases t h a t were operated on. The p r e s e n t - i n g s i g n s and symptoms i n p a t i e n t s w i t h a f i n a l d i a g n o s i s o f t h y r o i d malignancy were a l s o i n v e s t i g a t e d . MATERIAL AND METHODS The p r e s e n t study i n c l u d e s 896 p a t i e n t s w i t h suspected o r apparent t h y r o i d disease r e f e r r e d t o t h e Department o f C l i n i c a l Cytology f o r f i n e needle b i o p s y o r t o t h e Department o f Surgery f o r o p e r a t i o n d u r i n g t h e y e a r s 1979-80. A l t o - g e t h e r 910 f i n e needle b i o p s i e s (FNB) o f t h e t h y r o i d glands were performed on 860 o f these p a t i e n t s a t t h e L a b o r a t o r y o f C l i n i c a l C y t o l o g y , U n i v e r s i t y , Hospi- t a l , Uppsala. I n 36 p a t i e n t s t h e need f o r o p e r a t i o n was c l i n i c a l l y so & v i o u s t h a t n e i t h e r FNB n o r s c i n t i g r a m were regarded necessary. T h y r o i d s c i n t i g r a m s - performed w i t h 99mTc - were used i n more than h a l f o f t h e p a t i e n t s i n c l u d e d i n t h i s m a t e r i a l . I n t h i s study, however, o n l y t h e s c i n t i g r a p h i c f i n d i n g s i n t h e p a t i e n t s , who f i n a l l y g o t a d i a g n o s i s o f t h y r o i d carcinoma, w i l l be r e p o r t e d . The FNB and t h e c y t o l o g i c a l examinations were performed b y t h e same doctor. The smears were a i r - d r i e d and s t a i n e d a c c o r d i n g t o May Grunewald-Giemsa. C y s t c o n t e n t s were c e n t r i f u g e d and two smears were prepared, one s t a i n e d as above, t h e o t h e r e t h a n o l - f i x e d and s t a i n e d a c c o r d i n g t o Papanicolau. F o r h i s t o l o g i c a l examination t h e s u r g i c a l l y removed t h y r o i d specimens ( f i x e d o r u n f i x e d ) were c a r e f u l l y s e c t i o n e d i n t o t h i n s l i c e s o f JI-1 cm. Ten % n e u t r a l f o r m a l i n was used as f i x a t i v e . F i v e v m d e p a r a f f i n e d s e c t i o n s were s t a i n e d w i t h haematoxyl i n e o s i n o r a c c o r d i n g t o van Gieson. A l l h i s t o p a t h o l o g i c a l examina- t i o n s were performed b y t h e same p a t h o l o g i s t . The h i s t o l o g i c a l c l a s s i f i c a t i o n a c c o r d i n g t o t h e WHO was used. C l i n i c a l i n f o r m a t i o n r e l e v a n t t o t h e p r e s e n t study was o b t a i n e d from t h e m e d i c a l r e c o r d s o f t h e p a t i e n t s . RESULTS The h o s p i t a l s and d i f f e r e n t c l i n i c s from where t h e p a t i e n t s were r e f e r r e d f o r FNB a r e l i s t e d i n Table 1. 68 Table 1. The h o s p i t a l s and c l i n i c s r e f e r r i n g t h e p a t i e n t s (860) f o r f i n e needle biopsy Hospital (HI __ C1 i nic Nos. of b i o p s i e s U n i v e r s i t y H . Uppsal a Medic i ne Oncology 257 20 1 Surgery 116 Otolaryngology 36 Others 61 Regional Medicine and 159 community H* Surgery General 80 p r a c t i t i o n e r s * - Total number of b i o p s i e s 910 In some patients t h e biopsy was r e p e a t e d 1-3 times a s the m a t e r i a l was presumed n o t t o be r e p r e s e n t a t i v e f o r the l e s i o n o r t o o s c a r c e t o permit a r e l i a b l e d i a g n o s i s * In t h e county of Uppsala Table 2. Cytological f i n d i n g s i n 910 f i n e needle b i o p s i e s from 860 p a t i e n t s Cytological f i n d i n g s Nos. of b i o p s i e s a n d d i a