Detection of Metastatic Adrenal Carcinoma Using 131I-6-8-Iodomethyl-19-Norcholesterol
Total Body Scans
JAMES E. SEABOLD, THOMAS P. HAYNIE, DIOSDADO N. DEASIS, N. A. SAMAAN, HOWARD J. GLENN, AND MONROE F. JAHNS
The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030, and The University of Texas at Houston Graduate School of Biomedical Sciences, Houston, Texas 77030
ABSTRACT. Adrenal and total body scintigraphs with 1311-6-8-iodomethyl-19-norcholesterol were ob- tained in 5 patients who had had prior resection of adrenal cortical carcinoma. The results were com- pared with roentgenographic findings and liver, bone, and total body gallium-67 citrate scintigraphs. Metastatic lesions were detected with radiolabeled cholesterol in 4 of 5 patients, including 3 liver metastases, 2 bone metastases, and 1 lung metas- tasis. These lesions were also demonstrated by one
or more of the other diagnostic modalities. All initial findings were negative in a fifth patient, who developed brain metastases within two months. The 6-methyl-analog of iodocholesterol makes it possible to detect metastatic adrenocortical car- cinoma with total body scans. Whether or not this agent is “tumor specific” and will be of significant clinical utility will have to be determined more fully in a larger series of patients. (J Clin Endocrinol Metab 45: 788, 1977)
A’ DRENAL scintigraphy with 131I-19-iodo- cholesterol has been shown to have clinical applicability in the assessment of various anatomic and functional abnormalities of the adrenal glands (1-5). However, this analog does not concentrate sufficiently in adrenal carcinomas to obtain satisfactory images of the primary neoplasm or of its metastases (1,6-8). Recently, 131I-6-3-iodo- methyl-19-norcholesterol was found to achieve superior concentration in adrenal tissue (9).
In this paper we report our experience with this newer analog in 5 patients with metastatic adrenal cortical carcinoma. The results of total body iodocholesterol scans were also compared with those of 67Ga, bone, and liver scans.
Materials and Methods
Patients
Five patients with adrenal carcinoma were referred to the Nuclear Medicine Section, M. D.
Reprint requests to: James E. Seabold, M.D., Sec- tion of Nuclear Medicine, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Ave., Houston, Texas 77030.
Anderson Hospital, for adrenal scans to visualize possible metastatic adrenal carcinoma by means of 131I-6-8-iodomethyl-19-norcholesterol (sub- sequently referred to as 131I-6-methyl-choles- terol). Each patient had undergone endo- crinologic investigation to establish the degree and type of steroid production. All patients had an adrenalectomy to remove the primary neo- plasm and were taking cortisone acetate and OPDDD [I,I-dichloro-2(o-chlorophenyl)- 2(p-chlorophenyl)-ethane].
Adrenal scan procedure
131I-6-methyl-cholesterol, 2 mCi, was ad- ministered iv to each patient over 1-2 min. The thyroid was blocked with 200 mg of oral potas- sium perchlorate prior to the injection and this dose was continued twice a day for 7 days (10). Total-body scans with 6-to-1 minification were done at 200 cm/min, 5-8 days after injection of iodocholesterol, yielding a count density of approximately 100 counts/cm2. The scans were obtained using a Picker 1,000 dual probe recti- linear scanner equipped with high-energy col- limators. Camera images of the adrenal beds and abnormal suspicious foci elsewhere in the body were obtained with a Pho-gamma HP camera equipped with a 1,000 hole high-energy collimator and a 30% window peaked at 364 Kev. The scintiphotos were exposed to obtain 50,000-200,000 counts, depending on the avail- ability of counts in the areas of interest.
The 1311-6-methyl-cholesterol was obtained in lyophilized form from the University of Michigan Nuclear Medicine Unit. This material was then placed in a saline suspension (6.6% alcohol, 1.6% polysorbate-80) prior to administration. Chromatograms were performed on each prepara- tion prior to injection to assure that a high per- centage of 131I was labeled to the compound. Chromatographic systems used were Whatman No. 1 paper or Eastman Kodak 6061 silica gel thin layer supports with chloroform as the developing agent. All samples injected contained less than 10% free iodide. Appropriate pyrogen and sterility tests were also carried out.
