Case Challenges

Adenocarcinoma of the lung with isolated adrenal metastasis

A 56-year-old white man was seen in December 2007 for evaluation of a lung mass. The patient presented with chronic cough that prompted a chest X-ray. The X-ray showed a nodule in the right upper lobe. His past medical history was significant for hyperlipidemia and gastroesophageal reflux disease.

His medications were atorvastatin (Lipitor, Pfizer),ranitidine hydrochloride (Zantac, GlaxoSmithKline) and aspirin. The patient did not have any family history of cancer. He had a 40 pack-year smoking history and uses alcohol occasionally.

He had no past exposure to asbestos or chemicals. He denied shortness of breath, weight loss, headaches, dizziness or bone pain. Physical exam did not reveal any cervical, supraclavicular or axillary adenopathy. Cardiac and respiratory examination was normal.

His initial complete blood count and complete metabolic panel were normal. Chest CT revealed a 1.6 cm nodule involving the right upper lobe with cavitation. His PET/CT scan showed increased radiotracer uptake in the right upper lobe. In addition, he was found to have a lesion in his left adrenal gland that was suspicious for metastatic disease. MRI of the brain was normal.

Because since the adrenal gland appeared to be the only site of metastatic disease, resection of the primary tumor and a metastasectomy were planned for an attempt to cure. The patient underwent a video-assisted thoracoscopic mediastinoscopy in January 2008, and the frozen section of the mass showed moderately differentiated adenocarcinoma.

Because since the frozen section did not reveal any positive lymph nodes, the patient then underwent resection of the right upper lobe. One month later, he underwent laparoscopic left adrenalectomy. The final pathology of the adrenal gland was consistent with metastatic adenocarcinoma. His final pathologic staging was T1N0M1. The patient then completed four cycles of adjuvant chemotherapy with cisplatin and vinorelbine in May 2008.

Ramya Varadarajan, MD
Ramya Varadarajan

A follow-up CT scan in October 2008 showed interval increased enhancement and modest size increase in a subcentimeter right adrenal nodule compared with Feburary 2008. A CT scan in January 2009 showed appearance of numerous small subcentimeter pulmonary nodules bilaterally and continued enlargement of a contrast-enhancing right adrenal mass measuring 1.7 cm, compatible with adrenal metastasis.

PET scan showed increased uptake only in the right adrenal gland. The patient was enrolled in a clinical trial and was treated with sorafenib (Nexavar, Bayer) and pemetrexed (Alimta, Eli Lilly). Treatment was discontinued after two cycles due to mixed response, with improvement in pulmonary nodules but disease progression by RECIST criteria (26% increase) in the size of adrenal mass.

The patient was then treated off-protocol with pemetrexed and bevacizumab (Avastin, Genentech) in March and has completed 10 cycles thus far. His last CT scan from November shows stable disease with no appreciable change in the size of the adrenal mass compared with March.

Case Discussion

Although adrenal glands are a common metastatic site for non–small cell lung cancer, metastatic involvement limited to the adrenal gland alone is rare and represents 1.6% to 3.5% of patients presenting with resectable NSCLC. Metastases typically represent widespread systemic dissemination of disease and are associated with poor prognosis. Palliative chemotherapy is generally the accepted method of treatment. Over the last several years, numerous reports and studies have demonstrated that long-term survival after resection of isolated metastasis, such as brain metastasis, can be achieved in selected patient populations when the primary thoracic involvement is early-stage and potentially curable, ie, T1/2N0. A similar approach, but to a lesser extent, has been used in patients presenting with isolated adrenal metastasis as well.

One of the hypotheses for isolated adrenal metastases is that such cases may arise from direct lymphatic spread of the primary lung tumor via retroperitoneal channels representing a locoregional spread, in contrast to systemic spread. An isolated adrenal metastasis is usually defined as a synchronous metastasis if it is diagnosed within six months of the diagnosis of the primary lung cancer. It is deemed a metachronous metastasis if it occurred more than six months from the time of diagnosis of NSCLC.

In a multicenter study of 43 patients, reported by Porte et al, median survival of patients who underwent adrenalectomy was 11 months. Three patients survived longer than five years, suggesting that surgical treatment of solitary adrenal metastasis from resectable NSCLC could potentially improve survival. In this report, there was no significant difference in survival between synchronous and metachronous presentation of adrenal metastases.

In some series, the disease-free interval, which refers to the time from diagnosis of the primary lung cancer until the diagnosis of adrenal metastases, is prognostic. In a study published in the Journal of Clinical Oncology, Tanvetyanon did a retrospective analysis of studies on survival outcomes of adrenalectomy for NSCLC patients. Median overall survival was shorter for patients with synchronous metastasis than those with metachronous metastasis (12 months vs. 31 months, P=.02). The cause for decreased survival among synchronous tumors is probably secondary to the intrinsic biology of the tumors, in that those presenting as synchronous lesions grow faster or are more aggressive.