g n o s i s Fol 1 i c u l a r c e l l s without a t y p i a 703 Fol 1 icul a r c e l l s w i t h a t y p i a s l i g h t t o moderate grave or c a n c e r grave i n a s s o c i a t i o n w i t h t h y r o i d i ti s lymphoid type granul omatous type T h y r o i d i t i s Non-thyroid l e s i o n s 46 28 18 91 79 12 6 18 - I n s u f f ic i en t ma t e r i a1 Total 910 * Lymphomas, m e t a s t a s e s of renal or s a l i v a r y gland carcinoma 69 I n t h e m a j o r i t y o f t h e FNB f o l l i c u l a r c e l l s w i t h o u t a t y p i a were observed ( T a b l e 2 ) . I n t h i s p a t i e n t group a c l i n i c a l o r h i s t o p a t h o l o g i c a l d i a g n o s i s o f n o d u l a r g o i t r e was u s u a l l y made. B i o p s i e s from 46 l e s i o n s showed c e l l s w i t h s l i g h t t o moderate a t y p i a . I n another 46 cases c o r r e s p o n d i n g t o 5 % o f t h e m a t e r i a l t h e c e l l u l a r a t y p i a was found t o b e grave o r suggesting malignancy. T h i s f i g u r e i n c l u d e s 18 cases o f lymphoid t h y r o i d i t i s w i t h grave c e l l u l a r a t y p i a s . I n a l l t h e s e 18 cases t h e c l i n i c a l d i a g n o s i s o f t h y r o i d i t i s was c l i n i c a l l y and i m m u n o l o g i c a l l y w e l l e s t a b l i s h e d . These p a t i e n t s were f o l l o w e d c l i n i c a l l y and have h i t h e r t o n o t been o p e r a t e d on. T h y r e o i d i t i s o f t h e lymphoid o r granulomatous t y p e was diagnosed i n 9 1 o f t h e b i o p s i e s (10 % ) . I n 1 8 p a t i e n t s t h e m a t e r i a l o b t a i n e d a t t h e b i o p s y d i d n o t p e r m i t a d i a g n o s i s and i t was n o t p o s s i b l e t o p e r f o r m another FNB. D u r i n g t h e i n v e s t i g a t i o n p e r i o d 138 p a t i e n t s underwent surgery o f t h e t h y - r o i d gland, 102 o f which had been examined w i t h FNB. Most o f t h e p a t i e n t s i n whom t h e c y t o l o g i c a l smears had shown a t y p i a , u s u a l l y o f a s l i g h t degree were n o t operated on. These p a t i e n t s were u s u a l l y e l d e r l y w i t h a l o n g h i s t o r y of m u l t i n o d u l a r g o i t r e . Those where t h e a t y p i a was s u s p i c i o u s f o r malignancy and n o t a s s o c i a t e d w i t h lymphoid t h y r o i d i t i s were a l l operated. The main i n d i c a - t i o n s f o r surgery a r e g i v e n i n Table 3. Table 3. I n d i c a t i o n s f o r o p e r a t i o n I n d i c a t i o n s Nos. o f p a t i e n t s Toxic ( h o t ) n o d u l e ( s 1 6 Toxic g o i t r e 32 Col d nodul e( s 1 11 Nodule(s1 w i t h o u t c e l l u l a r a t y p i a * Nodule(s) w i t h c e l l u l a r a t y p i a o r cancer 13 25 C1 i n i c a l l y s t r o n g l y suspected ma1 ignancy** 3 Recurrence o f cancer or r e g i o n a l metastases 18 Tracheal compression*** 30 T o t a l 138 * ** No FNB performed *** Due t o a t o x i c g o i t r e Based on f i n e needle b i o p s y (FNB) 70 T ab le 4 . C o rr el at io n b et w ee n cy to lo g ic al an d h is to p at h o lo g ic al di ag no si s in 9 7 p at ie n ts w it h d is ea se d th yr oi d gl an d C yt ol og ic al di ag no si s H is to pa th ol og ic al di ag no si s or f in d in g s G oi tr e A de n om a C ar ci no m a T hy ro i d i t i s c e ll u la r c e ll u la r fo ll ic - H ur th le at y p ia at y p ia u la r -c el l F o ll ic u la r P ap il la ry M ed ul la ry A na pl as ti c (l ym ph oc yt ic t y p e) w it ho ut ty pe ty pe F ol l i cu