Chest computed tomography (CT) in patients with micronodular lung metastases of differentiated thyroid carcinoma

Inr J Radumn Onn~lo~y Bml Phw Vol. Printed in the U.S.A. All rights reserved.

I I, pp.

0360-3016/85 $03.00 + .I0 Copyright 0 1985 Pergamon Press Ltd.

1023-1027

??Brief Communication

CHEST

COMPUTED TOMOGRAPHY (CT) IN PATIENTS WITH MICRONODULAR LUNG METASTASES OF DIFFERENTIATED THYROID CARCINOMA

JEAN-DANIEL DOMINIQUE

PIEKARSKI, COUANET, Departement

M.D., M.D.,

MARTIN JACQUES

SCHLUMBERGER, MASSELOT,

d’Imagerie Diagnostique,

M.D.

M.D.,

JEROME

AND CLAUDE

Institut Gustave-Roussy,

LECLERE,

PARMENTIER,

M.D., M.D.

94800 Villejuif, France

Forty thoracic CI scans have been performed on 27 patients with micronodular lung metastases of differentiated thyroid carcinoma. Lung nodules were visualized in 14 out of 19 patients (78%) with functioning lung metastases, although their chest X rays were normal. However, only a small number of peripheral micronodules can he visualized by CT scan since the central micronodules remain undistinguishable from adjacent vessel structures. A close relationship has been found between the number of micronodules and the thyroglobulin (Tg) serum level. In patients previously treated by 13’1for proven lung metastases and who had no uptake for several years, but in whom Tg remained detectable in the serum, CT scans have shown micronodules in 7 of the 13 patients with normal chest X rays. The present data suggest that these nodules are mainly a result of fibrosis. CT scanning appears to be an important complementary tool with regard to “‘1 whole body scintigraphies in the radiologic diagnosis of lung nodules and in the assessment of radioiodine therapy. Thyroid carcinoma, Lung miliary, Chest X ray, Lung tomographies,

CT scans, Thyroglobulin.

who had been treated with radioiodine for proven lung metastases and had no detectable lung uptake for years.

INTRODUCIION Lung is a common site for metastases from differentiated thyroid carcinoma. In treated patients, functioning metastases are suspected when thyroglobulin (Tg) levels are elevated in the serum,‘,‘4 and their location in the lungs can be proven by a radioiodine uptake in the lungs. The radiological size of these metastases is usually less than 1 cm and they can therefore be classified as micronodules. When micronodules are diffuse, they may have a typical miliary pattern. In fact, the size of lung micronodules is frequently under the spatial resolution of the chest X ray, which may be norma1.2v7 Chest tomographies have been carried out for these patients, but the results appeared to be very similar to those of chest X rays. This study has been undertaken to assess the diagnostic improvement offered by CT scanning as compared to conventional X ray techniques in patients with functioning lung metastases from differentiated thyroid carcinoma. Following radioiodine therapy, a normalization of the chest X ray is often obtained but in several patients Tg remained detectable in the serum. CT scans have been carried out in search of residual disease in those patients

METHODS

AND

MATERIALS

Patients Twenty-six studies have been carried out in 18 patients (cases 1-18) with differentiated thyroid carcinoma who had, at the time of the study, functioning metastases proven by a diffuse uptake of radioiodine in the lungs as shown by a 13’1 total body scan. No other distant metastasis has been found in these patients. At the time of the study, eight patients had 13’1 uptake in the thyroid bed which was less than 2% 72 hours following the administration of radioiodine. Fourteen studies have been carried out in 13 patients (cases 3b, 5b, lOc, lOd, 19-27) with differentiated thyroid carcinoma, who had been treated with radioiodine 12 to 250 months before for functioning lung metastases and whose 13’1 total body scan have not shown any more uptake in the lungs. Clinical, biological and isotopic data are given in Table 1. Each study included Tg serum level under T4 therapy and after TSH stimulation, a radioiodine total body scan, a chest X-ray and a CT scan. Lung tomographies have been carried out on 19 of these 27 patients.

Reprint requests to: M. Schlumberger, M.D., Service de Mkdecine Nucltaire, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France.

