Vol. l O No. 2 February1995 Journal of Pain and Symptom Management 161 Clinical Note A Pain Syndrome Associated with Large Adrenal Metastases in Patients with Lung Cancer Mark S. Berger, MD, Mary E. Cooley, MSN, and Janet L. Abrahm, MD Hematology-Oncolog), Division (M.S.B., M.E.C.,J.LA ), Philadelphia VA Medical Center; and Hematology-Oncology Division (M.S.B., J.L.A.), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Abstract We report two cases of a pain syndrome caused by large adrenal metastases in patients with lung cancer. A review of the literature identified 23 previously reported patients with primary lung cancers who appear to have had a similar syndrome, although in none of these cases were other likely causes of the pain syndrome carefully excluded. The syndrome characteristically includes unilateral flank pain but may have abdominal components as well, and has only been reported in patients with large metastases ~5 cm in largest diameter). Although the mechanism by which large adrenal metastases cause the pain syndrome is not clear, we suggest that treatment that includes local anesthetic agents or steroids may be effective. The pain syndrome caused by large adrenal metastases is not included in reviews of cancer pain syndromes but needs to be considered in the differential diagnosis of patients with lung cancer and flank or abdominal pain.j Pain Symptom Manage 1995;10:161-166. Key Words Adrenal metastases, lung cancer, cancer pain, flank pain Introduction Adrenal metastases due to lung carcinoma are found in approximately 15% of patients at the time of diagnosis I and develop in others during disease progression. They are often asymptomatic, but adrenal insufficiency can occur. 2 Although a number of cases in which pain was believed to be caused by adrenal metastases have been reported, "~-7 the pain that adrenal metastases can cause is not mentioned in reviews of cancer pain syndromes, a-l and the occurrence of this pain syndrome only in patients with large (_>5 cm in largest dimension) adrenal metastases has not been noted. We describe a pain syndrome that occurs in patients with lung cancer and large adrenal metastases, and present data on its incidence in patients with lung cancer. Address reprint requests to: Mark S. Berger, MD, Hematology-Oncology Division, Philadelphia VA Medical Center, University and Woodland Avenues, Philadelphia, PA, USA. Accepted for publication: June 16, 1994. Case Reports Patient 1, a 62-year-old man with a 40-year history of cigarette use, presented with a persistent cough and was found to have a right U.S. Cancer Pain Relief Committee, 1995 0885-3924/95/$9.50 Published by Elsevier, New York, New York SSDI 0885-3924(94)00079-Z
162 Berger et al. Vol. lo No. 2February 1995 a b Fig. 1. Abdominal computerized tomogram of patient 1 (a) at initial presentation and (b) 14 months later at the time of presentation with right adrenal mass (indicated by the arrow). paratracheal mass. Small-cell lung cancer was diagnosed by bronchoscopic biopsy. An abdominal computerized tomogram (CT) showed no adrenal enlargement or other metastases. CT of the head revealed several asymptomatic brain metastases. Whole brain radiation therapy was administered followed by several courses of cytotoxic chemotherapy. The patient was then lost to follow-up. Twenty-three months after initial presentation, he developed
Vol. 10 No. 2 February 1995 Pain with Adrenal Metastases 163 a severe aching pain in the right infrascapular area posteriorly, and on CT scan was found to have a 5 x 5-cm right adrenal mass. The pain was constantly present, worsened during periods of recumbency, and radiated around the right side to the right upper quadrant of the abdomen. There was no shooting or burning component to the pain. He denied dysuria or hematuria. On a scale from 1 to 10, he rated the pain was a 10 at worst and a 5 at best. He noted that when the pain was at its worst it kept him from performing normal physical activity and awakened him from sleep. On physical examination there were no palpable abdominal masses, no costovertebral angle tenderness, and no sensory or motor deficits. He refused cytotoxic chemotherapy. Radiation therapy (3000 cgy) to the right adrenal bed did not reduce his pain, and he was managed with opioids. He had difficulty understanding how to take pain medication effectively, and obtained only minimal pain relief with a regimen of 60 mg per day of controlledrelease oral morphine and two tablets of acetaminophen-oxycodone combination product every 4 hr. A bone scintigram, which was performed to investigate the persistent pain, did not reveal any bony metastases. He ultimately agreed to treatment with cytoxan, adriamycin, and vincristine (CAV) chemotherapy. After two cycles were administered he had virtually complete resolution of the right infrascapular pain. ACT scan performed after a third cycle of CAV chemotherapy revealed a marked decrease in the size of the right adrenal mass. He then developed orthostatic hypotension, which resolved when replacement hydrocortisone was begun empirically. During the chemotherapy treatments, right hip pain developed. Initially this was a pain of low intensity that responded to acetaminophen. Shortly after the third cycle of chemotherapy, however, it progressed to a pain that he rated at a level of 10 at the worst moments, but only a level of 2-3 when resting. The right hip pain was aggravated with ambulation or sitting for long periods of time. A bone scintigram was negative and no new masses were seen on CT. Magnetic resonance imaging (MRI) of the spine showed subarachnoid metastases covering