l a r c e ll s w it h no a ty p ia 48 1 2 1 2* 3 1 sl ig h t at y p ia 2 2 m od er at e at yp i a 1 1 gr av e at y p ia 2 3 NO S 1 1 C ar ci no m a NO S Po l 1 ic u l a r Pa pi 1 1 a ry M ed ul l a ry A na pl a st ic 1 2 2 10 1 5 T hy ro i d i t i s 2 T ot al 51 2 5 1 7 19 1 6 5 * M ic ro in va si ve t yp e The c o r r e l a t i o n between t h e c y t o l o g i c a l f i n d i n g s and h i s t o p a t h o l o g i c a l d i a g n o s i s c o u l d be g i v e n f o r 97 p a t i e n t s ( T a b l e 4 ) . I n 33 o f these p a t i e n t s t h y r o i d carcinoma was h i s t o p a t h o l o g i c a l l y v e r i f i e d . I n 26 o f t h e carcinoma cases t h e c y t o l o g i c a l diagnoses were grave a t y p i a o r carcinoma. Moderate c e l l u l a r a t y p i a o c c u r r e d i n one case which t u r n e d o u t t o be a p a p i l l a r y c a r c i - noma. No c e l l u l a r a t y p i a was noted i n two cases w i t h f o l l i c u l a r carcinoma, i n 3 cases w i t h p a p i l l a r y and i n one case w i t h m e d u l l a r y carcinoma. The 6 cases w i t h f a l s e - n e g a t i v e f i n d i n g s a t FNB w i l l be d e s c r i b e d more e x t e n s i v e l y below. I n 2 cases t h e r e was a f a l s e - p o s i t i v e c a n c e r diagnosis, made on t h e c y t o - l o g i c a l smears, b o t h r e p r e s e n t i n g cases w i t h t h y r o i d i t i s o f t h e lymphoid type. The h i s t o p a t h o l o g i c a l examination r e v e a l e d t h a t a mu1 ti f o c a l growth p a t t e r n o f t h e d i f f e r e n t types o f carcinomas was f r e q u e n t . O f t h e 7 cases w i t h f o l l i - c u l a r carcinoma 5 showed a m u l t i f o c a l growth p a t t e r n and i n 2 t h e cancer had an a g g r e s s i v e growth e x t e n d i n g i n t o t h e a d j a c e n t c e r v i c a l t i s s u e . E i g h t o f t h e 19 cases w i t h p a p i l l a r y carcinoma appeared u n i l a t e r a l l y w i t h more o r l e s s s o l i t a r y l e s i o n s . I n 11 cases t h e p a p i l l a r y cancer was growing b i l a t e r a l l y , 3 % o f them had an i n f i l t r a t i v e growth. S i x p a t i e n t s w i t h p a p i l l a r y cancer had r e g i o n a l lymph node metastases a t t h e t i m e o f o p e r a t i o n . The case w i t h m e d u l l a r y cancer showed a m u l t i f o c a l growth. A l l a n a p l a s t i c cancers e x h i b i t e d an e x t e n s i v e growth p a t t e r n . The main symptoms presented a r e b r i e f l y summerized i n Table 5 . Table 5. C l i n i c a l symptoms presented i n cases o f t h y r o i d malignancy Symptoms D i f f u s e growth o f t h e t h y r o i d g l a n d 15 Nodular growth o f t h e t h y r o i d g l a n d a G o i t r e w i t h symptoms 10 C e r v i c a l nodules 5 L o c a l r e c u r r e n c e a f t e r p r e v i o u s 3 (compression, s tri d o r 1 s u r g e r y f o r t h y r o i d carcinoma T o t a l no. 41 N i n e t e e n o f t h e cancer p a t i e n t s i n t h i s study underwent p r e o p e r a t i v e s c i n t i - grams w i t h t h e f o l l o w i n g r e s u l t s : i n one case t h e examination showed a t o x i c ( h o t ) nodule, i n 10 cases c o l d nodules were found, and 3 cases were normal. I n t h e r e m a i n i n g 5 cases t h e r e s u l t s were i n c o n c l u s i v e . 