Accepted

1023

for publication

5 December

1984.

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Radiation Oncology 0 Biology 0 Physics

Table 1. Clinical,

biological,

isotopic

and radiologic

May 1985. Volume 11,Number 5 data for the 27 patients

Treatment Case number

Age

12 13 14 15 16 17 18

63 16 17 17 21 22 30 54 54 24 58 59 59 31 12 12 34 34 35 35 24 24 25 38 15 23 10 20 58 46

19a 19b 20 21 22 23 24 25 26 27

42 43 36 42 30 26 37 31 38 32

I

2a 2b 2c 3a 3b 4 5a 5b 6 7a 7b 7c 8 9a 9b 10a IOb 1oc 10d lla Ilb IIC

Sex

Histology*

M

P FMD -

M -

mCi administeredt 0 0

F F F M F M M

FMD P P P P P P

200 300 100 300 200 0 100 100 100 200 300 300 370 450 0 100 100 100 200 300 400 0 80 0 180 0 200 0

M

P P P FMD P FMD P P P

700 700 500 600 300 260 300 300 250 300

F M F F F F M F F -

F F F M F M M F

P P P P P FWD P P P

Time interval*

Uptake8

-

-

5 7 4 6 73 5 6 5 7 6 14 12 8

0.9 2.5 0.8 1.5 20 0.3 22 8 3 1.5 1.4 1.1 +

4 II 17 5 10 5 24 23 28 41 I2 24 36 44 21 60 276 89

0.5 + + 0.2 0.5 0.5 -

0.3 0.5

I 1 0.2 0.4 1.4 0.2 0.1 0.3 + 1.5

Uptake at the time of the study$

Under T4

After TSH

24 52 42 19 5 3

13 400 470 320 34 12 29 23 AbS Abt 460 73 -

1

1 0.5 0.5 + 0.5 + 0 0 0.5 0.5 0.6

Abt Abt 168 57 44 Abt 23 10 -

0.7 1.3 0.5 1.5 0.5 0.2

24 5 5 36 46 25 17 2 9 7 8

0 0 0 0 0 0 0 0 0 0

19 5 14 13 27 8 4 5 6 8

1

in the present

studv

Tg (ng/mI)

0.3 0.9 2.5 1.5 0 IO 0.3 0 2 3 1.5

included

Abt 86 14 34 21 6 23 78 82 57 15 205 8 60 9 43

Chest# X ray

Tomographies#

1

I

3 1 1

3 1

1

1

1 I

>I0 >I0

1 -

3

1 1 3 3

I 1 1

1 2 I I 1 3 3 3 2

I I 1 1 1 I

140 -

1 I

69 43 71 13 12 7 15 8

1 3

3 3 1

1 1 3 1

1 -

I I 1

1

1 -

1 I 1

3 >I0 3 2 0 0 5 3 1 0 >lO >I0 >lO 7 2 2 5 2 0 0 >lO >lO >lO 3 >lO 0 3 0 6 0

-

1

1

CT scan micronodulesY#

>I0 3 1

-

1 -

4 0 0 3 3 0

* P = papillary; FWD = follicular well differentiated; FMD = follicular moderately differentiated. TNumber of mCi of 13’1 administered previously to the study. *Time (in months) between the last treatment and the present study. $Radioiodine uptake in the lung expressed as percent of the administered dose of 13’I. #l = normal, 2 = doubtful, 3 = abnormal. TNumber of micronodules visualized by CT scan. Abf = presence of autoantibodies directed against Tg.

Methods 13’1 total body scans were performed 14 days after T3 withdrawal, 72 hours following the administration of I to 2 X 37. lo6 Bq (1 to 2 mCi) of ‘3’I.6.‘2 The radioiodine uptake in lung metastases was visualized and measured by quantitative scintiscan using a scintiscannep equipped with two opposed heads, a memory bank and a color TV monitor. Each metastasis was delineated on the TV

* Ohio Nuclear

84 FD scintiscanner.

image, and the integral of the counts within its area was calculated. Calibration of the equipment made it possible to assess metastatic uptake with a precision of 20% of the measured value. Uptake in the lungs as low as 37 X lo3 Bq ( 1 &i), corresponding to 0.1% of the administered dose of radioiodine, could be detected. The results were expressed as a percentage of the administered dose.

