Prospective Evaluation of Unilateral Adrenal Masses in Patients With Operable Non-Small-Cell Lung Cancer By Stephen E. Ettinghausen and Michael E. Burt Although adrenal metastases are frequently noted with non-small-cell lung cancer (NSCLC) at autopsy, their incidence in patients with operable NSCLC is unclear. We prospectively assessed consecutive patients with otherwise operable NSCLC for the incidence and histology of unilateral adrenal masses. Assessment included blood chemistries, lung function tests, bronchoscopy, chest x-ray, bone scan, and computed tomography (CT) of the head, chest, and upper abdomen. Of 246 patients with otherwise operable NSCLC, 10 (4.1%) had a unilateral adrenal mass. Unilateral adrenal masses were needle-aspirated under CT control. If cytology was nondiagnostic, adrenalectomy was performed. Four (40%) of 10 patients had adrenal metastases proven by needle aspiration. Of the six (60%) patients with benign unilateral adrenal masses, one was demonstrated by needle aspiration. In the other five patients, a nondiagnostic needle aspiration led to adrenalectomy, which yielded two
A DRENAL METASTASES
originating from non-small-cell carcinoma (NSCLC) are com-
adenomas, two hyperplastic nodules, and one hemorrhagic cyst. There was no significant difference between the patients with benign and metastatic unilateral adrenal masses with respect to patient age or stage and size of adrenal mass. Patients with benign unilateral adrenal masses underwent curative resection of their NSCLC and had significantly prolonged survival compared with patients with metastatic unilateral adrenal masses treated with chemotherapy (P = .037). Median survival of patients with benign and metastatic unilateral adrenal masses was greater than 30 months and 9 months, respectively. In conclusion, the presence of unilateral adrenal masses in patients with otherwise operable NSCLC should not preclude thoracotomy without pathologic proof of metastatic disease. J Clin Oncol 9:1462-1466. o 1991 by American Society of Clinical Oncology.
eral or bilateral adrenal masses in 3% to 18% of patients.6 7' 9
mon and occur in approximately 10% to 59% of
In one series, adrenal masses in 13 of 14 NSCLC patients (93%) were found to repre-
patients in autopsy series." Approximately 9% of
sent metastatic disease as determined by needle-
patients undergoing curative resection of lung cancer may harbor clinically unsuspected me-
aspiration cytology.7 However, histologic confirma-
tastases to the adrenal gland as shown in a series
11 inconsistently pursued in many studies.5,9-
of 202 patients who came to autopsy within 1 month after their pulmonary operation.4
The development of computed tomography (CT) has revolutionized the ability to assess patients
with carcinoma of the lung with respect to extent of primary disease as well as metastatic spread to 8
distant sites, including the adrenals." Evaluation of the adrenal glands in patients with biopsyproven carcinoma of the lung has yielded unilat-
tion of suspected adrenal metastases has been
Most reports addressing the nature of adrenal masses in patients with lung cancer have done so in consecutive patients, many of whom harbored advanced disease. Thus, these studies conclude that metastases account for a relatively high percentage of the adrenal masses found in patients
with lung cancer. However, this conclusion may not be applicable to adrenal masses in patients with otherwise operable or early-stage carcinoma of the lung.
From the Division of Thoracic Surgery, Department of Surgery, Memorial Sloan-Kettering CancerCenter, New York, NY. Submitted October30, 1990; accepted February 11, 1991. Presented in part at the 43rd Annual Meeting of the Society of Surgical Oncology, Washington, DC, May 20-22, 1990. Address reprint requests to Michael E. Burt, MD, PhD, Memorial Sloan-KetteringCancerCenter, 1275 York Ave, New York, NY 10021. b 1991 by American Society of Clinical Oncology. 0732-183X/91/0908-0007$3.00/0
1462
To better understand the importance of adrenal metastases in early-stage lung cancer, the current study was performed to assess prospectively the incidence and pathology of unilateral adrenal masses in operable NSCLC patients who had no other evidence of metastatic disease. Secondly, we assessed the overall survival of these patients with unilateral adrenal masses and otherwise operable NSCLC.