Other procedures
In each patient, liver scans with 3 mCi of 99mTc-sulfur colloid were done, and 600,000 counts were obtained for each view, by a gamma camera. Bone scans using 15 mCi of 99mTc- pyrophosphate were obtained in all patients, and 67Ga scans with 5 mCi of gallium-67 citrate were also obtained in 3 patients.
One patient died a month after injection of iodocholesterol. Specimens were obtained at
necropsy for measurement of radioactivity in normal tissue and metastatic lesions. Tissue samples in triplicate were weighed, placed in test tubes, digested with a small amount of sodium hydroxide solution and the volume equalized to the same volume with additional sodium hydroxide solution before counting in a well counter. Counts were compared with the count from a known aliquot of the injected dose diluted to the same volume as the tissue samples. Suitable corrections were made for background decay and dilution factors so that tissue radio- activity could be calculated in per cent dose per gram tissue. Two other patients died 3 and 4 months following the 131I-6-methyl-cholesterol doses, but the residual activity was too low to assay.
Case summaries
Case 1. A 43-year-old woman underwent a left adrenalectomy, splenectomy, and left nephrec- tomy in 1968 for an androgen-producing adrenal carcinoma. In February 1973, she had a left lobectomy for resection of metastatic neoplasm to lung, followed by external irradiation. In
| Case | Sex | Age at onset | Site of neoplasm* | Site of metastases | Date metastases detected | Hormone(s) secreted in excess | Period of excess secretion | Medications | Dose per 24 h | Date medication begun |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 43+ | L | L Lung | 2/73 | Androgens | 1968 | Prednisone | 7.5 mg | 12/73 |
| Lumbar Vert. | 12/73 | Androgens | 1973 | OPDDD | 5 g -+ 1 g | 12/73 | ||||
| R Liver | 11/75 | Androgens | 1975-76 | 2 g | 11/75 | |||||
| Metapirone | 750 mg | 11/75 | ||||||||
| OPDDD | 10 g -+ 0 g | 3/76 | ||||||||
| 2 g | 4/76 | |||||||||
| 2 | M | 31+ | R | Spine & Dura | 8/75 | Cortisol | 1975-76 | Cortisone | 37.5 mg | 12/75 |
| Lung & L Pelvis | 1/76 | Estrogens | 1975-76 | OPDDD | 12 g -+ 3 g | 12/75 | ||||
| Prox. Humeri & | Metapirone | 3 g | 12/75 | |||||||
| Femora & Skull | 2/76 | Aminogluth. | 1 g | 1/76 | ||||||
| Liver | 3/76 | |||||||||
| 3 | F | 35 | R | R Liver | 9/65 | None | 1965-76 | Cortisone | 37.5 mg | 1965 |
| L Liver | 6/67 | OPDDD | 12 g -+ 3 g | 1968 | ||||||
| L Pelvis | 9/68 | 3 g-+ 1 g | 1975 | |||||||
| L Lung | 11/68 | |||||||||
| R Lung | 8/71 | |||||||||
| Brain | 12/72 | |||||||||
| L Adrenal | 10/73 | |||||||||
| Vertebrae | 1/76 | |||||||||
| 4 | M | 54+ | L | Brain | 6/76 | None | 1975-76 | Prednisone | 7.5 g | 1/76 |
| Liver | 6/76 | OPDDD | 10 g -+ 3 g | 1/76 | ||||||
| Stopped | 3/76 | |||||||||
| 5 | M | 37 | R | Liver | 12/75 | None | 1975-76 | Cortisone | 37.5 mg | 12/75 |
| R Lung | 6/76 | OPDDD | 10 g -+ 3 g | 12/75 | ||||||
| 1 10 g | 6/76 | |||||||||
| Stopped | 7/76 | |||||||||
| 3 g | 9/76 |
* R, right: L, left. t Patient died.