CT for lung metastases of thyroid carcinoma 0 J.-D.

Serum thyroglobulin (Tg) was measuredI under T4 treatment and following TSH stimulation. The normal range is 2.5-28 ng/ml and the limit of detectability is 2.5 ng/ml. In this study, circulating Tg antibodies were detected with the tanned red cell agglutination technique? in three patients (cases 5b, 6 and 8). Chest X rays were made with high kilovoltage and lung tomographies with a filter, 1 cm apart. Computed tomography was done with a third generation scanner (CGR, CE-10000). The slices were made every centimeter with a 1 cm collimation. Scanning time was 6.8 seconds and the matrix was 512 X 5 12. No contrast medium has been injected. All the radiologic results have been blindly reviewed by three independent observers who have classified them as normal or abnormal according to the presence or absence of micronodules. Nodules visualized by CT scan were counted.

RESULTS Among the 26 studies performed on patients with functioning lung metastases (Table l), the chest X ray was abnormal in 7 studies and CT scans confirmed the presence of micronodules. In the 19 other studies, the chest X ray was normal (n = 17) or questionable (n = 2). Lung micronodules were detected by CT scanning in 14 of these studies, while it was normal in the other 5. One patient (case 16) had mediastinal lymph node metastases. which were removed by surgery at the time

PIEKARSKI et al.

1025

of the study; the CT scan of the lungs was normal but multiple micronodules of 2 to 3 mm in diameter were present at surgery in the peripheral part of the lungs and larger ones (5 to 6 mm in diameter) were present in the central part of the lungs. More than 10 nodules were detected by CT scan in 6 out of the 7 patients with abnormal chest X ray, and they were impossible to count accurately. However, in patients with a normal chest X ray, despite a diffuse uptake of 13’1 the number of detectable nodules was small, ranging’from 0 (in patients with normal CT scan) to 7, and was greater than 10 in only two patients (Figure 1). It must be stressed that in these patients, only peripheral micronodules were visualized by CT scanning since central nodules are undistinguishable from adjacent vessels. No discrepancy has been noticed among the observers in the review of CT scans nor between the initial interpretation and their review. In contrast, 6 discrepancies existed betwen the initial interpretation of chest X rays and their review. A close relationship has been found between the number of lung micronodules shown by CT scanning and the Tg levels in the serum (Figure 2), both under T4 therapy and following TSH stimulation. This was not the case with 13’1uptake in the lungs. CT scans were repeated on 7 patients 2 to 4 times after treatment with radioiodine. In 1 patient the CT scan was initially normal and remained so after treatment. In 3 patients, CT scans did not show any decrease

cl

NORMAL CHEST

X

RAY

X

RAY

DOUBTFUL CHEST

ABNORMAL CHEST

ER

Fig. 1. Number of micronodules shown by CT scan as a function radioiodine uptake in the lungs at the time of the study.

t Burroughs-Wellcome,

Research

Triangle

Park, N.C.

of chest

OF

X RAY

NODULES

X ray in the 26 studies

with

1026

Radiation Oncology 0 Biology 0 Physics

LUNG NODULES

ON CT SCAN

Tg ng ml

0

>lO

2-6

500

May 1985, Volume 11, Number 5

neoplastic tissue. However, its level was low under T4 treatment and inferior to that of patients with functioning metastases. Lung tomographies have been carried out in 19 patients: in 4 cases, chest X rays, lung tomographies and CT scans were abnormal. In 4 others, all three procedures were normal. In the 11 other patients, the chest X ray was normal and the CT scan abnormal, but lung tomographies showed nodules in only one of these patients. DISCUSSION

100

10

1 under

T4 treatment

2 following

TSH

stimulation

I

I

I

I

1

2

1

2

L

77---+

Fig. 2. Tg level in the serum as a function of the number of micronodules shown by CT scan in patients with radioiodine uptake in the lungs at the time of the study.