Journal of Clinical Oncology, Vol 9, No 8 (August), 1991: pp 1462-1466
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1463
ADRENAL MASSES IN OPERABLE NSCLC
MATERIALS AND METHODS All patients with potentially operable NSCLC were prospectively assessed by one of the authors (M.E.B.) and were eligible for study. The diagnostic work-up included a complete blood count, renal and liver function tests, pulmonary function tests, flexible fiberoptic bronchoscopy, chest x-rays, radionuclide bone scan, and CT of the head, chest, and upper abdomen (encompassing liver and both adrenal glands). Patients with otherwise operable lung cancer (anatomically and physiologically) except for a unilateral adrenal mass then underwent percutaneous aspiration of the mass with 22 or 19.5 gauge needles under CT guidance using standard techniques. Aspirated material was submitted for cytologic analysis. If a specimen was nondiagnostic, unilateral adrenalectomy was performed. Patients with cytologically or histologically benign adrenal masses subsequently underwent thoracotomy and potentially curative resection, while those with adrenal metastases received cisplatin-based chemotherapy.
StatisticalAnalysis Differences in primary disease stage were calculated by Fisher's exact test. Student's t test was used to compare the two groups with respect to patients' ages and sizes of adrenal mass. Survival was analyzed by the Kaplan-Meier method. Differences in survival were calculated by log-rank analysis. All P values reported are two-tailed.
RESULTS A total of 246 consecutive patients with otherwise operable NSCLC were prospectively assessed. Ten patients (4.1%) had a unilateral adrenal mass. Four of the 10 patients (40%) had adrenal metastases as proven by needle aspiration (Table 1). Thus, 1.6% of all patients with otherwise operable NSCLC had unilateral adrenal metastases. The adrenal metastases measured 3.3 + 0.9 cm (mean + SD). The mean patient age was 58.7 ± 13.1 years. Metastatic disease to the adrenal mass was proven in two patients with one needle-aspiration biopsy, and a second needleaspiration biopsy was required in two patients. The remaining six patients (60%) had a benign unilateral adrenal mass (Table 2). The benign adrenal masses measured 3.2 ± 2.1 cm (mean ± SD).
Table 2. Characteristics of Patients With Benign Adrenal Masses Stage
Adrenal Mass
Age (years)
Sex
Histology
T
N
Side
Size (cm)
68 68 66 37 69 46
F F F M M F
Bronchoolveolar Squamous Bronchoalveolar Squamous Adenocarcinoma Adenocarcinoma
1 2 1 1 2 3
0 2 0 2 1 0
R L L L L L
2.5 1.2 1.8 2.0 5.0 6.5
Abbreviations: F, female; M, male; L, left; R, right.
The mean patient age was 59 ± 13.9 years. Needle-aspiration biopsies of adrenal masses in five of these six patients were nondiagnostic. Of these five patients, three underwent one aspiration, and two aspirations were performed in two patients. Consequently, these five patients underwent adrenalectomy, and pathologic interpretation was adenoma (n = 2), hyperplastic nodule (n = 2), and hemorrhagic cyst (n = 1). Cytologic analysis of material obtained by one needle aspiration in the sixth patient demonstrated a cortical adenoma. After curative resection of a T1 NO bronchoalveolar carcinoma of the right middle lobe, this patient remains alive and disease-free 17 months later. There were no complications from the 14 needle aspirations or the five adrenalectomies. There was no statistically significant difference between benign adrenal masses and adrenal metastases with respect to size (P = .97) or age (P = .93). The stages of primary disease in patients with benign and metastatic adrenal masses were not significantly different (Fig 1). After the initial diagnostic assessment of these 10 patients, the median follow-up time for patients with benign and malignant adrenal masses was 16.5 and 8.5 months, respectively. Survival for
Table 1. Characteristics of Patients With Metastatic Adrenal Masses Stage Age (years)
Sex
52 63 45 75
M M M M
Histology
Squamous Squamous Adenocarcinoma Large cell
Adrenal Mass
T
N
Side
Size (cm)
2 2 3 2
0 2 0 2
L L L R
4.0 2.1 4.0 3.0
Abbreviations: M, male; L,left; R, right; T, tumor; N, node.
Fig 1. Stage of primary disease in patients with adrenal masses and otherwise operable NSCLC. Statistical comparison between patients with metastatic (A) and benign (B) adrenal masses shows no statistically significant difference (P = .38). A: stage II (0), 25%; stage Illa (Q), 75%. B: stage I (0), 33%; stage 11(0), 17%; stage Ilia (0), 50%.
