Br. J. Surg. Vol. 62 (1975) 207-214
Thyroid cancer: twenty years’ experience in a general hospital D. J . C A M P B E L L A N D R . H . S A G E * SUMMARY
Twenty years’ experience of thyroid cancer in a district general hospital has been reviewed. Its incidence, prognosis and natural history h a w been studied. Particular attention has been jocused on the relationship of malignant to benign goitre. The relevance of this to the treatment of ‘apparently benign goitre’ is discussed. Clinical evidence is presented supporting the hypothesis that differentiated thyroid carcinoma evolves from a solitary focus through a miiltinodular form before presenting the picture of a frankly malignant locally inoasiw cancer. At1 increase in the incidence of papillary carcinoma is confirmed.
CANCER of the thyroid is a rare disease which in the Birmingham region has an incidence of 2.0 females to 0.6 males per 100 000 of the population (Table I ) . It constitutes only 0.7 per cent of all cancers in the female and 0.2 per cent in the male (Waterhouse, 1974). In view of this, it is not surprising that the majority of series reporting thyroid cancer originate from either regional cancer centres or individuals renowned as thyroid surgeons. The selection applied to these series favours carcinoma (Crile and Dempsey, 1949) and consequently they do not reflect the experience of general surgeons nationally. Table I: INCIDENCE OF THYROID CANCER BY AGE IN THE BIRMINGHAM REGION DURING 1960-5 Age M F Age M F Age M F 0-4 5-9 10-14 1519 19-24 25--29 30-34
0.0
0.0 0.0 0.3 0.0 0.0 0.3
0.0 0.0 0.2 0.1
0.4 1.1 1.6
35-39 0.3 40-44 0.3 4 5 4 9 0.7 50-54 1.2 55-59 1.3 60-64 1.9 65-69 2.0
1.4 2.2 2.1 2.7 2.8 4.0 5.2
70-74 75-79 80-84 85-89 90-94 95+ All ages
2.8 5.5 2.8 5.3 0.0 0.0 0.6
6.0 7.8 10.4 11.2 16.4 0.0 2.0
lncidcnce rates per 100 000 of the population. Total number of cases of cancer, 88 males and 290 females. M . Male; F, Female. Table 11: CLASSlFlCATION OF PRIMARY THYROID MALIGNANCIES BY HISTOLOGICAL TYPE (1953-73) Type: Anaplastic No. of cases : I7 Follicular 11 Papillary 10 Mixed papillary-follicular 6 Medullary 2 Hurthle-celled 2 Rcticulum-celled sarcoma 2 Squamous-celled carcinoma 1 Lymphoma 1 Not classitied 2
-
Total
54
The identification of a malignant goitre amidst numerous benign or apparently benign goitres has always been a problem facing general surgeons. Whilst some cancers are readily diagnosed, others present in the guise of benign goitres. This latter group requires further elucidation as the literature abounds with conflicting evidence concerning the cancer risk in apparently benign goitres. This is the result of a wide variation in case selection and depends on whether patient sampling occurs in goitrous or non-goitrous areas (Wilson, 1973). The present study is based on the experience of thyroid cancer in a district general hospital during the period 1953-73. Attention has been focused primarily on the incidence of thyroid cancer in surgical practice. Its relationship to benign goitre, particularly the solitary nodule and non-toxic goitre, has been clarified. In addition, the natural history of thyroid cancer has been considered with particular reference to its response to treatment. It is felt that in this unselected group of patients is mirrored the experience of the vast majority of general surgeons. The Birmingham region does not include any areas of endemic goitre.
Clinical material Fifty-four primary thyroid malignancies have been reviewed. These were diagnosed and treated at Selly Oak Hospital, Birmingham, between 1953 and 1973 and have been under constant supervision following initial diagnosis. All patients subjected to thyroidectomy during this same period have been similarly studied. In every case the initial histological diagnosis has been verified by re-examination of the original slides. ‘Representative sections’ have been employed in both surgical and post-mortem studies. No ‘whole organ’ sections were prepared. The histological classification employed is based on the terminology of Meissner and Warren (1969). Where appropriate, figures relating to thyroid cancer in the entire Birmingham region have been obtained from the Regional Cancer Registry. Incidence During the period 1953-73, 1058 thyroidectomies were performed at Selly Oak Hospital. In 45 of these cases a diagnosis of primary carcinoma was confirmed; an overall operative incidence of 4.25 per cent. Nine primary carcinomas, not treated surgically, were verified at post-mortem, having been undiagnosed
*
Selly Oak Hospital, Birmingham.
207
D. J. Campbell and R. H. Sage clinically or considered inoperable. Three secondary thyroid carcinomas were encountered during the same period. Classification of primary growths by histological type is shown in Tabfe II. Fig. 1 shows the overall age distribution at presentation. A consideration of the carcinomas in females shows a marked difference in the age distribution of differentiated and anaplastic growths (Fig. 2). Differentiated carcinomas first appear during the teens (postpubertal rise) to reach a peak between the ages of 45-55 years (menopause). There is then a gradual decline in the postmenopausal period. In contrast, anaplastic tumours exhibit a markedly increased incidence in the perimenopausal period, reaching a peak at 70 years. A similar but less marked age differential is recorded in the male. The aetiological significance of these findings is unclear. Thyroid-stimulating hormone is known to be important in the development of differentiated thyroid carcinomas (Taylor, 1969a) and may be responsible for this distinctive age distribution. The NO.of cases
I2r
50 60 70 80 90 100 Age (yr) Pig. 1. Distribution by age of all thyroid cancers presenting at Selly Oak Hospital during the period 1953-73. 10
20
30
40
accurate determination of physiological variations in the concentration of thyroid-stimulating hormone is not possible with present assay techniques (Jacobs and Lawton, 1974). The aetiology of thyroid carcinoma will become clearer when improved techniques allow an assessment of the effect of puberty and the menopause on the output of thyroid-stimulating hormone . Increase in the incidence of papillary carcinoma An increase in incidence of papillary carcinoma has been observed. This is most marked in the male, but a gradual rise has also been observed in the female. The percentage distribution of papillary carcinoma for 3-year periods during 1960-71 is recorded in Table 111. The figures shown are those for the Birmingham region as they give a clearer indication of the trend than those obtained purely for Selly Oak Hospital. They confirm previous reports in the American literature (Beahrs et al., 1951 ; Crile, 1971). Papillary carcinoma is known to be associated with increased intake of iodine (Doniach, 1969). In the British Isles iodized table salt accounts for only 1.52.0 per cent of the total salt market. This, nevertheless, represents a sixfold increase when compared with the level of 1930 (Wenlock, 1974).
Diagnosis at presentation In 21 patients (38.9 per cent) a correct diagnosis was possible on clinical grounds alone. These were invariably rapidly progressive anaplastic tumours, which did not present diagnostic problems. Nineteen of these patients have since died of their disease. The remaining 33 carcinomas (61.1 per cent), viewed with varying degrees of clinical suspicion, were categorized as shown in Table IV. These categories afford clinical camouflage and it is therefore important to know the percentage of each group that is likely to be malignant. In this way an appropriate degree of clinical suspicion can be brought to bear in individual
% Fema!e
20
% Male
40
60
I 00
80
20
40
Age at diagnosis
Fig. 2. Distribution by age (A)and sex of differentiated (. cancers in the Birmingham region.
208
- .) and
undifferentiated (-)
thyroid
60
80
I00
Thyroid cancer cases. The percentages given in Table V are for those carcinomas that were not diagnosed clinically. It is felt that the degree of selection applied to these goitres is neither more nor less than that applied in any other general surgical unit. Consequently, although these figures do not represent the incidence of carcinoma in toxic and non-toxic goitre amongst the general population they are figures having an important significance in surgical practice.