72 Carcinoma cases with a f a l s e negative cytologic diagnosis: A 41-year-old woman w i t h a slowly ( s i n c e 10 y e a r s ) growing enlarge- ment ( p a r t l y nodular) of b o t h thyroid lobes with s l i g h t toxic symptoms (medi- c a l l y t r e a t e d ) . A scintiscan showed uptake o f Tmg9 only in one palpable nodule of the r i g h t lobe. FNB showed f o l l i c u l a r c e l l s without atypia. The r i g h t lobe was removed a n d histopathological examination showed nodular g o i t r e i n addition t o a small focus of papillary carcinoma. A t reoperation the l e f t thyroid-lobe was removed a n d found t o contain small foci of carcinoma o f the same type. Case 2. A 52-year-old woman with a b i l a t e r a l l y enlarged nodular thyroid gland located partly i n t r a t h o r a c i c a l l y . No toxic symptoms. Scintigram showed lowered uptake in the r i g h t lobe. A t FNB no c e l l u l a r atypia was found. Sub- t o t a l b i l a t e r a l thyroidectomy was performed. The histopathological diagnosis was nodular g o i t r e with an encapsulated highly d i f f e r e n t i a t e d f o l l i c u l a r c a r c i - noma of microinvasive type in the r i g h t lobe. A 36-year-old woman with an enlargement of t h e thyroid gland during t h e l a s t 3 years. No toxic symptoms b u t compression of the trachea. A s c i n t i - gram indicated nodular c o l l o i d goitre. FNB showed f o l l i c u l a r c e l l s w i t h o u t atypia. Bilateral subtotal thyroidectomy was undertaken. The histopatho- logical examination showed nodular g o i t r e with multiple foci of papillary carcinoma in b o t h lobes. A 48-year-old woman w i t h a slowly ( s i n c e 2 y e a r s ) growing nodule i n t h e l e f t thyroid lobe. No toxic symptoms. Scintigram showed no uptake in the l e f t and a normal r i g h t lobe. FNB indicated normal f o l l i c u l a r c e l l s . Left- -sided lobectomy was performed. The histopathology showed a highly d i f f e r e n t i - a t e d papillary carcinoma. The r i g h t lobe was removed l a t e r and a l s o contained small foci of papillary carcinoma. A renewed examination of the cytological smears revealed a few c l u s t e r s of thyroid c e l l s with atypia and cytoplasmic nuclear inclusions indicating papillary carcinoma were found. Case 5. A 63-year-old man with a mobile tumour above sternum since several years. The tumour a n d the l e f t thyroid lobe were removed a t a regional comun- i t y hospital. The histopathological examination revealed a medullary c a r c i - noma. The p a t i e n t was transferred t o Uppsala University Hospital f o r f u r t h e r examination. A scintigram showed focally decreased u p t a k e of Tmg9 i n the r i g h t lobe. FNB d i d n o t reveal any c e l l u l a r atypia. Bilateral thyroidectomy was performed. The following histopathological examination showed multiple foci of c e l l nests strongly suspected of representing medullary carcinoma i n t h e r i g h t lobe. The diagnosis of medullary cancer was v e r i f i e d by elevated l e v e l s of c a l c i t o n i n . Case 6. A 52-year-old woman with a rapidly growing (since 2 months) nodule Case 1. Case 3. Case 4 . 73 in the r i g h t thyroid lobe. FNB indi- c a t e d f o l l i c u l a r c e l l s without atypia. After 3 months of medical treatment w i t h thyroid hormone the r i g h t lobe was resected. The histopathological examin- a t i o n demonstrated a f o l l i c u l a r adenoma. However, behind t h i s adenoma a small f o l l i c u l a r carcinoma was l o c a t e d . Later on a l e f t - s i d e d lobectonly was per- formed. A scintigram showed uptake in this lobe. Histopathological examination did not show any signs of ma1 ignancy. DISCUSSION I n t h i s