in the number of nodules, although 13’1 uptake and Tg levels in the serum did not decrease significantly. In the 3 other patients, the number and size of the nodules decreased, while the CT scan became normal for one of them. This decrease was simultaneous with that of ‘“‘I lung uptake as well as that of the Tg level in the serum (Table 1). Fourteen studies have been carried out in 13 patients who had no detectable 13’1 lung uptake at the time of the study. In one patient, both chest X ray and CT scan were abnormal. Chest X rays were normal in the 13 other studies: CT scans showed micronodules in 7 studies and were normal in the other 6. In this group of patients the number of nodules detected by CT scan was also low: it was greater than 10 in only 3 cases. In one of these patients (case 19), the chest X ray was normal at the time of the study, but before any 13’1 treatment, the chest X ray showed a typical miliary image. The number of micronodules ranged from 1 to 4 in the other cases with abnormal CT scans. Even in these patients with normal roentgenograms, Tg was detectable in the serum under T4 treatment and increased following TSH stimulation, indicating the presence of

CT scans revealed micronodules in 4 out of 5 patients with functioning lung metastases of differentiated thyroid carcinoma, although their chest X rays were normal. In contrast, the results of lung tomographies did not appear better than those of chest X rays. This has already been demonstrated for metastases from other cancer origins,4 but these patients offer a unique model as their functioning metastases could be demonstrated by 13’1 total body scan at the time of the study. Furthermore, the accuracy in interpreting CT scans appears to be much better than that of chest X rays, which often remains questionable. However, only a small number of micronodules could be visualized despite diffuse uptakes of 13’1 in the lungs. CT scanning shows mostly peripheral micronodules, while the central ones can only be visualized if they are much larger than the adjacent vessels. In the case of patient 16 with a normal CT scan who had surgery, lung micronodules were present: 3 mm for the peripheral nodules and 6 mm for the central nodules. This probably represents the limits of detectability of the CT scan. In these patients, a close relationship has been observed between the number of micronodules on CT scans and Tg serum levels, under T4 therapy as well as after TSH stimulation. This has been observed despite the presence of thyroid remnants in eight patients, but the remnants were small and their functional activity was suppressed has not been during T4 treatment. I4 This relationship observed with 13’1 uptake and suggests that Tg is not only the marker of metastatic thyroid cancer, but could also be related to the volume of tumoral tissue. Although lung micronodules on CT scan are not specific and could correspond to granulomas,” their thyroid cancer origin is very likely as shown by radioiodine uptake, elevated Tg levels, and clinical data as most of the patients were young, without any past history of other illness such as tuberculosis or histoplasmosis. Lung density can be influenced by many factors such as breathing, declivity, and/or the patient’s age.’ A significant increase in lung density has been found in patients with sarcoidosis, although all of them had an obviously abnormal chest X ray.” However, to our knowledge, it has not yet been proven that CT scanning can detect changes in lung density in patients with

CT for lung metastases of thyroid carcinoma 0 J.-D. PIEKARW et al.

interstitial lesions similar to those of the patients included in this study, i.e., not detectable on the chest X ray. CT scans reveal the effectiveness of 1311treatment, which is often difficult to assess with chest X rays alone: the decrease in the number of the micronodules is parallel to the decrease of functional parameters (serum Tg level and radioiodine lung uptake). When the number of micronodules remained unchanged, lung uptake and Tg levels did not significantly decrease. In patients with no uptake 12 to 250 months after treatment, CT scans have shown the presence of micronodules in 6 out of 12 patients with normal chest X rays. These micronodules may correspond to tumor residue or to fibrosis, as has been described following the treatment of metastases with massive doses of radioiodine’ or chemotherapy.5 In all these patients, Tg was detectable in the serum under T4 therapy and increased following TSH stimulation, indicating the presence of neoplastic tissue, although its level was lower than in patients with functioning metastases. Therefore,

1027

two hypotheses are possible: (i) the volume of residual tumoral tissue is probably small and fibrosis is likely to be an important component of the visualized micronodules. (ii) The remaining neoplastic tissue is poorly differentiated and is unable to pick up 13’I.13 In conclusion, CT scanning is the most sensitive radiological method available at present for the detection of lung metastases. From a practical point of view, it appears to be complementary to 13’1total body scintigraphies. In cases with questionable abnormalities on the chest X ray, CT scanning is the most reliable technique for diagnosing micronodules, whereas the 13’1 total body scan appreciates their functional activity. It may be the only way to localize metastases to the lungs when they do not pick up 1311.It may be of value during the follow-up, for the evaluation of the tumoral response to 13’1treatment. Furthermore, the number of micronodules on the initial CT scan is related to the tumoral mass and further studies are needed to assess its prognostic significance.