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December 1973, she received local irradiation to a lesion in the second lumbar spine and started receiving 5 g of OPDDD and 7.5 mg of predni- sone daily (Table 1). Her symptoms improved with gradual resolution of the lesions in the lung and lumbar vertebrae.
She did well until November 1975, when the hirsutism recurred and there was a rise in andro- gen levels. Metapirone 250 mg t.i.d. was started and the OPDDD dosage was increased from 1 to 2 g/day (Table 1). A 1311-6-methyl-cholesterol total body scan was obtained in March 1976, which showed abnormal focal uptake in the posterior right liver (Fig. 1) which corresponded to a cold area detected in the same area on a 99mTc-sulfur colloid liver scan (Fig. 2). A bone scan, chest and skeletal roentgenogram revealed no evidence of other metastatic disease (Table 2).
A hepatic arteriogram was performed, which demonstrated a 4-to-6 cm avascular lesion in the posterior right lobe of the liver. The patient had become hypothyroid, hyponatremic, and developed a urinary tract infection. While under- going therapy for these conditions, she developed acute respiratory distress and died on June 13, 1976. A postmortem examination revealed surgical absence of the left kidney and left adrenal gland, cardiac dilatation, bilateral pul- monary edema, and pulmonary emboli. The only residual carcinoma observed was a 6 x 6 x 5-cm solitary lesion in the right lobe of the liver.
Case 2. A 31-year-old man initially presented with low back pain radiating to the right lower extremity. An iv pyelogram revealed a large right suprarenal mass, which was resected, and
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| Case | 1311-6-Methyl- cholesterol | 67Gallium scan | Liver scan | Bone scan | Roentgenograms | |
|---|---|---|---|---|---|---|
| Chest | Skeletal | |||||
| 1 | Right lobe of liver | Not done | Posterior right lobe | Normal | Post thoracotomy | 2nd lumbar vertebra |
| 3-10-76 | 3-2-76 | 3-3-76 | changes | 12-31-73 | ||
| 3-5-76 | Normal skeletal survey | |||||
| 3-5-76 | ||||||
| Hepatic arteriogram: | ||||||
| 6 cm avascular mass posterior right lobe 5-25-76 | ||||||
| 2 | Thoracic & lumbar | Thoracic & lumbar | Normal | Skull | 1.5 cm nodule | Mid thoracic & 2nd |
| Right humerus | vertebrae, bilat. | 2-12-75 | Thoracic & lumbar | right lung | lumbar vertebrae | |
| 2-10-76 | pelvis | 2-18-76 | vertebrae, ribs, | 1-15-76 | Bilat. pelvis | |
| Humeri & femora | bilat. pelvis | 2-10-76 | ||||
| Right mid lung | Humeri & femora | |||||
| 2-24-76 | 2-19-76 | |||||
| 3 | Left lobe of liver | Right lobe of liver | Posterior right lobe | 10th thoracic verte- | Chronic changes | Left ilium |
| Skull | Left femur | 3-2-76 | bra | at bases | Left femur | |
| Low thoracic verte- | Left pelvis | Left ilium & | 3-3-76 | 1-24-74 | ||
| brae | 3-23-76 | Left femur | 10th thoracic verte- | |||
| Left femur | 3-3-76 | bra | ||||
| Left pelvis | Left ilium | |||||
| 3-19-76 | Left femur | |||||
| 3-16-76 | ||||||
| 4 | Negative | Not done | Normal | Normal | Normal | Normal |
| 2-10-76 & 4-9-76 | 4-9-76 | 4-2-76 | 9-2-76 | 4-2-76 | ||
| 5 | Right lobe of liver | Right lobe of liver | Posterior right lobe | Normal | Normal | Not done |
| Right mid lung | 6-28-76 | 12-7-75 | 6-3-76 | 12-3-75 | ||
| 6-25-76 | Worsened | Nodular lesions | ||||
| 6-2-76 | Right lung | |||||
| Largest 3 cm | ||||||
| 6-2-76 | ||||||
the patient was referred to M. D. Anderson Hospi- tal for further therapy in November 1975. The patient presented with the typical physical mani- festations of Cushing’s syndrome. He also had gynecomastia without galactorrhea, and par- aesthesia over the lateral right thigh. Skeletal roentgenograms revealed destructive changes of L2 with an associated paravertebral soft tissue mass, and a myelogram showed a complete extradural block at L2, L3.