study 102 of 810 p a t i e n t s who underwent FNB were l a t e r operated and i n 97 a c o r r e l a t i o n between cytological and histopathological findings was possible. Of t h e 33 cases w i t h histopathologically diagnosed cancer, 5 were n o t diagnosed by FNB a n d i n one the malignant c e l l s were n o t observed until the smears were reexamined. T h u s , false-negative diagnoses were noted i n 6 (18 % I of the cancer cases. The corresponding figures f o r false-negative diagnoses presented by other groups varies between 7.7 and 27.5 % ( s e e Lowhagen e t a l . , 1981). The d i f f i c u l t y t o distinguish a f o l l i c u l a r adenoma from a highly differen- t i a t e d f o l l i c u l a r carcinoma i s well-known (6). According t o t h i s research g r o u p i t i s n o t f e a s i b l e t o make t h i s d i s t i n c t i o n with FNB. They suggest t h a t FNB should only aim a t recognizing a f o l l i c u l a r neoplasm leaving t h e d e f i n i t e diagnosis t o t h e histopathological examination. This strategy seems rational a s the diagnosis of a f o l l i c u l a r neoplasm always warrants a surgical explora- t i o n . By such management i t i s also possible t o minimize the risk of a f a l s e - -negative or f a l s e - p o s i t i v e diagnosis. The problems i n sampling the relevant i . e . malignant c e l l s i n small cancers are well i l l u s t r a t e d by cases 2 and 6 . I n case 2 a small microinvasive f o l l i c u l a r cancer was present in a nodular g o i t r e and i n case 6 a small f o l l i c u l a r cancer was found behind a "hot" f o l l i - c u l a r adenoma. T h u s , FNB i s not a tool t o d e t e c t occult cancers which has been pointed o u t also by Granberg e t a l . ( 3 ) . As i n a l l diagnostic procedures f a l s e p o s i t i v e findings should ideally n o t occur i n FNB. I t seems d i f f i c u l t t o avoid a low level of f a l s e positive find- ings i f one wishes t o avoid missing t h e diagnosis of cancer (7). T h e r a t e s of f a l s e positive diagnoses presented in the l i t e r a t u r e amounts to 0-2 % (1,5). I n our material there were 2 cytological biopsies f a l s e l y interpreted t o show cancer c e l l s . Both cases occurred i n p a t i e n t s w i t h lymphoid t h y r o i d i t i s , where a grave atypia of the f o l l i c u l a r c e l l s is common as is a lymphocytic i n f i l t r a - t i o n i n the periphery of a cancer. The d i f f i c u l t y i n making a c o r r e c t diag- nosis of lymphoid t h y r e o i d i t i s , especially i n a s o l i t a r y nodulus has been pointed out a l s o by Lowhagen e t a1 (6). Even histopathology may sometimes f a i l t o resolve d i f f e r e n t i a l d i a g n o s t i c problems i n t h e thyroid (9). 74 Only half of t h e cases w i t h a histologically v e r i f i e d cancer had a radio- nuclide scanning (99Tc) indicating cold nodule(s1. In a b o u t 15 % the s c i n t i s c a n s were "normal" a n d i n a n o t h e r 25 % inconclusive. One p a t i e n t had a papillary cancer although a " h o t " nodule was seen, indicating t h a t malignancy c a n n o t be excluded w h e n technetium i s used as radioactive compound (11). Our findings therefore p o i n t t o the limitation of thyroid scintiscans and underline t h a t scintigraphy alone cannot c l a s s i f y a nodule as malignant or benign. I t can only be considered an adjunct of physical examination and a guidance f o r FNB and cytological evaluation of a thyroid lesion. Knowledge a b o u