Surgical complications from adrenalectomy were infrequent in the case series. Studies have indicated that laparoscopic procedures yielded similar results to open procedures, but with less morbidity and a shorter hospital stay. However, the procedure may be limited by the size of the metastasis.

For a lesion 4.5 cm or smaller, survival is equivalent between open adrenalectomy and a laparoscopic approach. Few reports have been published on the role of radiotherapy on adrenal metastases. Soffen and colleagues reported the results of palliative radiotherapy in nine patients with lung carcinoma and an isolated adrenal metastasis, whose median survival was six months.

A key concern in patients presenting with synchronous metastasis is to establish that the adrenal metastasis is truly isolated when the lung cancer itself is otherwise resectable. Management of isolated adrenal metastasis in the context of advanced disease stage intrathoracically (eg, N2 or N3 nodal involvement), which in itself has a poor prognosis, should be approached on a case-to-case basis with the disease-free interval as an important criterion in decision-making.

In patients with clinical stage I or II NSCLC and a supposedly solitary adrenal metastasis, preoperative staging should at least include a PET scan, brain MRI and mediastinoscopy to exclude more advanced stages of disease.

In conclusion, adrenalectomy can be considered for some patients presenting with isolated adrenal metastasis and may improve survival in a selected group of patients, particularly in those with long disease-free interval.

Ramya Varadarajan, MD, is a Medical Oncology Fellow at Roswell Park Cancer Institute, Buffalo, N.Y., and is a member of the HemOnc Today Editorial Board. She would like to acknowledge Dr. Grace Dy for her guidance and support.

PERSPECTIVE

Why lung metastases should have a predilection for tiny adrenal glands is enigmatic. We previously suggested that the slow-flow portal venous structure of the gland (two capillary transitions) may entrap vaso-occlusive tumor emboli. A similar hypothesis can be proferred for the Waterhouse-Friderichsen syndrome of venous occlusive hemorrhage into the gland in complement-activating septic patients, patients in whom C5a aggregates vaso-occlusive granulocyte masses.

– Harry S. Jacob, MD

HemOnc Today Chief Medical Editor

For more information:

  • Ettinghausen SE. J Clin Oncol. 1991;9:1462-1466.
  • Porte HL. Ann Thorac Surg. 2001;71:981-985.
  • Porte HL. Ann Thorac Surg. 1998;65:331-335.
  • Shahidi H. Chest. 1996;109:271-1276.
  • Soffen EM. Cancer. 1990;65:1318-1320.
  • Tanvetyanon T. J Clin Oncol. 2008;26:1142-1147.

A 56-year-old white man was seen in December 2007 for evaluation of a lung mass. The patient presented with chronic cough that prompted a chest X-ray. The X-ray showed a nodule in the right upper lobe. His past medical history was significant for hyperlipidemia and gastroesophageal reflux disease.

His medications were atorvastatin (Lipitor, Pfizer),ranitidine hydrochloride (Zantac, GlaxoSmithKline) and aspirin. The patient did not have any family history of cancer. He had a 40 pack-year smoking history and uses alcohol occasionally.

He had no past exposure to asbestos or chemicals. He denied shortness of breath, weight loss, headaches, dizziness or bone pain. Physical exam did not reveal any cervical, supraclavicular or axillary adenopathy. Cardiac and respiratory examination was normal.

His initial complete blood count and complete metabolic panel were normal. Chest CT revealed a 1.6 cm nodule involving the right upper lobe with cavitation. His PET/CT scan showed increased radiotracer uptake in the right upper lobe. In addition, he was found to have a lesion in his left adrenal gland that was suspicious for metastatic disease. MRI of the brain was normal.

Because since the adrenal gland appeared to be the only site of metastatic disease, resection of the primary tumor and a metastasectomy were planned for an attempt to cure. The patient underwent a video-assisted thoracoscopic mediastinoscopy in January 2008, and the frozen section of the mass showed moderately differentiated adenocarcinoma.

Because since the frozen section did not reveal any positive lymph nodes, the patient then underwent resection of the right upper lobe. One month later, he underwent laparoscopic left adrenalectomy. The final pathology of the adrenal gland was consistent with metastatic adenocarcinoma. His final pathologic staging was T1N0M1. The patient then completed four cycles of adjuvant chemotherapy with cisplatin and vinorelbine in May 2008.

Ramya Varadarajan, MD
Ramya Varadarajan

A follow-up CT scan in October 2008 showed interval increased enhancement and modest size increase in a subcentimeter right adrenal nodule compared with Feburary 2008. A CT scan in January 2009 showed appearance of numerous small subcentimeter pulmonary nodules bilaterally and continued enlargement of a contrast-enhancing right adrenal mass measuring 1.7 cm, compatible with adrenal metastasis.

PET scan showed increased uptake only in the right adrenal gland. The patient was enrolled in a clinical trial and was treated with sorafenib (Nexavar, Bayer) and pemetrexed (Alimta, Eli Lilly). Treatment was discontinued after two cycles due to mixed response, with improvement in pulmonary nodules but disease progression by RECIST criteria (26% increase) in the size of adrenal mass.