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1464
ETTINGHAUSEN AND BURT
those with malignant and benign adrenal masses is shown in Fig 2. Those with benign adrenal masses had a significantly longer survival (P = .037). The median survival for patients with adrenal metastases treated with chemotherapy was 9 months. In patients with a benign adrenal mass, the median survival had not been reached at 30 months. The one death in the group with a benign adrenal mass occurred 11 months after curative pneumonectomy ard mediastinal lymph node dissection in a 69-year-old male with T2 N1 adenocarcinoma of the left lung. The cause of death was unknown, and he had been free of disease at last follow-up 2 months antemortem. The four patients with metastatic adrenal masses died of widespread metastatic disease 8 to 23 months after initial presentation. DISCUSSION Although adrenal metastases in patients with NSCLC occur in up to 59% of autopsy series, data on the incidence of adrenal metastases in patients with otherwise operable NSCLC are sparse.1' We prospectively screened 246 patients with otherwise operable NSCLC, and using CT, identified 10 patients (4.1%) with a unilateral adrenal mass. By cytologic or histologic analysis, four patients (40%) proved to have adrenal metastases, and six (60%) had benign disease. Thus, 1.6% of all patients with otherwise operable NSCLC had unilateral adrenal metastasis. Patients with benign adrenal enlargement subsequently underwent curative resection of their primary lung cancer and have had significantly longer overall survival than patients with adrenal metastases treated with chemotherapy. 1 0.8 0.6 0.4 0.2
0 0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 Time (months)
Fig 2. Overall survival of patients with otherwise operable NSCLC and benign (O, n = 6) and malignant (*, n = 4) adrenal masses. Statistical comparison of the overall survival for the two patient groups demonstrates a significant differ-
ence (P = .037). Median follow-up time for patients with benign and metastatic adrenal masses is 16.5 and 8.5 months, respectively.
The median survival of 9 months for patients with adrenal metastases is similar to the median survival reported in large series of patients with metastatic NSCLC.'4 All four patients in the
present series died with not only progressive disease at the primary site and adrenal gland but also at other typical locations for metastatic spread. Here, the presence of unilateral adrenal metastasis appeared to be a harbinger of wide-spread systemic disease, although later systemic spread from in situ primary disease after the initial diagnosis may also have occurred. By contrast, rare patients with lung cancer and solitary adrenal metastases may experience long-term survival after adrenalectomy and intensive treatment of their primary site by surgery or radiation." Similarly, unifocal brain metastases from different primary cancers without other evidence of spread may, in selected patients, be amenable to craniotomy and curative resection with long-term survival. 6 The incidence of adrenal masses in clinical studies of patients with NSCLC is generally higher (10% to 18%) in previous reports as compared with the current series.7 '10'12 Moreover, the incidence of metastatic lung cancer as the cause of adrenal masses may be as high as 93% in contrast to the 40% incidence in our report.' The apparent disparity in results emanates from the different composition of the patient cohorts, since other reports have frequently surveyed consecutive patients with NSCLC, many of whom have advancedstage disease. Furthermore, patients with unilateral as well as bilateral adrenal masses have been included in the analysis. Cytologic or histologic verification of presumed adrenal metastases has been omitted in up to 80% to 85% of patients with lung cancer.5,9-12 In these retrospective studies, metastatic disease involving the adrenal gland has been suggested when presumed spread of disease is noted at other sites, an increase in adrenal size is observed on serial CT scans, or pathologic proof is gathered at autopsy. Unfortunately, the determination of benignity or malignancy of adrenal masses by serial CT scanning over several months adds unnecessary delay in the institution of definitive treatment. Clearly, in the present report of prospectively gathered patients, the assumption that a unilateral adrenal mass in a patient with NSCLC represented metastatic disease would have precluded thoracotomy and.potentially curative resection in
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1465