the nerve roots of the cauda equina from L1 to L4. Radiation therapy treatment was begun but was only poorly effective in controlling the hip pain. The right infrascapular pain never recurred. He expired 3 months later, 11 months after the onset of the right infrascapular pain. Patient 2, a 67-year-old man, presented with a lung mass, weight loss of 20 Lb, cough, and left-sided flank pain. The pain was dull and aching in quality and not affected by movement. There was no shooting or burning component to his pain, and it did not radiate. The pain was constantly present, rated at a level of 8 on a scale of 10, and interrupted his sleep at night. The patient's past medical history was significant for chronic use of cigarettes, as well as ethanol abuse and chronic pancreatitis. At presentation there was no evidence for pancreatitis in the history or the laboratory data, and the pain was distinctly left sided. On physical examination there was no costovertebral angle tenderness and no sensory or motor deficits. ACT scan revealed a 3 x 5-cm left adrenal mass, as well as evidence of chronic pancreatitis (parenchymal calcification and beaded pancreatic ducts) and small (1-2 cm) para-aortic lymph nodes. Abdominal CT scan 2 years previously was the same except that it lacked the left adrenal mass and the small lymph nodes. CT guided biopsy of the lung mass and the left adrenal mass documented non-small-cell lung carcinoma at both sites. Bone scintigram was negative for metastatic disease. The flank pain was initially palliated with 30 mg per day of controlled release oral morphine, but it worsened and became associated with intermittent epigastric discomfort. The morphine dose was progressively increased to 120 mg per day, resulting in moderate pain control. Hyperkalemia developed and, despite a normal cosyntropin stimulation test, resolved when hydrocortisone was started. Radiation therapy (3500 cgy) to the left adrenal bed was only moderately successful in controlling the pain. Repeat CT scan after the radiation therapy treatments showed that the left adrenal was further enlarged and several liver metastases were now present. This was accompanied by poor pain control with 420 mg per day of controlled-release oral morphine and adequate doses of immediate-release morphine for breakthrough pain. The patient was admitted to the hospital for treatment of worsening left
164 Berger et al. Vol. l O No. 2February 1995 a b Fig. 2. Abdominal computerized tomogram of patient 2 (a) 2 years prior to presentation with lung cancer and (b) at the time of presentation with left adrenal mass (indicated by the arrow). flank pain, which was controlled with intravenous morphine. He expired 3 days later, 3 months after presentation. Discussion As the two patients reported here illustrate, large adrenal metastases from lung cancer can cause a pain syndrome that has not been noted in reviews of cancer pain. The pain caused by this syndrome is usually unilateral flank pain, but can have abdominal components as well. The defining element of the syndrome is the detection of a large adrenal metastasis on the same side as the flank pain. This "lateral retroperitoneal syndrome" should be added to
Vol. 10 No. 2 February 1995 Pain with Adrenal Metastases 165 the group of retroperitoneal painful lesions that have previously been identified in patients with cancer. 1 The differential diagnosis includes bone and epidural spinal cord metastases, as well as renal diseases such as renal stones. This syndrome is relatively rare, occurring in only two of 217 patients with lung cancers who presented to the Philadelphia VA Lung Tumor Clinic in a 21/2-year period. Nevertheless, this pain should be considered as a potential cause of flank or abdominal pain in patients with primary lung cancers. We attempted to determine if a similar pain syndrome has been described in patients with primary adrenocortical carcinomas. This relatively rare disease has been reported to be associated with abdominal pain in 28%-50% of patients. 11,12 One series concluded that pain as a presenting symptom of adrenocortical carcinoma is found only in those patients not initially seen for signs and symptoms of excess adrenal hormone production. 1"3 This suggests that the pain is found only in locally advanced adrenocortical carcinomas, but a comprehensive description of the natural history of pain in this rare tumor type is not available. As metastatic disease to the adrenal is common in patients with primary lung carcinoma, we performed a literature search to find reports of previous cases with this pain syndrome. Our review of the previous literature documented reports of 23 patients with lung cancer and pain apparently caused by adrenal metastases. ~7 The pain was most often localized to the ipsilateral flank region (11 cases), but was also described as abdominal (ten cases) and more rarely as back pain (two cases). In only five of these cases was the size of the adrenal metastasis noted, and all were 7 cm or larger. Previous authors did not rigorously exclude other potential causes of their patients' pain syndromes. None of the previously reported patients were noted to have both abdominal CT scans and bone scintigrams. Six of the reported patients had CT scans of the abdomen but no bone scintigrams. Two had bone scintigrams and abdominal ultrasound studies. For 15 cases, the studies done to exclude other causes of the pain were not mentioned. None of the case reports make note of neurologic symptoms that would suggest epidural spinal cord metastases, but none specifically note the lack of these symptoms. In only one of the reported cases were symptoms or signs of adrenal insufficiency noted; that patient had orthostatic hypotension, which resolved during radiation therapy treatment of the adrenal metastasis. 