t t h e growth pattern of t h e cancers i s a l s o valuable when analyzing the r e s u l t s . This i s t r u e b o t h f o r the c y t o l o g i s t where the need f o r multiple biopsies i s evident a n d f o r the surgeon when deciding how radical the operation has t o be. In approximately half of the cases there were more than one area of cancer growth i n the thyroid gland. Metastases a t the time of the primary operation was also a r e l a t i v e l y common finding. I t i s d i f f i c u l t t o evaluate t o w h a t extent the r e s u l t s of the FNB contributed t o the actual deci- sion of surgical intervention or whether i t s main b e n e f i t was t o help the surgeon t o plan t h e operation. Most of the patients already had c l i n i c a l symp- toms suggesting malignancy. However, i n two groups of patients the cytological diagnoses probably made a s i g n i f i c a n t contribution t o the decision t o operate. These were the patients w i t h g o i t r e and/or adenomas a n d those w i t h enlarged cervical glands. T h e findings of the present study strongly indicate t h a t FNB i s a valuable a d j u n c t in thyroid d i a g n o s i s . I t i s a l s o obvious t h a t FNB should be considered complementary and optimal r e s u l t s can only be obtained when there i s a d i a g n o s - t i c cooperation among the c l i n i c i a n , radiologist, c y t o l o g i s t and pathologist. REFERENCES 1. 2 . 3. 4 . 5. 6. Droese, M . : tumours. Verh Dtsch Ges Pathol 61:283-291, 1977. Einhorn, J. & Franzgn, S.: Fine needle biopsy i n the diagnosis of thyroid disease. Acta Radio1 (Stockh) 57:321-340, 1962. Granberg, P . O . , Hamberger, B . , Lundell, G . , Lowhagen, T. & Willems, J.S.: Preoperative evaluation o f the s o l i t a r y thyroid nodule. In: Surgery of the Thyroid a n d Parathyroid glands (ed. E . L . Kaplan) , Churchill & Livingstone, 1983. Katz, A.D. & Warren, J.Z.: Am J Surg 132:459-462, 1976. L a n g , W . , Atay, Z . & Georgii, A . : The cytological c l a s s i f i c a t i o n o f f o l l i c u l a r tumours i n the thyroid gland. Virchows A r c h (Pathol Anat) Lowhagen, T . , Willems, J . S . , Lundell, G . , Sundblad, R . & Granberg, P . O . : Aspiration biopsy cytology i n t h e diagnosis of thyroid cancer. World J Surg 5:61-73, 1981. A s p i r a t i o n biopsy cytology in the diagnosis of thyroid The malignant "cold" nodule of the thyroid. 378:199-211, 1978. 75 7. M i l l e r , J.M., Hanberger, J.J. & K i n i , S.R.: The impact o f needle b i o p s y on t h e p r e o p e r a t i v e d i a g n o s i s o f t h y r o i d nodules. Henry F o r d Hosp Med J 8. Psarras, A., Papadopoulos, S.N., Livados, D., Pharmakiotis, A.D. & Kontras, D.A.: The s i n g l e t h y r o i d nodule. B r J Surg 59:545, 1972. 9. Sax&, E., F r a n s s i l a , K., Bjarnasson, O., Norrman, T. & R i n z e r t z , N.: Observer v a r i a t i o n i n h i s t o l o g i c c l a s s i f i c a t i o n o f t h y r o i d cancer. Acta P a t h o l M i c r o b i o l Scand A 86:483-486, 1978. 10. Soderstrom, N.: A s p i r a t i o n b i o p s y p u n c t u r e o f g o i t e r . Acta Med Scand 144:237, 1952. 11. Thompson, N.W.: The t h y r o i d nodule - s u r g i c a l management. I n : Endocrine Surgery (ed. D.A. Johnston & N.W. Thompson), pp. 14-24. B u t t e r w o r t h s I n t e r n a t i o n a l Medical Reviews, 1983. 28:2-3, 145-148, 1980. Address f o r r e p r i n t s : Sighild Westman-Naeser, M.D. N a t i o n a l Board o f H e a l t h and Welfare Department o f Drugs Box 607 76