ADRENAL MASSES IN OPERABLE NSCLC 60% of our patients. As demonstrated in two autopsy series surveying 8,176 patients, incidental adrenal adenomas occur with an incidence of 3.4%.17'" With the widespread use of CT, clinically inapparent adrenal masses unrelated to the primary indication for scanning have been reported in 0.7% of patients. '9"' This incidence will undoubtedly rise with technologic improvements in CT. Despite the significant incidence of abnormal adrenal glands due to benign disease in the general population and in patients with early-stage lung cancer, adrenal glands with a normal appearance on C- in patients with NSCLC may also contain metastatic cancer.7 In a surprising and worrisome report, Pagani found a 12% incidence of adrenal metastases using fine-needle aspiration in 32 patients with NSCLC and normal adrenal glands. The problem of a falsely negative adrenal gland assessment by CT has recently been readdressed by Allard et al. 21 The authors retrospectively reviewed 91 autopsied lung cancer patients who underwent abdominal CT within 90 days of death. Of 53 adrenal glands with histologically verified metastases, the CT was interpreted as positive in 20.0% to 41.1%, depending on the radiologist's positivity threshold. With a specificity of 84.5% to 99.4% by CT, the investigators concluded that, with a highly suspicious scan for adrenal metastases, confirmatory biopsy may not be necessary. However, these recommendations are based on patients with small-cell lung cancer and NSCLC undergoing autopsy and presumably with widespread disease. Thus, these conclusions may not be applicable to the population of patients with early-stage NSCLC that we describe. In the present series, a cytologic diagnosis of malignancy had a 100% accuracy rate. All four
patients with cytologically proven adrenal metastases developed further enlargement of their mass on serial follow-up scans and eventually succumbed to their cancer. Although critically dependent on the skill of the cytologist, the reliability of needle-aspiration cytology of adrenal metastases has been suggested by other authors.7. 2' 3'"22 In the current report, a benign diagnosis by aspiration cytology could only be made in one of six patients, or 17%. This patient, who had an adrenal adenoma, remains alive and disease-free 17 months after curative resection of her T1 NO bronchoalveolar carcinoma of the right lung. Nondiagnostic aspirations were obtained in the other five patients. Accordingly, adrenalectomy was performed, and benign disease was found in all five. With cytologic analysis, benign disease has been established as the cause of adrenal enlargement in 5% to 56% of patients with different primary cancers, including NSCLC.7.'12
9 222
In many cases,
however, the finding of normal adrenal tissue after attempted aspiration of an adrenal mass may generate doubt as to whether the mass or adjacent tissue was truly sampled. Moreover, follow-up data are not always complete, and the true benignity of the adrenal mass as judged by cytology cannot be totally assured. In conclusion, an adrenal mass found in a patient with otherwise operable NSCLC should be systematically assessed by fine-needle aspiration biopsy. If a definitive diagnosis cannot be made, then adrenalectomy should be carried out to unequivocally establish the correct diagnosis. Sixty percent of patients with operable NSCLC and a unilateral adrenal mass will have benign adrenal disease and, therefore, remain candidates for thoracotomy and potentially curative resection.
REFERENCES 1. Abrams IlL, Sprio R, Goldstein N: Metastases in carcinoma: Analysis of 1000 autopsied cases. Cancer 3:7485, 1950 2. Englemen RM, McNamara WL: Bronchogenic carcinoma: A statistical review of two hundred twenty-four autopsies. J Thorac Surg 27:227-237, 1954 3. Matthews MJ: Problems in morphology and behavior of bronchopulmonary malignant disease, in Israel L, Chahinian AL (eds): Lung Cancer: Natural History, Prognosis, and Therapy. San Diego, CA, Academic Press, 1976, pp 23-62 4. Matthews MJ, Kanhouwa S, Pickren J, et al: Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer Chemother Rep 4:63-67, 1973
5. Dunnick NR, Ihde DC, Early-Johnson A: Abdominal CT in the evaluation of small cell carcinoma of the lung. Am J Roentgenol 133:1085-1088, 1979 6. Harper PG, Houang M, Spiro SG, et al: Computerized axial tomography in the pretreatrment assessment of smallcell carcinoma of the bronchus. Cancer 47:1775-1780, 1981 7. Pagani JJ: Non-small cell carcinoma adrenal metastases: Computed tomography and percutaneous needle biopsy in their diagnosis. Cancer 53:1058-1060, 1984 8. Katz RL, Shirkhoda A: Diagnostic approach to incidental adrenal nodules in the cancer patient: Results of a clinical, radiologic, and fine needle aspiration study. Cancer 55:1995-2000, 1985 9. Vas W, Zylak CJ, Mather D, et al: The value of
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1466
ETTINGHAUSEN AND BURT