A compression laminectomy of Ll to L3 was performed in December 1975 and was followed by radiotherapy to the same area. The patient was discharged with a regimen of OPDDD, 3 g/day, Metapirone, 750 mg P.O. q.i.d., cortisone acetate 37.5 mg/day and Aminoglutethimide, 250 mg P.O. q.i.d. was added in January 1976 (Table 1).
A 131I-6-methyl-cholesterol scan done 8 days after iv injection showed no appreciable uptake in the non-resected adrenal gland, but increased localization was seen in the thoracic and lumbar spine (Fig. 3). A bone scan (Fig. 4) and a 67Ga
scan (Fig. 5) done the following week showed extensive skeletal lesions. A repeat liver scan was normal (Table 2). In early March 1976, the patient was re-injected with iodocholesterol to obtain a total body scan shortly after injection in an effort to obtain a higher count rate. However, the patient had been experiencing recurrent episodes of congestive heart failure and his condi- tion deteriorated so rapidly a repeat scan could not be performed. He died on March 6, 1976 following acute cardiorespiratory arrest. An autopsy revealed hemorrhagic pulmonary edema with hyaline membrane formation, bilateral pleural effusions, a pericardial effusion and left ventricular hypertrophy, as well as metastatic adrenal cortical carcinoma in several thoracic and lumbar vertebrae, the skull, lungs and small foci throughout the liver. The residual tissue levels of 131I radioactivity was measured (Table 3).
Case 3. A 35-year-old woman was found to have metastatic adrenal carcinoma to the liver during an abdominal hysterectomy in 1965 (Table 1).
At a second operation, a right adrenal carcinoma and a solitary metastatic liver lesion were re- sected. Two years later she had a partial resec- tion of the left lobe of the liver for recurrent neoplasm, followed by hepatic arterial perfusion with yttrium-90 labeled microspheres and methotrexate.
In September 1968, she developed left hip pain due to lytic and blastic lesions in the left ilium. She received 3,400 rads of external irradia- tion to the pelvis, with regression of the lesions and of pain. In November 1968, she under- went resection of the posterior basal segment of the left lower lobe of the lung, and in 1971, she had a right lower lobectomy for lung metastases. Throughout this period she received adrenal cortical hormones and started receiving OPDDD in 1968 (Table 1).
In March 1976, she was reevaluated when she developed abdominal pain. A follow-up liver scan showed no change from a previous scan. Total body 131I-6-methyl-cholesterol and 67Ga
scans showed abnormal focal uptake in the liver, pelvis and left femur suggesting viable neoplasm in these areas. A bone scan demonstrated a focal lesion in the 10th thoracic vertebrae not de- tected on the 1311-6-methyl-cholesterol or 67Ga scans (Table 2). The patient experienced sympto- matic improvement following external irradiation to the thoracic vertebrae.
Case 4. A 54-year-old man had operative evacua- tion of a retroperitoneal hematoma in September 1973. A low grade fever persisted, accompanied with low back pain and an intravenous pyelo- gram revealed a left suprarenal mass. In Decem- ber 1975, a markedly hemorrhagic adrenal corti- cal carcinoma was removed from the left retro- peritoneum.