The patient was then treated off-protocol with pemetrexed and bevacizumab (Avastin, Genentech) in March and has completed 10 cycles thus far. His last CT scan from November shows stable disease with no appreciable change in the size of the adrenal mass compared with March.

Case Discussion

Although adrenal glands are a common metastatic site for non–small cell lung cancer, metastatic involvement limited to the adrenal gland alone is rare and represents 1.6% to 3.5% of patients presenting with resectable NSCLC. Metastases typically represent widespread systemic dissemination of disease and are associated with poor prognosis. Palliative chemotherapy is generally the accepted method of treatment. Over the last several years, numerous reports and studies have demonstrated that long-term survival after resection of isolated metastasis, such as brain metastasis, can be achieved in selected patient populations when the primary thoracic involvement is early-stage and potentially curable, ie, T1/2N0. A similar approach, but to a lesser extent, has been used in patients presenting with isolated adrenal metastasis as well.

One of the hypotheses for isolated adrenal metastases is that such cases may arise from direct lymphatic spread of the primary lung tumor via retroperitoneal channels representing a locoregional spread, in contrast to systemic spread. An isolated adrenal metastasis is usually defined as a synchronous metastasis if it is diagnosed within six months of the diagnosis of the primary lung cancer. It is deemed a metachronous metastasis if it occurred more than six months from the time of diagnosis of NSCLC.

In a multicenter study of 43 patients, reported by Porte et al, median survival of patients who underwent adrenalectomy was 11 months. Three patients survived longer than five years, suggesting that surgical treatment of solitary adrenal metastasis from resectable NSCLC could potentially improve survival. In this report, there was no significant difference in survival between synchronous and metachronous presentation of adrenal metastases.

In some series, the disease-free interval, which refers to the time from diagnosis of the primary lung cancer until the diagnosis of adrenal metastases, is prognostic. In a study published in the Journal of Clinical Oncology, Tanvetyanon did a retrospective analysis of studies on survival outcomes of adrenalectomy for NSCLC patients. Median overall survival was shorter for patients with synchronous metastasis than those with metachronous metastasis (12 months vs. 31 months, P=.02). The cause for decreased survival among synchronous tumors is probably secondary to the intrinsic biology of the tumors, in that those presenting as synchronous lesions grow faster or are more aggressive.

Surgical complications from adrenalectomy were infrequent in the case series. Studies have indicated that laparoscopic procedures yielded similar results to open procedures, but with less morbidity and a shorter hospital stay. However, the procedure may be limited by the size of the metastasis.

For a lesion 4.5 cm or smaller, survival is equivalent between open adrenalectomy and a laparoscopic approach. Few reports have been published on the role of radiotherapy on adrenal metastases. Soffen and colleagues reported the results of palliative radiotherapy in nine patients with lung carcinoma and an isolated adrenal metastasis, whose median survival was six months.

A key concern in patients presenting with synchronous metastasis is to establish that the adrenal metastasis is truly isolated when the lung cancer itself is otherwise resectable. Management of isolated adrenal metastasis in the context of advanced disease stage intrathoracically (eg, N2 or N3 nodal involvement), which in itself has a poor prognosis, should be approached on a case-to-case basis with the disease-free interval as an important criterion in decision-making.

In patients with clinical stage I or II NSCLC and a supposedly solitary adrenal metastasis, preoperative staging should at least include a PET scan, brain MRI and mediastinoscopy to exclude more advanced stages of disease.

In conclusion, adrenalectomy can be considered for some patients presenting with isolated adrenal metastasis and may improve survival in a selected group of patients, particularly in those with long disease-free interval.

Ramya Varadarajan, MD, is a Medical Oncology Fellow at Roswell Park Cancer Institute, Buffalo, N.Y., and is a member of the HemOnc Today Editorial Board. She would like to acknowledge Dr. Grace Dy for her guidance and support.

PERSPECTIVE

Why lung metastases should have a predilection for tiny adrenal glands is enigmatic. We previously suggested that the slow-flow portal venous structure of the gland (two capillary transitions) may entrap vaso-occlusive tumor emboli. A similar hypothesis can be proferred for the Waterhouse-Friderichsen syndrome of venous occlusive hemorrhage into the gland in complement-activating septic patients, patients in whom C5a aggregates vaso-occlusive granulocyte masses.

– Harry S. Jacob, MD

HemOnc Today Chief Medical Editor

For more information:

  • Ettinghausen SE. J Clin Oncol. 1991;9:1462-1466.
  • Porte HL. Ann Thorac Surg. 2001;71:981-985.
  • Porte HL. Ann Thorac Surg. 1998;65:331-335.
  • Shahidi H. Chest. 1996;109:271-1276.
  • Soffen EM. Cancer. 1990;65:1318-1320.
  • Tanvetyanon T. J Clin Oncol. 2008;26:1142-1147.