abdominal computed tomography in the pre-treatment assessment of small cell carcinoma of the lung. Radiology 138:417-418, 1981 10. Nielson ME Jr, Heaston DK, Dunnick NR, et al: Preoperative CT evaluation of adrenal glands in non-small cell bronchogenic carcinoma. Am J Roentgenol 139:317320, 1982 11. Sandler MA, Pearlberg JL, Madrazo BL, et al: Computed tomographic evaluation of the adrenal gland in the preoperative assessment of bronchogenic carcinoma. Radiology 145:733-736, 1982 12. Oliver TW, Bernardino ME, Miller JI, et al: Isolated adrenal masses in nonsmall-cell bronchogenic carcinoma. Radiology 153:217-218, 1984 13. Whittlesey D: Prospective computed tomographic scanning in the staging of bronchogenic cancer. J Thorac Cardiovasc Surg 95:876-882, 1988 14. Minna JD, Pass H, Glatstein E, et al: Cancer of the lung, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 3rd ed. Philadelphia, PA, Lippincott, 1989, pp 591-705 15. Twomey P, Montgomery C, Clark O: Successful treatment of adrenal metastases from large-cell carcinoma of the lung. JAMA 248:581-583, 1982 16. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494-500, 1990
17. Commons RR, Callaway CP: Adenomas of the adrenal cortex. Arch Int Med 81:37-41, 1948 18. Hedeland H, Ostberg G, Hokfelt B: On the prevalence of adrenocortical adenomas in autopsy material in relation to hypertension and diabetes. Acta Med Scand 184:211-214, 1968 19. Glazer HS, Weyman PJ, Sagel SS, et al: Nonfunctioning adrenal masses: Incidental discovery on computed tomography. Am J Roentgenol 139:81-85, 1982 20. Belldegrun A, Hussain S, Seltzer SE, et al: Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 163:203-208, 1986 21. Allard P, Yankaskas BC, Fletcher RH, et al: Sensitivity and specificity of computed tomography for the detection of adrenal metastatic lesions among 91 autopsied lung cancer patients. Cancer 66:457-462, 1990 22. Berkman WA, Bernardino ME, Sewell CW, et al: The computed tomography-guided adrenal biopsy: An alternative to surgery in adrenal mass diagnosis. Cancer 53:20982103, 1984 23. Bernardino ME, Walther M, Phillips VM, et al: CT-guided adrenal biopsy: Accuracy, safety, and indications. Am J Roentgenol 144:67-69, 1985 24. Katz RL, Shirkhoda A: Diagnostic approach to incidental adrenal nodules in the cancer patient. Cancer 55:19952000, 1985
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A DRENAL METASTASES
originating from non-small-cell carcinoma (NSCLC) are com-
adenomas, two hyperplastic nodules, and one hemorrhagic cyst. There was no significant difference between the patients with benign and metastatic unilateral adrenal masses with respect to patient age or stage and size of adrenal mass. Patients with benign unilateral adrenal masses underwent curative resection of their NSCLC and had significantly prolonged survival compared with patients with metastatic unilateral adrenal masses treated with chemotherapy (P = .037). Median survival of patients with benign and metastatic unilateral adrenal masses was greater than 30 months and 9 months, respectively. In conclusion, the presence of unilateral adrenal masses in patients with otherwise operable NSCLC should not preclude thoracotomy without pathologic proof of metastatic disease. J Clin Oncol 9:1462-1466. o 1991 by American Society of Clinical Oncology.
eral or bilateral adrenal masses in 3% to 18% of patients.6 7' 9
mon and occur in approximately 10% to 59% of
In one series, adrenal masses in 13 of 14 NSCLC patients (93%) were found to repre-
patients in autopsy series." Approximately 9% of
sent metastatic disease as determined by needle-
patients undergoing curative resection of lung cancer may harbor clinically unsuspected me-
aspiration cytology.7 However, histologic confirma-
tastases to the adrenal gland as shown in a series
11 inconsistently pursued in many studies.5,9-
of 202 patients who came to autopsy within 1 month after their pulmonary operation.4
The development of computed tomography (CT) has revolutionized the ability to assess patients
with carcinoma of the lung with respect to extent of primary disease as well as metastatic spread to 8
distant sites, including the adrenals." Evaluation of the adrenal glands in patients with biopsyproven carcinoma of the lung has yielded unilat-
tion of suspected adrenal metastases has been
Most reports addressing the nature of adrenal masses in patients with lung cancer have done so in consecutive patients, many of whom harbored advanced disease. Thus, these studies conclude that metastases account for a relatively high percentage of the adrenal masses found in patients
with lung cancer. However, this conclusion may not be applicable to adrenal masses in patients with otherwise operable or early-stage carcinoma of the lung.