Solitary nodules Eight of the clinically undiagnosed carcinomas presented in the form of a solitary nodule. They had been present for an average of 23 months (range, 1 month to 5 years) and were most common in the female (F : M ratio, 5 : 3). They presented at all ages, but most frequently in the 30-40 age group (average, 43 years). Two hundred and ninety-eight clinically solitary nodules were excised during the same period, giving a carcinoma incidence amongst excised solitary nodules of 2.7 per cent. Six nodules were well differentiated carcinomas, the remaining 2 being medullary (Table VZ). Two of the well-differentiated growths showed evidence of early local invasion. All solitary nodule carcinomas responded remarkably well to treatment. This involved subtotal resection of the affected lobe and, in one instance, resection of the isthmus. Two patients with evidence of local spread were additionally treated with suppressive doses of thyroxine, one of them also receiving local external irradiation. All these patients are alive, with no evidence of local or disseminated recurrence (Table V f f ) .Average follow-up is 5 years 9 months, with a range of 1-1 5 years. Multinodular goitre Eighteen of the undiagnosed carcinomas presented as non-toxic multinodular goitres. They were selected for surgery on the usual clinical grounds. During the same period 141 non-toxic multinodular goitres were excised, giving a carcinoma incidence of 12.8 per cent. When all excised non-toxic goitres are considered together this figure becomes diluted to 8.7 per cent. In contrast to solitary nodules the majority of these goitres had been present for many years, with an average of 6 years and 8 months. They therefore present later in life, the average age at presentation being 55, and predominantly in females (F : M ratio, 8 : 1). These patients do consistently worse than those with solitary nodules. Six died of disseminated carcinoma, with a longest survival time of 6 years. Four patients are still receiving treatment for metastatic disease. In 6 patients carcinoma supervened on a longstanding goitre (more than 10 years). As a group, these responded badly to treatment. Three died of disseminated disease, while 2 others have developed both local and distant metastases. Toxic goitre Three toxic goitres were found to contain carcinoma. Two of these were removed surgically, while the third 15
Table Ill: CHANGING INCIDENCE OF PAPILLARY CARCINOMA IN THE BIRMINGHAM REGION (1960-7 1) Incidence of papillary carcinoma (%) Period
Male
Female
1960-62 1963-65 1966-68 1969-71
11.1 29.0 25.0 44.7
28.7 30.2 31.2 39.6
Percentages are of total thyroid cancers.
Table IV: CLINICAL DIAGNOSIS APPLIED TO THYROID CANCER AT PRESENTATION
21 29
Carcinoma diagnosed clinically Carcinoma undiagnosed clinically Solitary nodule Non-toxic multinodular Non-toxic diffuse Toxic goitre Post-mortem diagnosis
8 18
I 2 4
54
Total
Table V: PERCENTAGE OF MALIGNANCY AMONGST APPARENTLY BENIGN GOITRES Total no. Malignant Type of goitre 1953-73 No. Solitary nodule Non-toxic multinodular goitre Non-toxic diffuse goitre All non-toxic eoitres Toxic goitre
298 141 77 218 482
-
8 18 1 19 2
2.7 12.8 1.3 8.7 0.4
Table VI: TYPES OF THYROID CANCER FOUND IN SOLITARY NODULES AND MULTINODULAR GOITRE Type of cancer
Solitary nodules
Non-toxic multinodular
Papillary Follicular Mixed papillary-follicular Anaplastic Medullary Others
1 2 3 0 2 0
4 6
8
18
Total
1
4 0 3*
* One lymphoma, 2 Hurthle-celled. Table VII: NATURAL HISTORY AND PROGNOSIS OF DIFFERENTIATED THYROID CARCINOMA RELATED TO CLINICAL STAGING Single-+ Multinodular-+ Frankly nodule malignant Stage 2 Stage 3 Stage 1 Local invasion at presentation rk) Distant spread at presentation (%) Result of treatment 5-Year survival (%) 10-Year survival (%)
25
50
90
0
17
24
Fair 71 70
Bad 15 10
Excellent 100 100
Table V111: SURVIVAL FIGURES BY SEX FOR ALL THYROID CANCER N o . of 5-Year 10-Year Sex cases survival (%) survival (%) Female Male
42 12
57 25
52 20
209
D. J. Campbell and R. H. Sage Papillary: Eight patients received treatment for papillary carcinoma. Two untreated carcinomas were discovered incidentally in patients dying of unrelated conditions. Amongst the treated group (Table X I I ) , only one 'tumour death' has been recorded during the period 1953-73. This appears to have resulted from both extensive local infiltration at presentation and inadequacies in the treatment prescribed. Primary treatment, following confirmatory lymph node biopsy, Results of treatment was achieved with external irradiation alone. Thyroxine was not introduced until 10 months later following the The effect of age and sex on survival Results of treatment for thyroid carcinoma in the development of systemic metastases. Thyroidectomy female are significantly better than those obtained in was not performed. Only one other patient has shown the male. Female 10-year survival figures are better evidence of spread from papillary carcinoma. In than those achieved at 5 years in the male (Table VII"). this patient local infiltration made total excision The age at presentation also exerts a marked influence impossible. She has therefore been treated with on survival, as shown in Table I X . Patients with radioactive iodine. In the remaining patients, tumours were confirmed carcinoma presenting after 60 fare significantly worse than those with carcinoma occurring earlier. This within the thyroid capsule. Unilateral or bilateral applies equally to both sexes. It would appear, how- resections were performed in response to operative ever, that females are selectively protected until they findings. In no case was thyroid resection extended at reach the postmenopausal period (Table X ) . Their a second operation in response to the histological good prognosis before this is responsible for the good findings. Histological examinations were always overall survival figures for carcinoma presenting at an performed on 'representative sections'. Follicular : Ten follicular carcinomas were treated early age. during 1953-73. One other case was noted incidentally at post-mortem. The effect of histological type of' survival Three patients died from disseminated carcinoma, The biological individuality of the various histological types of thyroid carcinoma has been confirmed by while a fourth died with a heniiplegia 2 weeks following both pathological and epidemiological studies (Cuello operation (Table XIII). The 3 'tumour deaths' et a]., 1969). The difference in morbidity and mortality occurred in patients who presented with locally amongst the patients treated in the present series invasive carcinoma. Complete surgical excision was not possible and therefore radical radiotherapy was verifies this (Table X I ) . employed. Despite the resultant thyroid destruction, 2 patients never received thyroxine, while in the third Table IX: COMBINED MALE AND FEMALE (M. S., 1967) it was given only after the development SURVIVAL FlGURES BY AGE FOR ALL THYROID of frank myxoedema. Clearly these hormoneCANCER dependent tumours were exposed to high levels of 5-Year 10-Year No. of Age at survival(",) survival (yo) thyroid-stimulating hormone. cases presentation Two patients went on to develop metastatic < 30 4 100 100 carcinoma which has since been controlled. In both, 30-60 22 I5 64 > 60 28 18 9 carcinoma had extended locally and was eradicated by combined surgery and radiotherapy. Thyroxine was prescribed for one of these (J. J., 1958) only after Table X: FEMALE SURVIVAL FIGURES BY AGE FOR the development of myxoedema. This patient had had ALL THYROID CANCER a previous thyroidectomy for non-toxic multinodular Age at No. of 5-Year 10-Year presentation cases survival (yo) survival (7;) goitre. The second patient (P. G., 1966) required tracheostomy for tracheal collapse 1 year after I00 < 30 3 100 thyroidectomy. Locally invasive carcinoma was then 16 92 87.5 30-60 10 discovered. > 60 23 21 Only 4 patients remain recurrence-free. In these, carcinoma was confined within the thyroid capsule, Table XI: RESULTS OF TREATMENT IN FOUR facilitating complete excision. Clearly only one of this HlSTOLOGlCAL TYPES OF PRIMARY THYROID group (L. R., 1957) has been followed for any length CANCER of time, but it is significant that no patient with NonAlive RecurType of No. Tumour tumour with rencedisseminated growth had tumour confined to the cancer treated deaths deaths recurrence free thyroid when first seen. 0 1 6 Papillary 8 1 Anuplastic : Thirteen patients were treated for ana10 3 1 2 4 Follicular plastic carcinoma, while 4 others with advanced 5 0 0 I 4 Mixed disease died rapidly with no treatment. With 3 exceppapillarytions, all the patients died within 5 months of presentafollicular Anaplastic 13 11 0 2 0 tion. Extensive local infiltration was a feature in all
was discovered at post-mortem, the patient having died of thyrotoxic heart disease. Two were papillary, and the other a mixed follicular-papillary type. The carcinoma incidence of 0.4 per cent in excised goitres is similar to the 0.354 per cent of Hurxthal and Heinemann (1958). Olen and Klinck (1966) reported an incidence of 2.5 per cent amongst hyperthyroid glands.