6 The differential diagnosis of the pain syndrome of adrenal metastasis includes metastatic lesions to bone, to the epidural space, and to other abdominal or retroperitoneal viscera. Both of the patients reported here had large (>5 cm) adrenal metastases and a severe pain syndrome that was apparently due to their adrenal masses. Both had prior CT scans lacking the enlarged adrenal gland, which appeared at the same time and on the same side as their pain. There was no evidence for bone metastases or other abdominal or retroperitoneal metastases that would explain the pain syndrome in either of these patients, both of whom had bone scintigrams and CT scans performed. Both had evidence of symptomatic hypoadrenalism, suggesting that the other adrenal, although normal in size on CT scan, was also functionally abnormal. MRI scans of the spinal cord were not done initially, but both of these patients lived long enough for other possible metastatic causes of their pain syndromes to progress and become clinically obvious. Patient 1 did develop subarachnoid metastases, which caused pain elsewhere, but this occurred during chemotherapy treatment that caused his right adrenal mass to become smaller, relieving his right infrascapular pain. In addition, the pain from his subarachnoid metastases had a different pattern of aggravating stimuli than that caused by his adrenal mass. Thus, unlike the cases reported previously in the literature, we have documented that the pain syndrome in these two patients was clearly related to their large adrenal metastases. Effective treatment of the adrenal mass usually provides palliation of the pain. Sixteen of the previously reported cases were treated with radiation therapy, with 11 achieving significant palliation of the pain. 5,6 One patient with small-cell lung cancer was treated with cytotoxic chemotherapy, which effectively relieved his pain. 5 Four patients had surgical adrenalectomies, but no reports of their postoperative pain relief are available. :~,4 One of our patients, who had no response to radiation therapy, did obtain pain relief when the small-cell carcinoma responded to cytotoxic chemotherapy, and the other had a short-lived response to radiation therapy treatment. Clearly, a better
166 Berger et al. Vol. 10 No. 2 February 1995 approach to the treatment of this pain syndrome is needed. The cause of pain from adrenal metastases has been hypothesized to be involvement of or pressure on the celiac ganglia that contain visceral afferent fibers. 6 While this may occur in some cases, it would be expected to lead to central abdominal pain and would not cause the distinctly unilateral posterior pain seen in the patients reported here. Although the intensity of the pain syndrome in these two patients suggested neuropathic pain, there were no symptoms or physical exam findings to suggest epidural spinal cord compression or other causes of neuropathic pain. Additional adjustment of the opioid dose administered to these patients may have reduced the intensity of the pain. The occurrence of this pain syndrome only in patients with large (_>5 cm) metastases suggests instead that it is, at least in part, mediated by pressure on, or invasion of, nociceptive nerve endings in the adrenal or adjacent retroperitoneal space. If this is the case, then effective pain relief may be obtained by local anesthetic treatment of thoracic peripheral nerves supplying those regions, or by steroid treatment. These treatment modalities should be tried in future cases, as the present approach to treatment of this pain syndrome has not been uniformly effective. Acknowledgments We thank Dr. Russell Portenoy for helpful discussion and Dr. Dan Haller for critical review of the manuscript. References 1. Silvestri GA, Lenz JE, Harper SN, Morse RA, Colice GL. The relationship of clinical findings to CT scan evidence of adrenal gland metastases in the staging of bronchogenic carcinoma. Chest 1992; 102:1748-1751. 2. Redman BG, Pazdur R, Zingas AP, Loredo R. Prospective evaluation of adrenal insufficiency in patients with adrenal metastasis. Cancer 1987;60: 103-107. 3. Raviv G, Klein E, Yellin A, Schneebaum S, Ben-ari G. Surgical treatment of solitary adrenal metastases from lung carcinoma. J Surg Oncol 1990;43:123-124. 4. Reyes L, Parvez Z, Nemoto T, Regal A, Takita H. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol 1990;44:32-34. 5. Banerjee A, Carvalho P. Back pain, lung cancer and adrenal metastases. Br J Rheumatol 1990;29: 402. 6. Soften EM, Solin LJ, Rubenstein JH, Hanks GE. Palliative radiotherapy for symptomatic adrenal metastases. Cancer 1990;65:1318-1320. 7. Earle MF, LichterJ,Jacobs SA, Stoller RG, Santicky MJ. Adrenal metastases as a cause of flank pain in patients with advanced metastatic cancer [abst]. Proc Am Soc Clin Oncol 1983;2:12. 8. BonicaJJ. The management of pain. Philadelphia: Lea and Febiger, 1990. 9. Foley KM. Management of cancer pain. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. Philadelphia: JB Lippincott, 1993:2417-2448. 10. Cherny NI, Portenoy RK. Cancer pain: principles of assessment and syndromes. In: Melzack R, Wall PD, eds. Textbook of pain. New York: Churchill Livingstone, 1994:787-823. 11. Luton J, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N EnglJ Med 1990;322:1195-1201. 12. Decker RA, Kuehner ME. Adrenocortical carcinoma. Am Surg 1991 ;57:502-513. 13. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992;112:963-971.