From the Division of Thoracic Surgery, Department of Surgery, Memorial Sloan-Kettering CancerCenter, New York, NY. Submitted October30, 1990; accepted February 11, 1991. Presented in part at the 43rd Annual Meeting of the Society of Surgical Oncology, Washington, DC, May 20-22, 1990. Address reprint requests to Michael E. Burt, MD, PhD, Memorial Sloan-KetteringCancerCenter, 1275 York Ave, New York, NY 10021. b 1991 by American Society of Clinical Oncology. 0732-183X/91/0908-0007$3.00/0
1462
To better understand the importance of adrenal metastases in early-stage lung cancer, the current study was performed to assess prospectively the incidence and pathology of unilateral adrenal masses in operable NSCLC patients who had no other evidence of metastatic disease. Secondly, we assessed the overall survival of these patients with unilateral adrenal masses and otherwise operable NSCLC.
Journal of Clinical Oncology, Vol 9, No 8 (August), 1991: pp 1462-1466
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1463
ADRENAL MASSES IN OPERABLE NSCLC
MATERIALS AND METHODS All patients with potentially operable NSCLC were prospectively assessed by one of the authors (M.E.B.) and were eligible for study. The diagnostic work-up included a complete blood count, renal and liver function tests, pulmonary function tests, flexible fiberoptic bronchoscopy, chest x-rays, radionuclide bone scan, and CT of the head, chest, and upper abdomen (encompassing liver and both adrenal glands). Patients with otherwise operable lung cancer (anatomically and physiologically) except for a unilateral adrenal mass then underwent percutaneous aspiration of the mass with 22 or 19.5 gauge needles under CT guidance using standard techniques. Aspirated material was submitted for cytologic analysis. If a specimen was nondiagnostic, unilateral adrenalectomy was performed. Patients with cytologically or histologically benign adrenal masses subsequently underwent thoracotomy and potentially curative resection, while those with adrenal metastases received cisplatin-based chemotherapy.
StatisticalAnalysis Differences in primary disease stage were calculated by Fisher's exact test. Student's t test was used to compare the two groups with respect to patients' ages and sizes of adrenal mass. Survival was analyzed by the Kaplan-Meier method. Differences in survival were calculated by log-rank analysis. All P values reported are two-tailed.
RESULTS A total of 246 consecutive patients with otherwise operable NSCLC were prospectively assessed. Ten patients (4.1%) had a unilateral adrenal mass. Four of the 10 patients (40%) had adrenal metastases as proven by needle aspiration (Table 1). Thus, 1.6% of all patients with otherwise operable NSCLC had unilateral adrenal metastases. The adrenal metastases measured 3.3 + 0.9 cm (mean + SD). The mean patient age was 58.7 ± 13.1 years. Metastatic disease to the adrenal mass was proven in two patients with one needle-aspiration biopsy, and a second needleaspiration biopsy was required in two patients. The remaining six patients (60%) had a benign unilateral adrenal mass (Table 2). The benign adrenal masses measured 3.2 ± 2.1 cm (mean ± SD).
Table 2. Characteristics of Patients With Benign Adrenal Masses Stage
Adrenal Mass
Age (years)
Sex
Histology
T
N
Side
Size (cm)
68 68 66 37 69 46
F F F M M F
Bronchoolveolar Squamous Bronchoalveolar Squamous Adenocarcinoma Adenocarcinoma
1 2 1 1 2 3
0 2 0 2 1 0
R L L L L L
2.5 1.2 1.8 2.0 5.0 6.5
Abbreviations: F, female; M, male; L, left; R, right.
The mean patient age was 59 ± 13.9 years. Needle-aspiration biopsies of adrenal masses in five of these six patients were nondiagnostic. Of these five patients, three underwent one aspiration, and two aspirations were performed in two patients. Consequently, these five patients underwent adrenalectomy, and pathologic interpretation was adenoma (n = 2), hyperplastic nodule (n = 2), and hemorrhagic cyst (n = 1). Cytologic analysis of material obtained by one needle aspiration in the sixth patient demonstrated a cortical adenoma. After curative resection of a T1 NO bronchoalveolar carcinoma of the right middle lobe, this patient remains alive and disease-free 17 months later. There were no complications from the 14 needle aspirations or the five adrenalectomies. There was no statistically significant difference between benign adrenal masses and adrenal metastases with respect to size (P = .97) or age (P = .93). The stages of primary disease in patients with benign and metastatic adrenal masses were not significantly different (Fig 1). After the initial diagnostic assessment of these 10 patients, the median follow-up time for patients with benign and malignant adrenal masses was 16.5 and 8.5 months, respectively. Survival for
Table 1. Characteristics of Patients With Metastatic Adrenal Masses Stage Age (years)
Sex
52 63 45 75
M M M M
Histology
Squamous Squamous Adenocarcinoma Large cell
Adrenal Mass
T
N
Side
Size (cm)
2 2 3 2
0 2 0 2
L L L R
4.0 2.1 4.0 3.0
Abbreviations: M, male; L,left; R, right; T, tumor; N, node.