210
Thyroid cancer the cases. Seventy-five per cent of the patients developed systemic metastases. Of the 3 patients who survived for longer than 5 months, one has since died at 3 years. This patient’s carcinoma was atypical in exhibiting areas of both ‘trabecular and follicular’ pattern. The other 2 patients are alive with recurrent disease at 15 and 20 months. The latter has a ‘fibrosarcomatous’ tumour similar to those described by Woolner et al. (1961). Mixed follicular-papillary: Only 6 tumours of this kind were recorded and one of these was noted incidentalfy at post-mortem. Four patients have remained recurrence free (average follow-up 8 years) following unilateral or bilateral subtotal thyroidectomy. Two of these, showing evidence of microscopic invasion, were in addition treated with external irradiation and thyroxine. The fifth developed local neck recurrence and deposits in her thyroidectomy scar. These have responded well to repeat surgery, radioactive iodine and suppressive doses of thyroxine. She is recurrencefree at I I years.
Discussion Carcinoma of the thyroid can present in several forms and it is certainly true to say that ‘any goitre may be malignant’ (Staunton and Greening, 1973). A percentage of these will be clinically apparent although estimates range between 10 per cent (Hurxthal and Heinemann, 1958) and 66 per cent (Till, 1965). It would appear that in specialized centres a preoperative diagnosis should be achieved in 50-60 per cent of all cases (Beahrs et al., 1951; Alhadeff et al., 1956; Shimaoka et al., 1962). The figure of 38.9 per cent reported in this series represents that of a nonspecialist district general hospital. Of great concern is the group of patients whose carcinoma presents in a form often indistinguishable from that of benign goitres; 61.1 per cent of patients in this series fall within this category. The recommendation of Shimaoka et al. (1962) that goitres should be classified as ‘benign’, ‘cancer suspected’ and ‘cancer probable’ would seem to be of value. In attempting to differentiate thyroid cancer from
Table XII: DETAILS OF PATIENTS TREATED FOR PAPILLARY CARCINOMA Treatment Patient
Age Sex
Stage of carcinoma at presentation
C . H., 1956
25
F
Confined to thyroid
C . J.,
1959
70
M
M.M., 1960
31
F
Extensive local infiltration Confined to thyroid
A. P.,
1962
41
F
Confined to thyroid
R. S . , I964 M . B., 1969
41 34
F F
Confined to thyroid Confined to thyroid
J . A,, 1973 M. F., 1973
26 79
F F
Confined to thyroid Local infiltration
Surgery Bilateral subtotal thyroidectomy Lymph node biopsy
Radiotherapy, hormonal
Follow-up
Nil
Recurrence-free at 15 yr
External irradiation (thyroxine) Nil
Death from tumour at 2 y r
Bilateral subtotal thyroidectomy Bilateral subtotal thyroid- 1311 thyroxine ectomy Right subtotal lobectomy Nil Right subtotal lobectomy Nil Nil Resection of isthmus Right subtotal lobectomy. 1 3 1 1 lncomulete excision
Recurrence-free at 14 yr Recurrence-free at 12 yr Recurrence-free at 7 yr Recurrence-free at 1 yr Emigrated. Recurrence-free at 1 y r Follow-up 3 mth
Table XIII: DETAILS OF PATIENTS TREATED FOR FOLLICULAR CARCINOMA Treatment Patient
Age Sex
Stage of carcinoma at presentation
Surgery
Radiotherapy, hormonal
Follow-up ~
’
.
Extensive local infiltration Confined to thyroid Local infiltration
Left partial lobectomy. In- External irradiation complete remOYd1 Local excision Nil Bilateral subtotal thyroid- External irradiation ectomy (thyroxine) Lymph node biopsy
F
Presented with scalp secondary Local infiltration
86
F
Local infiltration
C. W., 1968 G . E., 1971
35 86
F M
Confined to thyroid Confined to thyroid
B. B., 1972
34
M
Confined to thyroid
D. I., 1973
47
F
Extensive local infiltration
G . P., 1953
44
M
L. R., 1957 J. J.. 1958
58 34
F
P. B.,
1965
88
F
P. G . , 1966
44
M . S . , 1967
15*
F
Death from tumour at 9 yr
Recurrence-free at 16 yr Bone secondary at 13 yr; treated with radiotherapy. Recurrence-free at I6 yr External irradiation. Death from tumour at 2 yr 1811
Bilateral subtotal thyroidectomy. Tracheostomy Bilateral subtotal thyroidectomy. Incomplete resection. Tracheostomy Right subtotal lobectomy Bilateral subtotal thyroidectomy Right subtotal thyroidectomy Incomplete excision. Tracheostomy
External irradiation. Bone secondary at 4 yr, lung 5 yr; treated with 1311. Thyroxine external irradiation. N o active disease at 7 yr External irradiation. Death from tumour at 3 yr l 3 I l . Thyroxine Nil Nil
Recurrence-free at 5 yr Recurrence-free at 3 yr
Nil
Recurrence-free at 1 & yr
Nil
Postoperative death
211
D. J. Campbell and R. H. Sage benign goitre they achieved a high degree of correlation between actual and suspected cancer incidences. When it was not possible to arrive at a histological diagnosis on purely clinical grounds the patients in this series were categorized as shown in Table IV. They were observed to have either a solitary nodule or generalized goitre, which was invariably non-toxic. The difference in behaviour of solitary nodule carcinomas and those presenting as multinodular goitre seems to suggest that they represent stages in a continuous process (Table VII). Cases not diagnosed at the solitary nodule stage may present later with a multinodular form. It is well recognized that from 61.7 per cent (Rose et al., 1963) to 80 per cent (Clark et al., 1966) of unilateral thyroid cancers have demonstrable intraglandular dissemination. These microscopic foci may explain the transformation of a malignant solitary nodule into the multinodular form. Cases presenting at a more advanced stage are invariably diagnosed as carcinoma. This scheme applies to differentiated carcinomas only. The rapid progress of anaplastic tumours precludes the recognition of discernible stages. Occasionally a thyroid carcinoma may develop de nouo in a pre-existing goitre (Burn and Taylor, 1962). Solitary nodule carcinomas present on average 12 years before those in multinodular goitres. In this series they had been present for a mean of 23 months compared with the 6 years and 8 months of rnultinodular goitres. In addition, while multinodular carcinomas exhibit significant local and distant metastases, this is rare for solitary nodule carcinoma. The more advanced state of the multinodular carcinoma is reflected in its poorer prognosis. Thus, of 18 patients treated in this category, 6 have died while 4 others are alive with metastases. The survival figures shown in Table VII do not indicate the high incidence of metastases occurring in the patients. All the solitary nodule carcinomas responded well to treatment. Clearly it is important to recognize thyroid carcinoma during its solitary nodule phase, when cure may reasonably be attained. Crile (in Discussion, Crile and Dempsey, 1949) suggested that a ‘high index of suspicion’ should be directed at all solitary nodules and was able to report a 90 per cent success rate in diagnosing carcinoma preoperatively in solitary nodules. In contrast, Hoffmann et al. (1972) stated that ‘there is no way of differentiating benign from malignant solitary nodules and therefore all must be resected’; a view previously expressed by Liechty et al. (1965) and Taylor (1969b). It is known that only 50 per cent of clinically solitary nodules are truly solitary (Taylor, 1969b). In these, cancer incidences reaching as high as 33 per cent have been recorded (Cattell and Colcock, 1953). The 2-7 per cent incidence reported in this series is lower than that of most other series as it relates to clinically solitary nodules only. This represents the cancer risk amongst patients subjected to thyroidectomy. The vast majority of operations for solitary nodules are therefore performed for benign nodules. 212