The patient was referred to M. D. Anderson in January 1976, at which time results of a physi- cal examination were within normal limits. Hor- mone studies were normal except for a low tes- tosterone level. He started receiving Prednisone
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FIG. 5. Gallium-67 citrate scan (Case 2). a) Anterior view, le- sions in proximal humeri. b) Pos- terior view, lesions in thoracic and lumbar vertebrae, right lung (arrow), bilateral pelvis, proxi- mal humeri and femora.
| Tissue (% dose/g) | Concentration ×10-3 | |
|---|---|---|
| Mean | SEM | |
| Adrenal gland | 10.8 | ± 0.23 |
| Vertebral metastases | 6.9 | ± 1.30 |
| Liver metastases | 6.5 | ± 0.55 |
| Uninvolved liver | 2.8 | ± 0.20 |
| Uninvolved bone | 0.9 | ± 0.23 |
| Uninvolved kidney | 0.9 | ± 0.08 |
| Uninvolved vertebral disk | 0.2 | ± 0.03 |
and OPDDD (Table 1). In February, a total body 131I-6-methyl-cholesterol scan showed no abnormal uptake. In March 1976, the OPDDD had to be discontinued, due to extreme nausea. In April 1976, a repeat 1311-6-methyl-cholesterol scan, and a liver and bone scan were all nega- tive (Table 2).
OPDDD therapy was not restarted because of the patient’s previous poor tolerance of the drug. In late May, he developed progressive lethargy, weakness, slow mentation, nausea and vomiting. He was admitted to a local hospital where a brain scan revealed multiple lesions. Despite external irradiation to the brain metastases, his condition worsened, and he died in August 1976. A postmortem examination was not per- formed.
Case 5. A 39-year-old man developed abdominal pain thought to be caused by peptic ulcer disease in July 1974. In April 1975, a liver scan re- vealed a lesion in the posterior-inferior right lobe and an iv pyelogram showed a left suprarenal mass. Selective arteriograms demonstrated a rather large retroperitoneal neoplasm, and he was referred to M. D. Anderson Hospital in June 1975. On admission a left upper quadrant abdominal mass was palpable, but there was no clinical evidence of excess adrenal hormone secretion and hormonal studies were normal. The pa- tient underwent a left adrenalectomy with re- moval of a 25 × 15-cm tumor weighing 2.2 kg.
A liver scan obtained in the postoperative period showed a posterior defect thought to be secondary to the operation. A follow-up liver scan obtained in December 1975 showed en- largement of posterior defect and therapy with OPDDD was initiated (Table 1). In late May, he developed epigastric discomfort and fur-
ther liver enlargement. A liver scan showed progression of the previous abnormalities and a bone scan was normal (Table 2). A 131I-6-methyl- cholesterol showed suspicious foci in the anterior chest and increased activity around the margins of lesions seen on the liver scan (Fig. 6). The 67Ga scan showed more uptake in the liver le- sions, but failed to show abnormal uptake in the chest. A follow-up chest roentgenogram showed nodular densities in the right medial lung field.
Results
The 131I-6-methyl-cholesterol total-body scintigraphs detected metastatic lesions in 4 of the 5 patients who had previous resections of adrenal cortical carcinoma. Three of the 5 patients had “nonfunctional” neoplasms. All patients were taking OPDDD and pred- nisone or cortisone acetate prior to and dur- ing the time of the scans, and 2 patients were also taking metapirone. A fifth patient (Case 4) had a negative scan while taking both medications and no definite abnormality was seen on a later scan performed 1 week after both medications had been discontinued. Although initial studies, with the exception of a slight elevation in LDH were negative in this patient, he developed brain metas- tases within months and died.
Three patients (Cases 1, 3 and 5) demon- strated increased focal uptake of 1311-6- methyl-cholesterol in liver metastases, which corresponded to focal cold areas de- tected on 99mTc-sulfur-colloid liver scans. Two of these patients showed increased up- take mainly at the margins of the lesions. The 67Ga scans showed a greater degree of uptake in the liver metastases of these same patients. One patient (Case 2) failed to show liver metastases by all 3 procedures, yet at necropsy 1 month later, small liver foci were found.