REFERENCES 1. Ashcraft, N.W., Van Herle, A.J.: The comparative

value of serum thyroglobulin measurements and iodine 131 total scans in the follow-up study of patients with treated differentiated thyroid cancer. Am. J. Med. 71: 806-8 14, 1981.

9.

2. Catz, B., Starr, P.: Cancer of the thyroid with metastases to the lungs, condition shown by scintigram in absence of definite X ray findings. J.A.M.A. 160: 1046-1047, 1956.

10.

3. Felson, B.: The interstitium. Felson, B. (Ed.). Philadelphia, 1973, pp. 314-349.

11.

In Chest Roentgenofogy, W.B. Saunders Company.

4. Heitzman, E.R.: Computed tomography of the thorax: Current perspectives. Am. J. Roentgenol. 136: 2- 12, 198 1. 5. Nachman, J.B., Baum, E.S., White, H., Gruissi, F.G.: Bleomycin-induced pulmonary fibrosis mimicking recurrent metastatic disease in a patient with testicular carcinoma: case report of the CT scan appearance. Cancer 47: 236-239, 198 1. 6. Parmentier, C., Aubert, B., Charbord, P., Fragu, P., Gardet, P.: Follow-up of differentiated thyroid cancers after treatment. Resume and practical guide for the development of follow-up program. Ann. Radio/. (Paris) 20: 841-855, 1977. I. Pochin, E.E.: Radioiodine therapy of thyroid cancer. Sem. Nucl. Med. 1: 503-515, 1971. 8. Rail, J.E., Alpers, J.B., Lewallen, C.G., Sonenberg, M., Berman, M., Rawson, R.W.: Radiation pneumonitis and fibrosis: A complication of radioiodine treatment of pul-

12.

13.

14.

monary metastases from cancer of the thyroid. J. Clin. Endocrinol. Metab. 17: 1263-1216, 1957. Rosemblum, L.J., Mauceri, R.A., Wellenstein, D.E., Thomas, F.D., Bassano, D.A., Raasch, B.N., Chamberlain, CC., Heitzman, E.R.: Density patterns in the normal lung as determined by computed tomography. Radiology 137: 409-4 16, 1980. Sagel, S.: Lung, pleura, pericardium. and chest wall. In Computed Body Tomography, Lee J.K.T., Sagel, S.S., Stanley R.J. (Eds.). New York, Raven Press. 1983, pp. 99-129. Salomon, A., Kreel, L., MC Nicol, M., Johnson, N.: Computed tomography in pulmonary sarcoidosis. J. Comput. Assist. Tomogr. 3: 754-758, 1979. Schlumberger, M., Charbord, P., Fragu, P., Gardet, P., Lumbroso, J., Parmentier, C., Tubiana, M.: Relationship between thyrotropin stimulation and radioiodine uptake in lung metastases of differentiated thyroid carcinoma. J. Clin. Endocrinol. Metab. 57: 148-151, 1983. Schlumberger, M., Charbord, P., Fragu, P., Lumbroso, J., Parmentier, C., Tubiana, M.: Circulating thyroglobulin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: Relationship to serum thyrotropin levels. J. Clin. Endocrinol. Metab. 51: 5 13519, 1980. Schlumberger, M., Fragu, P., Parmentier, C., Tubiana, M.: Thyroglobulin assay in the follow up of patients with differentiated thyroid carcinomas: Comparison of its value in patients with or without normal residual tissue. Acta Endocrinol. (Kbh) 98: 2 15-22 1, 198 1.