Excellent results for solitary nodule Carcinoma can only be achieved, however, if the surgery employed prophylactically is at the same time therapeutic for cancer (Crile, 1953). Prophylactic surgery is of no value if it results in local dissemination of incompletely removed carcinoma. Enucleation of solitary nodules as advocated by Lahey and Hare (1951) is clearly inadequate. Taylor (1965) and Shands and Gatling (1970) have recommended total lobectomy as the minimum procedure for solitary nodules. Hinton and Lord (1945) and Beahrs et al. (1951) advocated the removal of all non-toxic multinodular goitres because of the high incidence of unsuspected carcinoma. The present study confirms this in reporting a 12.8 per cent incidence of carcinoma in nontoxic multinodular goitres. This figure, however, applies to surgical practice only. The incidence of carcinoma in non-toxic multinodular goitre amongst the general population is much lower than that seen surgically. Carcinoma incidences of 10 per cent (Cope et al., 1949), 10.9 p:r cent (Crile and Dempsey, 1949) and 17.1 per cent (Cole et al., 1949) have previously been reported in excised non-toxic multinodular goitres. A major problem is the identification of the patients with non-toxic multinodular goitre who require thyroidectomy. Criteria helping to distinguish benign from malignant non-toxic multinodular goitres have been defined (Hurxthal and Heinemann, 1958; Sokal, 1959) in the belief that the removal of all goitres would result in more life lost than saved. Crile (1953) has stated that ‘a woman with multinodular goitre would probably be better protected against the development of fatal cancer by removal of a normal appearing breast or cervix than by removal of the goitre’. While this may apply to the population at large, its relevance to the selected patients seen in surgical clinics is less clear. In this situation the processes of selection favouring cancer have a concentrating effect which may be as high as tenfold (Sokal, 1954; Veith et al., 1964). A decision not to operate on a non-toxic multinodular goitre can only be made in the knowledge that carcinoma has not been absolutely excluded. Patients seen in surgical clinics with non-toxic multinodular goitre should therefore be regarded as having selected themselves for surgery. If total lobectomy is regarded as the minimal surgical procedure for the solitary nodule, then, it has been argued, total thyroidectomy must be the prophylaxis for multinodular goitre (Cope et al., 1949). Lesser procedures may in theory have resulted in local dissemination of carcinoma in 12.8 per cent of the patients seen in this series. Nevertheless, it would be irrational to advise total thyroidectomy, with its attendant complications, in all non-toxic multinodular goitres. A more realistic approach is the employment of bilateral subtotal thyroidectomy, with conversion to total thyroidectomy as needed. McKenzie (1971) has shown that total thyroidectomy eliminates the local recurrences seen to follow less radical operations. It has the added advantage of facilitating treatment with radio-iodine and prevents the transformation of
Thyroid cancer differentiated into anaplastic carcinomas (Clark et al., 1966). In this series total thyroidectomy was not employed in the treatment of differentiated carcinomas and must, in part, be responsible for poor results obtained in the multinodular carcinomas. Wade (1969) has stressed the need to prevent local recurrence in the treatment of differentiated thyroid carcinoma. Four tumour deaths were recorded amongst the differentiated thyroid carcinomas. All received external irradiation for locally invasive disease. In the single papillary carcinoma thyroxine was not introduced until systemic metastases appeared. Only 1 of the 3 follicular carcinomas received thyroxine and then only after the development of myxoedema. These tumours were clearly exposed to high levels of thyroidstimulating hormone a t a time when suppressive doses of thyroxine should have been employed. The hormonal dependency of differentiated thyroid cancer is now firmly established (Balme, 1954; Crile, 1966) following Dunhill’s (1937) initial observation of tumour regression when treated with thyroid extract. It is imperative, therefore, that when dealing with differentiated thyroid carcinoma periods of hypothyroidism should be restricted to a minimum. This applies equally to carcinoma undergoing treatment with radioactive iodine (Crile and Wilson, 1959). A clearer understanding of the value of thyroxine, coupled with a wider use of total thyroidectomy, would have undoubtedly improved the prognosis amongst the patients reported in this series. The prognosis of any cancer is determined primarily by its histological type and clinical stage. Good results obtained in treating differentiated thyroid carcinoma compare markedly with those obtained with anaplastic growths. While confirming this, the present study emphasizes the importance of clinical staging of the primary tumour. Clinically obvious carcinomas carry uniformly bad prognoses. They are invariably anaplastic as differentiated carcinomas reach this stage far less frequently. The slower growth of differentiated cancer usually results in them presenting at an earlier stage, when they may be mistaken for benign goitres. Differencesin the pattern of behaviourof differentiated carcinomas a t these early stages suggest that they pass through solitary nodule and multinodular forms before presenting the picture of a frankly malignant locally invasive goitre. These results emphasize the value of T N M staging when applied to thyroid cancer (Harmer, 1969). Fujimori (1969) was able to relate prognosis to the individual components of the T N M classification and clearly showed that increasing ‘T number’ was accompanied by worsening of prognosis.
Acknowledgements We wish to thank M r J. McKinnell, Consultant Pathologist, for reviewing the histological preparations and confirming diagnoses for all our patients. Our thanks are also due to Miss J . Powell of the Regional Cancer Registry for her invaluable help, particularly in the preparation of data referable to the Birmingham region.
References and TAYLOR s. (1956) A clinicopathological study of thyroid carcinoma. Br. J. Surg. 43, 6 17-626. BALME H. (1954) Metastatic carcinoma of the thyroid successfully treated with thyroxine. Lancet 1, 8 12-8 1 3. BEAHRS 0. H., PEMBERTON J. and BLACK B. M. (1951) Nodular goiter and malignant lesions of the thyroid gland. J . Clin. Endocrinol. Metah. 11, 1157-1 165. BURN J. 1. and TAYLOR s. F. (1962) Natural history of thyroid carcinoma. Br. Med. J. 2, 1218-1223. CATTELL R. B. and COLCOCK B. P. (1953) The present day problem of cancer of the thyroid. J . Clin. Endocrinol. Metah. 13, 1408-1415. CLARK R. L., IBANEZ M. L. and WHITE E. C. (1966) What constitutes an adequate operation for carcinoma of the thyroid? Arch. Surg. 92, 23-26. COLE w. H., MAJARAKIS J. D. and SLAUGHTER D. P. ( I 949) Incidence of carcinoma of the thyroid in nodular goiter. J . Clin. Endocrinol. Metab. 9, 1007-1 01 1. COPE o., DOBYNS B. M., HAMLIN E. and HOPKIRK J. (1949) What thyroid nodules are to be feared? J. Clin. Endocrinol. Metab. 9, 1012-1022. CRILE G. (1953) Adenoma and carcinoma of the thyroid gland. New Engl. J. Med. 249, 585-590. CRILE G. (1966) Endocrine dependency of papillary carcinoma of the thyroid. JAMA 195,721-724. CRILE G. (1971) Changing end results in patients with papillary carcinoma of the thyroid. Surg. Gynecol. Obstet. 132, 460488. CRlLE G. and DEMPSEY W. S. (1949) Indications for removal of non-toxic nodular goiter. JAMA 139, 1247-1250. CRILE G. and WILSON D. H. (1959) Transformation of a low grade papillary carcinoma of the thyroid to a n anaplastic carcinoma after treatment with radioiodine. Surg. Gynecol. Ohstet. 108, 357-360. CUELLO c., CORREA P. and EISENBERG H. (1969) Geographic pathology of thyroid carcinoma. Cancer 23, 230-239. DONIACH I. ( 1 969) Epidemiology of thyroid cancer. J . R . CON. Surg. Edinb. 14, 261-262. DUNHILL T. P. (1937) The surgery of the thyroid gland. Trans. Med. SOC.Lond. 60, 234282. FUJIMORI M. (1969) Clinical classification of thyroid carcinoma in Japan by T.N.M. system. I n : HEDINGER c. E. (ed.) Thyroid Cancer. UlCC Monograph Series, vol. 12. London, Heinemann, pp. 249-251. HARMER M. H. (1969) Application of the T.N.M. classification rules to malignant tumours of the thyroid gland. In: HEDINGER c. E. (ed.) Thyroid Cancer UICC Monograph Series, vol. 12. London, Heinemann, pp. 246-247. HINTON J. w. and LORD J. w. (1945) Is surgery indicated in all cases of nodular goiter? JAMA 129, 605-606. HOFFMANN G. L., THOMPSON N. w. and HEFFRON c. (1972) The solitary thyroid nodule. Arch. S w g . 105, 379-385. ALHADEFF R., SCOTT F.