Skeletal lesions (Cases 1 and 2) were dem- onstrated better by 99mTc-pyrophosphate than by 131I-6-methyl-cholesterol or 67Ga scans. Two patients (Cases 2 and 5) had lung metastases. The 131I-6-methyl-choles- terol scan showed slight increased focal up-
take in the lung lesions of (Case 5), while the 67Ga scan did not show abnormal uptake in these areas. The 48 h 67Ga scan showed uptake in the lung (Case 2), while the 131I-6- methyl-cholesterol scan obtained 8 days after injection failed to demonstrate lung lesions. Precise comparison of 1311-6- methyl-cholesterol and 67Ga scans was not possible, since equivalent doses and time intervals between the dose and scan were not used. In general, both nuclides ap- peared to show similar patterns of uptake in metastatic adrenal cortical carcinoma.
Discussion
Tumor scanning with selective radio- nuclides has been in clinical use since
131I was introduced in the detection and later, therapy of thyroid cancer (10-12). Gallium-67 citrate, indium-111 chloride and indium-111 bleomycin have been shown to have nonspecific affinity for several malig- nant neoplasms (13). Although several meta- bolic precursors have been investigated as possible localizing agents, none have shown satisfactory clinical use in the detection of specific neoplasms (13-14). While 1311-19- iodocholesterol concentrates well in various benign adrenal cortical neoplasms, the con- centrations achieved in adrenal cortical carcinomas have not been sufficient to ob- tain satisfactory images of either primary or metastatic lesions (1,6-8).
Recently, 131I-6-methyl-iodocholesterol has been shown to achieve improved levels
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in adrenal cortical tissue (9). We have been able to measure tissue levels of this nuclide in one patient with adrenal cortical carcinoma (Table 3), and the levels were higher in the metastatic lesions of this pa- tient than those previously reported for 131I-19-iodocholesterol (1,7). Two factors may play a role in this improved concen- tration in the metastatic lesions: 1) Resec- tion of the adrenal cortical carcinoma prior to the adrenal scan procedure reduces competition for the tracer by the primary neoplasm. 2) Cortisone acetate was ad- ministered for several weeks prior to ad- ministration of the radionuclide, which suppressed uptake in the remaining nor- mal adrenal gland.
Sufficient uptake of 1311-6-methyl-choles- terol was achieved to image metastatic le- sions despite simultaneous therapy with OPDDD, which has a cytoxic action on adrenal cortical cells (15-17). This drug might be expected to decrease the con- centration of 1311-6-methyl-cholesterol in adrenal tissue. These same factors, were present in all patients while total body scans were being obtained.
Watanabe et al. have reported scinti- graphic detection of metastatic adrenal cortical carcinoma 4 months following the resection of a left adrenal cortical car- cinoma and postoperative irradiation to the site of the neoplasm (18). A 131I-6-methyl- cholesterol scintigraph showed abnormal uptake in multiple hepatic metastases. Neither hormonal nor chemotherapy had been administered to this patient prior to the scan, and thus differs in that respect from the cases reported here. If a 1311-6-methyl- cholesterol scan could have been obtained in the immediate postoperative period in our patient (Case 5), it might have helped to differentiate between postoperative changes causing a defect in the posterior right lobe of the liver from that due to residual neoplasm.
Our results indicate that it is clinically feasible to image both functional and “non- functional” metastatic adrenal cortical car-
cinoma with 1311-6-methyl-cholesterol and gallium-67 citrate. The 6-methyl analog allows for improved detection of metastatic adrenal cortical carcinoma over 1311-19- iodocholesterol. The scans obtained with 131I-6-methyl-cholesterol were not quali- tatively better than those obtained with gallium-67 citrate. However, the dose of gallium-67 administered was 21/2 times greater. Additional studies are needed not only to assess better the sensitivity and specificity of 1311-6-methyl-cholesterol, but also to determine the effects of hormonal and chemotherapy on its localization in neoplastic tissue. Other analogs (19) or radiolabeled enzymatic inhibitors (20) may allow further progress in the development of adrenal tumor-specific radionuclides.
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