Fig 1. Stage of primary disease in patients with adrenal masses and otherwise operable NSCLC. Statistical comparison between patients with metastatic (A) and benign (B) adrenal masses shows no statistically significant difference (P = .38). A: stage II (0), 25%; stage Illa (Q), 75%. B: stage I (0), 33%; stage 11(0), 17%; stage Ilia (0), 50%.
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1464
ETTINGHAUSEN AND BURT
those with malignant and benign adrenal masses is shown in Fig 2. Those with benign adrenal masses had a significantly longer survival (P = .037). The median survival for patients with adrenal metastases treated with chemotherapy was 9 months. In patients with a benign adrenal mass, the median survival had not been reached at 30 months. The one death in the group with a benign adrenal mass occurred 11 months after curative pneumonectomy ard mediastinal lymph node dissection in a 69-year-old male with T2 N1 adenocarcinoma of the left lung. The cause of death was unknown, and he had been free of disease at last follow-up 2 months antemortem. The four patients with metastatic adrenal masses died of widespread metastatic disease 8 to 23 months after initial presentation. DISCUSSION Although adrenal metastases in patients with NSCLC occur in up to 59% of autopsy series, data on the incidence of adrenal metastases in patients with otherwise operable NSCLC are sparse.1' We prospectively screened 246 patients with otherwise operable NSCLC, and using CT, identified 10 patients (4.1%) with a unilateral adrenal mass. By cytologic or histologic analysis, four patients (40%) proved to have adrenal metastases, and six (60%) had benign disease. Thus, 1.6% of all patients with otherwise operable NSCLC had unilateral adrenal metastasis. Patients with benign adrenal enlargement subsequently underwent curative resection of their primary lung cancer and have had significantly longer overall survival than patients with adrenal metastases treated with chemotherapy. 1 0.8 0.6 0.4 0.2
0 0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 Time (months)
Fig 2. Overall survival of patients with otherwise operable NSCLC and benign (O, n = 6) and malignant (*, n = 4) adrenal masses. Statistical comparison of the overall survival for the two patient groups demonstrates a significant differ-
ence (P = .037). Median follow-up time for patients with benign and metastatic adrenal masses is 16.5 and 8.5 months, respectively.
The median survival of 9 months for patients with adrenal metastases is similar to the median survival reported in large series of patients with metastatic NSCLC.'4 All four patients in the
present series died with not only progressive disease at the primary site and adrenal gland but also at other typical locations for metastatic spread. Here, the presence of unilateral adrenal metastasis appeared to be a harbinger of wide-spread systemic disease, although later systemic spread from in situ primary disease after the initial diagnosis may also have occurred. By contrast, rare patients with lung cancer and solitary adrenal metastases may experience long-term survival after adrenalectomy and intensive treatment of their primary site by surgery or radiation." Similarly, unifocal brain metastases from different primary cancers without other evidence of spread may, in selected patients, be amenable to craniotomy and curative resection with long-term survival. 6 The incidence of adrenal masses in clinical studies of patients with NSCLC is generally higher (10% to 18%) in previous reports as compared with the current series.7 '10'12 Moreover, the incidence of metastatic lung cancer as the cause of adrenal masses may be as high as 93% in contrast to the 40% incidence in our report.' The apparent disparity in results emanates from the different composition of the patient cohorts, since other reports have frequently surveyed consecutive patients with NSCLC, many of whom have advancedstage disease. Furthermore, patients with unilateral as well as bilateral adrenal masses have been included in the analysis. Cytologic or histologic verification of presumed adrenal metastases has been omitted in up to 80% to 85% of patients with lung cancer.5,9-12 In these retrospective studies, metastatic disease involving the adrenal gland has been suggested when presumed spread of disease is noted at other sites, an increase in adrenal size is observed on serial CT scans, or pathologic proof is gathered at autopsy. Unfortunately, the determination of benignity or malignancy of adrenal masses by serial CT scanning over several months adds unnecessary delay in the institution of definitive treatment. Clearly, in the present report of prospectively gathered patients, the assumption that a unilateral adrenal mass in a patient with NSCLC represented metastatic disease would have precluded thoracotomy and.potentially curative resection in