213
D. J. Campbell and R. H. Sage and HEINEMANN A. c. (I 958) Nodular goiter and thyroid cancer. New Engl. J. Med. 258, 457465. JACOBS H. s. and LAWTON N. F. (1974) Pituitary and placental glycopeptide hormones. Br. Med. Bull. 30, 55-61. LAHEY F. H. and HARE H. F. (1951) Malignancy in adenomas of the thyroid. JAMA 145, 689-695. LIECHTY R. D., GRAHAM H. and FREEMEYER P. (1965) Benign solitary thyroid nodules. Surg. Cynecol. Obstet. 121, 571-573. MCKENZIE A. D. (1971) The natural history of thyroid cancer. Arch. Surg. 102, 274-277. MEISSNER w. A. and WARREN s. (1969) Tumors of the thyroid gland. In : Atlas of Tumor Pathology, 2nd ser., fascicle 4. Washington, Armed Forces Institute of Pathology. OLEN E. and KLINCK G. H. (1966) Hyperthyroidism and thyroid cancer. Arch. Pathol. 81, 531-535. HURXTHAL L. M.
ROSE R. G., KELSEY M. P., RUSSELL W. O., IBANEZ M. L., WHITE E. L. and CLARK R. L. (1963) Follow up
study of thyroid cancer treated by unilateral lobectomy. Am. J. Surg. 106, 494500. SHANDS w. c. and GATLING R. R. (1970) Cancer of the thyroid-review of 109 cases. Ann. Surg. 171, 735-745. SHIMAOKA K., BADELLO J., SOKAL J. E. and MARCHETTA F. c. (1 962) Clinical differentiation between thyroid cancer and benign goiter. JAMA 181, 179-1 85. SOKAL J . E. (1954) Incidence of malignancy in toxic and non-toxic nodular goiter. JAMA 154, 1321-1325.
214
(1959) The problem of malignancy in nodular goiter. JAMA 170, 405412. STAUNTON M. D. and GREENING w. P. (1973) Clinical diagnosis of thyroid cancer. Br. Med. J. 4, 532-535. TAYLOR s. (1965) Surgical treatment of carcinoma of the thyroid. Br. J . Surg. 52, 740-742. TAYLOR s. (1969a) Carcinoma of the thyroid gland. J. R . Coll. Surg. Edinb. 14, 183-192. TAYLOR s. (1969b) The solitary thyroid nodule. J. R . Coll. Surg. Edinb. 14, 267-271. TILL A. s. (1965) Types of carcinoma of the thyroid and their presentation. Br. J . Surg. 52, 734735. VEITH F. J., BROOKS J. R., GRIGSBY w. P. and SELENKOW H. A. (1964) The nodular thyroid gland and cancer. New Engl. J . Med. 270, 431436. WADE J . s. H. (1969) Review of thyroid carcinomas in the United Cardiff Hospitals. Proc. R . SOC.Med. 62, 812-814. WATERHOUSE J. A. H. (1974) Cancer Handbook of Epidemiology and Prognosis. Edinburgh, Churchill Livingstone, p. 174. WENLOCK R. w. (1974) Personal communication. Ministry of Agriculture, Fisheries and Food. WILSON w. w. (1973) Thyroid disease and some complications. Ann. R. Coll. Surg. Engl. 53, 27-39. SOKAL J. E.
WOOLNER L. B., BEAHRS 0. H., BLACK B. M., MCCONAHEY w. M. and KEATING F. R. (1961) Classification and
prognosis of thyroid carcinoma. Am. J. Surg. 102, 354387.
Thyroid cancer: twenty years’ experience in a general hospital D. J . C A M P B E L L A N D R . H . S A G E * SUMMARY
Twenty years’ experience of thyroid cancer in a district general hospital has been reviewed. Its incidence, prognosis and natural history h a w been studied. Particular attention has been jocused on the relationship of malignant to benign goitre. The relevance of this to the treatment of ‘apparently benign goitre’ is discussed. Clinical evidence is presented supporting the hypothesis that differentiated thyroid carcinoma evolves from a solitary focus through a miiltinodular form before presenting the picture of a frankly malignant locally inoasiw cancer. At1 increase in the incidence of papillary carcinoma is confirmed.
CANCER of the thyroid is a rare disease which in the Birmingham region has an incidence of 2.0 females to 0.6 males per 100 000 of the population (Table I ) . It constitutes only 0.7 per cent of all cancers in the female and 0.2 per cent in the male (Waterhouse, 1974). In view of this, it is not surprising that the majority of series reporting thyroid cancer originate from either regional cancer centres or individuals renowned as thyroid surgeons. The selection applied to these series favours carcinoma (Crile and Dempsey, 1949) and consequently they do not reflect the experience of general surgeons nationally. Table I: INCIDENCE OF THYROID CANCER BY AGE IN THE BIRMINGHAM REGION DURING 1960-5 Age M F Age M F Age M F 0-4 5-9 10-14 1519 19-24 25--29 30-34
0.0
0.0 0.0 0.3 0.0 0.0 0.3
0.0 0.0 0.2 0.1
0.4 1.1 1.6
35-39 0.3 40-44 0.3 4 5 4 9 0.7 50-54 1.2 55-59 1.3 60-64 1.9 65-69 2.0
1.4 2.2 2.1 2.7 2.8 4.0 5.2
70-74 75-79 80-84 85-89 90-94 95+ All ages
2.8 5.5 2.8 5.3 0.0 0.0 0.6
6.0 7.8 10.4 11.2 16.4 0.0 2.0
lncidcnce rates per 100 000 of the population. Total number of cases of cancer, 88 males and 290 females. M . Male; F, Female. Table 11: CLASSlFlCATION OF PRIMARY THYROID MALIGNANCIES BY HISTOLOGICAL TYPE (1953-73) Type: Anaplastic No. of cases : I7 Follicular 11 Papillary 10 Mixed papillary-follicular 6 Medullary 2 Hurthle-celled 2 Rcticulum-celled sarcoma 2 Squamous-celled carcinoma 1 Lymphoma 1 Not classitied 2
-
Total
54
The identification of a malignant goitre amidst numerous benign or apparently benign goitres has always been a problem facing general surgeons. Whilst some cancers are readily diagnosed, others present in the guise of benign goitres. This latter group requires further elucidation as the literature abounds with conflicting evidence concerning the cancer risk in apparently benign goitres. This is the result of a wide variation in case selection and depends on whether patient sampling occurs in goitrous or non-goitrous areas (Wilson, 1973). The present study is based on the experience of thyroid cancer in a district general hospital during the period 1953-73. Attention has been focused primarily on the incidence of thyroid cancer in surgical practice. Its relationship to benign goitre, particularly the solitary nodule and non-toxic goitre, has been clarified. In addition, the natural history of thyroid cancer has been considered with particular reference to its response to treatment. It is felt that in this unselected group of patients is mirrored the experience of the vast majority of general surgeons. The Birmingham region does not include any areas of endemic goitre.
Clinical material Fifty-four primary thyroid malignancies have been reviewed. These were diagnosed and treated at Selly Oak Hospital, Birmingham, between 1953 and 1973 and have been under constant supervision following initial diagnosis. All patients subjected to thyroidectomy during this same period have been similarly studied. In every case the initial histological diagnosis has been verified by re-examination of the original slides. ‘Representative sections’ have been employed in both surgical and post-mortem studies. No ‘whole organ’ sections were prepared. The histological classification employed is based on the terminology of Meissner and Warren (1969). Where appropriate, figures relating to thyroid cancer in the entire Birmingham region have been obtained from the Regional Cancer Registry. Incidence During the period 1953-73, 1058 thyroidectomies were performed at Selly Oak Hospital. In 45 of these cases a diagnosis of primary carcinoma was confirmed; an overall operative incidence of 4.25 per cent. Nine primary carcinomas, not treated surgically, were verified at post-mortem, having been undiagnosed
*
Selly Oak Hospital, Birmingham.
207
D. J. Campbell and R. H. Sage clinically or considered inoperable. Three secondary thyroid carcinomas were encountered during the same period. Classification of primary growths by histological type is shown in Tabfe II. Fig. 1 shows the overall age distribution at presentation. A consideration of the carcinomas in females shows a marked difference in the age distribution of differentiated and anaplastic growths (Fig. 2). Differentiated carcinomas first appear during the teens (postpubertal rise) to reach a peak between the ages of 45-55 years (menopause). There is then a gradual decline in the postmenopausal period. In contrast, anaplastic tumours exhibit a markedly increased incidence in the perimenopausal period, reaching a peak at 70 years. A similar but less marked age differential is recorded in the male. The aetiological significance of these findings is unclear. Thyroid-stimulating hormone is known to be important in the development of differentiated thyroid carcinomas (Taylor, 1969a) and may be responsible for this distinctive age distribution. The NO.of cases
I2r
50 60 70 80 90 100 Age (yr) Pig. 1. Distribution by age of all thyroid cancers presenting at Selly Oak Hospital during the period 1953-73. 10
20
30
40
accurate determination of physiological variations in the concentration of thyroid-stimulating hormone is not possible with present assay techniques (Jacobs and Lawton, 1974). The aetiology of thyroid carcinoma will become clearer when improved techniques allow an assessment of the effect of puberty and the menopause on the output of thyroid-stimulating hormone . Increase in the incidence of papillary carcinoma An increase in incidence of papillary carcinoma has been observed. This is most marked in the male, but a gradual rise has also been observed in the female. The percentage distribution of papillary carcinoma for 3-year periods during 1960-71 is recorded in Table 111. The figures shown are those for the Birmingham region as they give a clearer indication of the trend than those obtained purely for Selly Oak Hospital. They confirm previous reports in the American literature (Beahrs et al., 1951 ; Crile, 1971). Papillary carcinoma is known to be associated with increased intake of iodine (Doniach, 1969). In the British Isles iodized table salt accounts for only 1.52.0 per cent of the total salt market. This, nevertheless, represents a sixfold increase when compared with the level of 1930 (Wenlock, 1974).
Diagnosis at presentation In 21 patients (38.9 per cent) a correct diagnosis was possible on clinical grounds alone. These were invariably rapidly progressive anaplastic tumours, which did not present diagnostic problems. Nineteen of these patients have since died of their disease. The remaining 33 carcinomas (61.1 per cent), viewed with varying degrees of clinical suspicion, were categorized as shown in Table IV. These categories afford clinical camouflage and it is therefore important to know the percentage of each group that is likely to be malignant. In this way an appropriate degree of clinical suspicion can be brought to bear in individual
% Fema!e
20
% Male
40
60
I 00
80
20
40
Age at diagnosis
Fig. 2. Distribution by age (A)and sex of differentiated (. cancers in the Birmingham region.
208
- .) and
undifferentiated (-)
thyroid
60
80
I00
Thyroid cancer cases. The percentages given in Table V are for those carcinomas that were not diagnosed clinically. It is felt that the degree of selection applied to these goitres is neither more nor less than that applied in any other general surgical unit. Consequently, although these figures do not represent the incidence of carcinoma in toxic and non-toxic goitre amongst the general population they are figures having an important significance in surgical practice.
Solitary nodules Eight of the clinically undiagnosed carcinomas presented in the form of a solitary nodule. They had been present for an average of 23 months (range, 1 month to 5 years) and were most common in the female (F : M ratio, 5 : 3). They presented at all ages, but most frequently in the 30-40 age group (average, 43 years). Two hundred and ninety-eight clinically solitary nodules were excised during the same period, giving a carcinoma incidence amongst excised solitary nodules of 2.7 per cent. Six nodules were well differentiated carcinomas, the remaining 2 being medullary (Table VZ). Two of the well-differentiated growths showed evidence of early local invasion. All solitary nodule carcinomas responded remarkably well to treatment. This involved subtotal resection of the affected lobe and, in one instance, resection of the isthmus. Two patients with evidence of local spread were additionally treated with suppressive doses of thyroxine, one of them also receiving local external irradiation. All these patients are alive, with no evidence of local or disseminated recurrence (Table V f f ) .Average follow-up is 5 years 9 months, with a range of 1-1 5 years. Multinodular goitre Eighteen of the undiagnosed carcinomas presented as non-toxic multinodular goitres. They were selected for surgery on the usual clinical grounds. During the same period 141 non-toxic multinodular goitres were excised, giving a carcinoma incidence of 12.8 per cent. When all excised non-toxic goitres are considered together this figure becomes diluted to 8.7 per cent. In contrast to solitary nodules the majority of these goitres had been present for many years, with an average of 6 years and 8 months. They therefore present later in life, the average age at presentation being 55, and predominantly in females (F : M ratio, 8 : 1). These patients do consistently worse than those with solitary nodules. Six died of disseminated carcinoma, with a longest survival time of 6 years. Four patients are still receiving treatment for metastatic disease. In 6 patients carcinoma supervened on a longstanding goitre (more than 10 years). As a group, these responded badly to treatment. Three died of disseminated disease, while 2 others have developed both local and distant metastases. Toxic goitre Three toxic goitres were found to contain carcinoma. Two of these were removed surgically, while the third 15
Table Ill: CHANGING INCIDENCE OF PAPILLARY CARCINOMA IN THE BIRMINGHAM REGION (1960-7 1) Incidence of papillary carcinoma (%) Period
Male
Female
1960-62 1963-65 1966-68 1969-71
11.1 29.0 25.0 44.7
28.7 30.2 31.2 39.6
Percentages are of total thyroid cancers.
Table IV: CLINICAL DIAGNOSIS APPLIED TO THYROID CANCER AT PRESENTATION
21 29
Carcinoma diagnosed clinically Carcinoma undiagnosed clinically Solitary nodule Non-toxic multinodular Non-toxic diffuse Toxic goitre Post-mortem diagnosis
8 18
I 2 4
54
Total
Table V: PERCENTAGE OF MALIGNANCY AMONGST APPARENTLY BENIGN GOITRES Total no. Malignant Type of goitre 1953-73 No. Solitary nodule Non-toxic multinodular goitre Non-toxic diffuse goitre All non-toxic eoitres Toxic goitre
298 141 77 218 482
-
8 18 1 19 2
2.7 12.8 1.3 8.7 0.4
Table VI: TYPES OF THYROID CANCER FOUND IN SOLITARY NODULES AND MULTINODULAR GOITRE Type of cancer
Solitary nodules
Non-toxic multinodular
Papillary Follicular Mixed papillary-follicular Anaplastic Medullary Others
1 2 3 0 2 0
4 6
8
18
Total
1
4 0 3*
* One lymphoma, 2 Hurthle-celled. Table VII: NATURAL HISTORY AND PROGNOSIS OF DIFFERENTIATED THYROID CARCINOMA RELATED TO CLINICAL STAGING Single-+ Multinodular-+ Frankly nodule malignant Stage 2 Stage 3 Stage 1 Local invasion at presentation rk) Distant spread at presentation (%) Result of treatment 5-Year survival (%) 10-Year survival (%)
25
50
90
0
17
24
Fair 71 70
Bad 15 10
Excellent 100 100
Table V111: SURVIVAL FIGURES BY SEX FOR ALL THYROID CANCER N o . of 5-Year 10-Year Sex cases survival (%) survival (%) Female Male
42 12
57 25
52 20
209