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 21, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1465
ADRENAL MASSES IN OPERABLE NSCLC 60% of our patients. As demonstrated in two autopsy series surveying 8,176 patients, incidental adrenal adenomas occur with an incidence of 3.4%.17'" With the widespread use of CT, clinically inapparent adrenal masses unrelated to the primary indication for scanning have been reported in 0.7% of patients. '9"' This incidence will undoubtedly rise with technologic improvements in CT. Despite the significant incidence of abnormal adrenal glands due to benign disease in the general population and in patients with early-stage lung cancer, adrenal glands with a normal appearance on C- in patients with NSCLC may also contain metastatic cancer.7 In a surprising and worrisome report, Pagani found a 12% incidence of adrenal metastases using fine-needle aspiration in 32 patients with NSCLC and normal adrenal glands. The problem of a falsely negative adrenal gland assessment by CT has recently been readdressed by Allard et al. 21 The authors retrospectively reviewed 91 autopsied lung cancer patients who underwent abdominal CT within 90 days of death. Of 53 adrenal glands with histologically verified metastases, the CT was interpreted as positive in 20.0% to 41.1%, depending on the radiologist's positivity threshold. With a specificity of 84.5% to 99.4% by CT, the investigators concluded that, with a highly suspicious scan for adrenal metastases, confirmatory biopsy may not be necessary. However, these recommendations are based on patients with small-cell lung cancer and NSCLC undergoing autopsy and presumably with widespread disease. Thus, these conclusions may not be applicable to the population of patients with early-stage NSCLC that we describe. In the present series, a cytologic diagnosis of malignancy had a 100% accuracy rate. All four
patients with cytologically proven adrenal metastases developed further enlargement of their mass on serial follow-up scans and eventually succumbed to their cancer. Although critically dependent on the skill of the cytologist, the reliability of needle-aspiration cytology of adrenal metastases has been suggested by other authors.7. 2' 3'"22 In the current report, a benign diagnosis by aspiration cytology could only be made in one of six patients, or 17%. This patient, who had an adrenal adenoma, remains alive and disease-free 17 months after curative resection of her T1 NO bronchoalveolar carcinoma of the right lung. Nondiagnostic aspirations were obtained in the other five patients. Accordingly, adrenalectomy was performed, and benign disease was found in all five. With cytologic analysis, benign disease has been established as the cause of adrenal enlargement in 5% to 56% of patients with different primary cancers, including NSCLC.7.'12
9 222
In many cases,
however, the finding of normal adrenal tissue after attempted aspiration of an adrenal mass may generate doubt as to whether the mass or adjacent tissue was truly sampled. Moreover, follow-up data are not always complete, and the true benignity of the adrenal mass as judged by cytology cannot be totally assured. In conclusion, an adrenal mass found in a patient with otherwise operable NSCLC should be systematically assessed by fine-needle aspiration biopsy. If a definitive diagnosis cannot be made, then adrenalectomy should be carried out to unequivocally establish the correct diagnosis. Sixty percent of patients with operable NSCLC and a unilateral adrenal mass will have benign adrenal disease and, therefore, remain candidates for thoracotomy and potentially curative resection.
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abdominal computed tomography in the pre-treatment assessment of small cell carcinoma of the lung. Radiology 138:417-418, 1981 10. Nielson ME Jr, Heaston DK, Dunnick NR, et al: Preoperative CT evaluation of adrenal glands in non-small cell bronchogenic carcinoma. Am J Roentgenol 139:317320, 1982 11. Sandler MA, Pearlberg JL, Madrazo BL, et al: Computed tomographic evaluation of the adrenal gland in the preoperative assessment of bronchogenic carcinoma. Radiology 145:733-736, 1982 12. Oliver TW, Bernardino ME, Miller JI, et al: Isolated adrenal masses in nonsmall-cell bronchogenic carcinoma. Radiology 153:217-218, 1984 13. Whittlesey D: Prospective computed tomographic scanning in the staging of bronchogenic cancer. J Thorac Cardiovasc Surg 95:876-882, 1988 14. Minna JD, Pass H, Glatstein E, et al: Cancer of the lung, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 3rd ed. Philadelphia, PA, Lippincott, 1989, pp 591-705 15. Twomey P, Montgomery C, Clark O: Successful treatment of adrenal metastases from large-cell carcinoma of the lung. JAMA 248:581-583, 1982 16. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494-500, 1990
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