D. J. Campbell and R. H. Sage Papillary: Eight patients received treatment for papillary carcinoma. Two untreated carcinomas were discovered incidentally in patients dying of unrelated conditions. Amongst the treated group (Table X I I ) , only one 'tumour death' has been recorded during the period 1953-73. This appears to have resulted from both extensive local infiltration at presentation and inadequacies in the treatment prescribed. Primary treatment, following confirmatory lymph node biopsy, Results of treatment was achieved with external irradiation alone. Thyroxine was not introduced until 10 months later following the The effect of age and sex on survival Results of treatment for thyroid carcinoma in the development of systemic metastases. Thyroidectomy female are significantly better than those obtained in was not performed. Only one other patient has shown the male. Female 10-year survival figures are better evidence of spread from papillary carcinoma. In than those achieved at 5 years in the male (Table VII"). this patient local infiltration made total excision The age at presentation also exerts a marked influence impossible. She has therefore been treated with on survival, as shown in Table I X . Patients with radioactive iodine. In the remaining patients, tumours were confirmed carcinoma presenting after 60 fare significantly worse than those with carcinoma occurring earlier. This within the thyroid capsule. Unilateral or bilateral applies equally to both sexes. It would appear, how- resections were performed in response to operative ever, that females are selectively protected until they findings. In no case was thyroid resection extended at reach the postmenopausal period (Table X ) . Their a second operation in response to the histological good prognosis before this is responsible for the good findings. Histological examinations were always overall survival figures for carcinoma presenting at an performed on 'representative sections'. Follicular : Ten follicular carcinomas were treated early age. during 1953-73. One other case was noted incidentally at post-mortem. The effect of histological type of' survival Three patients died from disseminated carcinoma, The biological individuality of the various histological types of thyroid carcinoma has been confirmed by while a fourth died with a heniiplegia 2 weeks following both pathological and epidemiological studies (Cuello operation (Table XIII). The 3 'tumour deaths' et a]., 1969). The difference in morbidity and mortality occurred in patients who presented with locally amongst the patients treated in the present series invasive carcinoma. Complete surgical excision was not possible and therefore radical radiotherapy was verifies this (Table X I ) . employed. Despite the resultant thyroid destruction, 2 patients never received thyroxine, while in the third Table IX: COMBINED MALE AND FEMALE (M. S., 1967) it was given only after the development SURVIVAL FlGURES BY AGE FOR ALL THYROID of frank myxoedema. Clearly these hormoneCANCER dependent tumours were exposed to high levels of 5-Year 10-Year No. of Age at survival(",) survival (yo) thyroid-stimulating hormone. cases presentation Two patients went on to develop metastatic < 30 4 100 100 carcinoma which has since been controlled. In both, 30-60 22 I5 64 > 60 28 18 9 carcinoma had extended locally and was eradicated by combined surgery and radiotherapy. Thyroxine was prescribed for one of these (J. J., 1958) only after Table X: FEMALE SURVIVAL FIGURES BY AGE FOR the development of myxoedema. This patient had had ALL THYROID CANCER a previous thyroidectomy for non-toxic multinodular Age at No. of 5-Year 10-Year presentation cases survival (yo) survival (7;) goitre. The second patient (P. G., 1966) required tracheostomy for tracheal collapse 1 year after I00 < 30 3 100 thyroidectomy. Locally invasive carcinoma was then 16 92 87.5 30-60 10 discovered. > 60 23 21 Only 4 patients remain recurrence-free. In these, carcinoma was confined within the thyroid capsule, Table XI: RESULTS OF TREATMENT IN FOUR facilitating complete excision. Clearly only one of this HlSTOLOGlCAL TYPES OF PRIMARY THYROID group (L. R., 1957) has been followed for any length CANCER of time, but it is significant that no patient with NonAlive RecurType of No. Tumour tumour with rencedisseminated growth had tumour confined to the cancer treated deaths deaths recurrence free thyroid when first seen. 0 1 6 Papillary 8 1 Anuplastic : Thirteen patients were treated for ana10 3 1 2 4 Follicular plastic carcinoma, while 4 others with advanced 5 0 0 I 4 Mixed disease died rapidly with no treatment. With 3 exceppapillarytions, all the patients died within 5 months of presentafollicular Anaplastic 13 11 0 2 0 tion. Extensive local infiltration was a feature in all
was discovered at post-mortem, the patient having died of thyrotoxic heart disease. Two were papillary, and the other a mixed follicular-papillary type. The carcinoma incidence of 0.4 per cent in excised goitres is similar to the 0.354 per cent of Hurxthal and Heinemann (1958). Olen and Klinck (1966) reported an incidence of 2.5 per cent amongst hyperthyroid glands.
210
Thyroid cancer the cases. Seventy-five per cent of the patients developed systemic metastases. Of the 3 patients who survived for longer than 5 months, one has since died at 3 years. This patient’s carcinoma was atypical in exhibiting areas of both ‘trabecular and follicular’ pattern. The other 2 patients are alive with recurrent disease at 15 and 20 months. The latter has a ‘fibrosarcomatous’ tumour similar to those described by Woolner et al. (1961). Mixed follicular-papillary: Only 6 tumours of this kind were recorded and one of these was noted incidentalfy at post-mortem. Four patients have remained recurrence free (average follow-up 8 years) following unilateral or bilateral subtotal thyroidectomy. Two of these, showing evidence of microscopic invasion, were in addition treated with external irradiation and thyroxine. The fifth developed local neck recurrence and deposits in her thyroidectomy scar. These have responded well to repeat surgery, radioactive iodine and suppressive doses of thyroxine. She is recurrencefree at I I years.
Discussion Carcinoma of the thyroid can present in several forms and it is certainly true to say that ‘any goitre may be malignant’ (Staunton and Greening, 1973). A percentage of these will be clinically apparent although estimates range between 10 per cent (Hurxthal and Heinemann, 1958) and 66 per cent (Till, 1965). It would appear that in specialized centres a preoperative diagnosis should be achieved in 50-60 per cent of all cases (Beahrs et al., 1951; Alhadeff et al., 1956; Shimaoka et al., 1962). The figure of 38.9 per cent reported in this series represents that of a nonspecialist district general hospital. Of great concern is the group of patients whose carcinoma presents in a form often indistinguishable from that of benign goitres; 61.1 per cent of patients in this series fall within this category. The recommendation of Shimaoka et al. (1962) that goitres should be classified as ‘benign’, ‘cancer suspected’ and ‘cancer probable’ would seem to be of value. In attempting to differentiate thyroid cancer from
Table XII: DETAILS OF PATIENTS TREATED FOR PAPILLARY CARCINOMA Treatment Patient
Age Sex
Stage of carcinoma at presentation
C . H., 1956
25
F
Confined to thyroid
C . J.,
1959
70
M
M.M., 1960
31
F
Extensive local infiltration Confined to thyroid
A. P.,
1962
41
F
Confined to thyroid
R. S . , I964 M . B., 1969
41 34
F F
Confined to thyroid Confined to thyroid
J . A,, 1973 M. F., 1973
26 79
F F
Confined to thyroid Local infiltration
Surgery Bilateral subtotal thyroidectomy Lymph node biopsy
Radiotherapy, hormonal
Follow-up
Nil
Recurrence-free at 15 yr
External irradiation (thyroxine) Nil
Death from tumour at 2 y r
Bilateral subtotal thyroidectomy Bilateral subtotal thyroid- 1311 thyroxine ectomy Right subtotal lobectomy Nil Right subtotal lobectomy Nil Nil Resection of isthmus Right subtotal lobectomy. 1 3 1 1 lncomulete excision
Recurrence-free at 14 yr Recurrence-free at 12 yr Recurrence-free at 7 yr Recurrence-free at 1 yr Emigrated. Recurrence-free at 1 y r Follow-up 3 mth
Table XIII: DETAILS OF PATIENTS TREATED FOR FOLLICULAR CARCINOMA Treatment Patient
Age Sex
Stage of carcinoma at presentation
Surgery
Radiotherapy, hormonal
Follow-up ~
’
.
Extensive local infiltration Confined to thyroid Local infiltration
Left partial lobectomy. In- External irradiation complete remOYd1 Local excision Nil Bilateral subtotal thyroid- External irradiation ectomy (thyroxine) Lymph node biopsy
F
Presented with scalp secondary Local infiltration
86
F
Local infiltration
C. W., 1968 G . E., 1971
35 86
F M
Confined to thyroid Confined to thyroid
B. B., 1972
34
M
Confined to thyroid
D. I., 1973
47
F
Extensive local infiltration
G . P., 1953
44
M
L. R., 1957 J. J.. 1958
58 34
F
P. B.,
1965
88
F
P. G . , 1966
44
M . S . , 1967
15*
F
Death from tumour at 9 yr
Recurrence-free at 16 yr Bone secondary at 13 yr; treated with radiotherapy. Recurrence-free at I6 yr External irradiation. Death from tumour at 2 yr 1811
Bilateral subtotal thyroidectomy. Tracheostomy Bilateral subtotal thyroidectomy. Incomplete resection. Tracheostomy Right subtotal lobectomy Bilateral subtotal thyroidectomy Right subtotal thyroidectomy Incomplete excision. Tracheostomy
External irradiation. Bone secondary at 4 yr, lung 5 yr; treated with 1311. Thyroxine external irradiation. N o active disease at 7 yr External irradiation. Death from tumour at 3 yr l 3 I l . Thyroxine Nil Nil
Recurrence-free at 5 yr Recurrence-free at 3 yr
Nil
Recurrence-free at 1 & yr
Nil
Postoperative death
211
D. J. Campbell and R. H. Sage benign goitre they achieved a high degree of correlation between actual and suspected cancer incidences. When it was not possible to arrive at a histological diagnosis on purely clinical grounds the patients in this series were categorized as shown in Table IV. They were observed to have either a solitary nodule or generalized goitre, which was invariably non-toxic. The difference in behaviour of solitary nodule carcinomas and those presenting as multinodular goitre seems to suggest that they represent stages in a continuous process (Table VII). Cases not diagnosed at the solitary nodule stage may present later with a multinodular form. It is well recognized that from 61.7 per cent (Rose et al., 1963) to 80 per cent (Clark et al., 1966) of unilateral thyroid cancers have demonstrable intraglandular dissemination. These microscopic foci may explain the transformation of a malignant solitary nodule into the multinodular form. Cases presenting at a more advanced stage are invariably diagnosed as carcinoma. This scheme applies to differentiated carcinomas only. The rapid progress of anaplastic tumours precludes the recognition of discernible stages. Occasionally a thyroid carcinoma may develop de nouo in a pre-existing goitre (Burn and Taylor, 1962). Solitary nodule carcinomas present on average 12 years before those in multinodular goitres. In this series they had been present for a mean of 23 months compared with the 6 years and 8 months of rnultinodular goitres. In addition, while multinodular carcinomas exhibit significant local and distant metastases, this is rare for solitary nodule carcinoma. The more advanced state of the multinodular carcinoma is reflected in its poorer prognosis. Thus, of 18 patients treated in this category, 6 have died while 4 others are alive with metastases. The survival figures shown in Table VII do not indicate the high incidence of metastases occurring in the patients. All the solitary nodule carcinomas responded well to treatment. Clearly it is important to recognize thyroid carcinoma during its solitary nodule phase, when cure may reasonably be attained. Crile (in Discussion, Crile and Dempsey, 1949) suggested that a ‘high index of suspicion’ should be directed at all solitary nodules and was able to report a 90 per cent success rate in diagnosing carcinoma preoperatively in solitary nodules. In contrast, Hoffmann et al. (1972) stated that ‘there is no way of differentiating benign from malignant solitary nodules and therefore all must be resected’; a view previously expressed by Liechty et al. (1965) and Taylor (1969b). It is known that only 50 per cent of clinically solitary nodules are truly solitary (Taylor, 1969b). In these, cancer incidences reaching as high as 33 per cent have been recorded (Cattell and Colcock, 1953). The 2-7 per cent incidence reported in this series is lower than that of most other series as it relates to clinically solitary nodules only. This represents the cancer risk amongst patients subjected to thyroidectomy. The vast majority of operations for solitary nodules are therefore performed for benign nodules. 212
Excellent results for solitary nodule Carcinoma can only be achieved, however, if the surgery employed prophylactically is at the same time therapeutic for cancer (Crile, 1953). Prophylactic surgery is of no value if it results in local dissemination of incompletely removed carcinoma. Enucleation of solitary nodules as advocated by Lahey and Hare (1951) is clearly inadequate. Taylor (1965) and Shands and Gatling (1970) have recommended total lobectomy as the minimum procedure for solitary nodules. Hinton and Lord (1945) and Beahrs et al. (1951) advocated the removal of all non-toxic multinodular goitres because of the high incidence of unsuspected carcinoma. The present study confirms this in reporting a 12.8 per cent incidence of carcinoma in nontoxic multinodular goitres. This figure, however, applies to surgical practice only. The incidence of carcinoma in non-toxic multinodular goitre amongst the general population is much lower than that seen surgically. Carcinoma incidences of 10 per cent (Cope et al., 1949), 10.9 p:r cent (Crile and Dempsey, 1949) and 17.1 per cent (Cole et al., 1949) have previously been reported in excised non-toxic multinodular goitres. A major problem is the identification of the patients with non-toxic multinodular goitre who require thyroidectomy. Criteria helping to distinguish benign from malignant non-toxic multinodular goitres have been defined (Hurxthal and Heinemann, 1958; Sokal, 1959) in the belief that the removal of all goitres would result in more life lost than saved. Crile (1953) has stated that ‘a woman with multinodular goitre would probably be better protected against the development of fatal cancer by removal of a normal appearing breast or cervix than by removal of the goitre’. While this may apply to the population at large, its relevance to the selected patients seen in surgical clinics is less clear. In this situation the processes of selection favouring cancer have a concentrating effect which may be as high as tenfold (Sokal, 1954; Veith et al., 1964). A decision not to operate on a non-toxic multinodular goitre can only be made in the knowledge that carcinoma has not been absolutely excluded. Patients seen in surgical clinics with non-toxic multinodular goitre should therefore be regarded as having selected themselves for surgery. If total lobectomy is regarded as the minimal surgical procedure for the solitary nodule, then, it has been argued, total thyroidectomy must be the prophylaxis for multinodular goitre (Cope et al., 1949). Lesser procedures may in theory have resulted in local dissemination of carcinoma in 12.8 per cent of the patients seen in this series. Nevertheless, it would be irrational to advise total thyroidectomy, with its attendant complications, in all non-toxic multinodular goitres. A more realistic approach is the employment of bilateral subtotal thyroidectomy, with conversion to total thyroidectomy as needed. McKenzie (1971) has shown that total thyroidectomy eliminates the local recurrences seen to follow less radical operations. It has the added advantage of facilitating treatment with radio-iodine and prevents the transformation of
Thyroid cancer differentiated into anaplastic carcinomas (Clark et al., 1966). In this series total thyroidectomy was not employed in the treatment of differentiated carcinomas and must, in part, be responsible for poor results obtained in the multinodular carcinomas. Wade (1969) has stressed the need to prevent local recurrence in the treatment of differentiated thyroid carcinoma. Four tumour deaths were recorded amongst the differentiated thyroid carcinomas. All received external irradiation for locally invasive disease. In the single papillary carcinoma thyroxine was not introduced until systemic metastases appeared. Only 1 of the 3 follicular carcinomas received thyroxine and then only after the development of myxoedema. These tumours were clearly exposed to high levels of thyroidstimulating hormone a t a time when suppressive doses of thyroxine should have been employed. The hormonal dependency of differentiated thyroid cancer is now firmly established (Balme, 1954; Crile, 1966) following Dunhill’s (1937) initial observation of tumour regression when treated with thyroid extract. It is imperative, therefore, that when dealing with differentiated thyroid carcinoma periods of hypothyroidism should be restricted to a minimum. This applies equally to carcinoma undergoing treatment with radioactive iodine (Crile and Wilson, 1959). A clearer understanding of the value of thyroxine, coupled with a wider use of total thyroidectomy, would have undoubtedly improved the prognosis amongst the patients reported in this series. The prognosis of any cancer is determined primarily by its histological type and clinical stage. Good results obtained in treating differentiated thyroid carcinoma compare markedly with those obtained with anaplastic growths. While confirming this, the present study emphasizes the importance of clinical staging of the primary tumour. Clinically obvious carcinomas carry uniformly bad prognoses. They are invariably anaplastic as differentiated carcinomas reach this stage far less frequently. The slower growth of differentiated cancer usually results in them presenting at an earlier stage, when they may be mistaken for benign goitres. Differencesin the pattern of behaviourof differentiated carcinomas a t these early stages suggest that they pass through solitary nodule and multinodular forms before presenting the picture of a frankly malignant locally invasive goitre. These results emphasize the value of T N M staging when applied to thyroid cancer (Harmer, 1969). Fujimori (1969) was able to relate prognosis to the individual components of the T N M classification and clearly showed that increasing ‘T number’ was accompanied by worsening of prognosis.
Acknowledgements We wish to thank M r J. McKinnell, Consultant Pathologist, for reviewing the histological preparations and confirming diagnoses for all our patients. Our thanks are also due to Miss J . Powell of the Regional Cancer Registry for her invaluable help, particularly in the preparation of data referable to the Birmingham region.
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