ORIGINAL ARTICLE - ENDOCRINE TUMORS
Malignant Adrenal Neoplasm Masquerading as Worrisome Adrenal Hemorrhage
Luis A. Benavente-Chenhalls, MD1, Adrian Vella, MD2, David R. Farley, MD1, Geoffrey B. Thompson, MD1, Clive S. Grant, MD1, and Melanie L. Richards, MD1
1Division of Gastroenterologic and General Surgery, Mayo Clinic College of Medicine, Rochester, MN; 2Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
ABSTRACT
Background. Adrenal hemorrhage (AH) associated with adrenal neoplasm is rare. This study assesses the clinical and pathological impact of AH in the setting of malignant adrenal neoplasm to establish management strategies.
Materials and Methods. Patients admitted over a 25-year period with a diagnosis of AH and malignant adrenal neoplasm were retrospectively reviewed.
Results. Malignant adrenal neoplasms were reported in 14 of 217 patients (6.4%) presenting with AH. Of these, 4 were women. Mean age was 56 years. The most common presenting symptom was abdominal pain (n = 6), followed by altered mental status and shock (2) and hypercortisolism (1). Five patients were asymptomatic. In 10 patients the adrenal tumor was metastatic. Four patients had adreno- cortical carcinoma (ACC). All primary adrenal tumors were unilateral. Risk factors for AH were identified in 5 patients (anticoagulation, 3; trauma, 1; and recent surgery, 1). Computed tomography (n = 12) demonstrated adrenal masses ranging in size from 6.8 to 11.0 cm (mean, 9 cm). Nine patients were managed by surgical resection (adre- nalectomy, 4; radical nephrectomy, 2; adrenalectomy/ splenectomy, 1; adrenalectomy/bowel resection, 1; and laparotomy and packing, 1) Actual survival time ranged from 9 days to 7.8 years (median 329 days).
Conclusion. Most patients with AH in the setting of malignant adrenal neoplasm had metastatic tumors to the adrenal glands. These patients do not typically present in hemorrhagic shock, allowing for adequate preoperative
evaluation for function and assessment for primary tumors. Long-term survival of these patients is rare.
Adrenal hemorrhage (AH) is a life-threatening condition that can lead to patient demise from massive bleeding or from untreated adrenal insufficiency. It has historically been a diagnosis made on postmortem evaluation, with bilateral adrenal hemorrhage occurring in 1% of autopsies.1 A review from the Mayo Clinic evaluated 141 patients with AH who were without known underlying adrenal disease or malignancy.2 The majority of cases of AH were found at autopsy or in patients with severe stress or sepsis. The underlying causes were variable, and AH was classified into seven categories: incidentalomas, spontaneous AH, AH associated with antiphospholipid syndrome and hepa- rin associated thrombocytopenia, postoperative AH, AH associated with anticoagulation therapy, AH associated with trauma, and AH associated with severe stress or sepsis. A high index of suspicion, treatment of possible adrenal insufficiency, and early imaging with computed tomography (CT) can establish the diagnosis in a timely fashion.2
There are few reports of adrenal hemorrhage (AH) associated with malignant neoplasm and no evidence-based guidelines to assist the management of patients with coincident AH and neoplasm. This study assesses the clinical and pathological impact of AH in the setting of adrenal neoplasms in an attempt to establish management strategies.
PATIENTS AND METHODS
With approval from our Institution Review Board, we performed a computer search of adult patients (age > 16 years) with the diagnosis of AH or adrenal hematoma
@ Society of Surgical Oncology 2010
Published Online: 25 May 2010
with a concomitant malignant adrenal mass between the years 1976 and 2001. We identified 217 patients with the diagnosis of adrenal hemorrhage or hematoma; 14 of them had the concomitant diagnosis of adrenal cancer or malig- nancy. We retrospectively reviewed these patient charts and collected the data in a standardized manner to include demographic characteristics, past medical and surgical history, clinical presentation, radiologic stud ies, inter- ventions, procedures, treatments, pathology, and patient outcomes.
RESULTS
From a total of 217 patients with AH or adrenal hema- toma, 14 adults had a concomitant adrenal malignancy. Mean age of the study group was 56 years (range 26-79). Of the 14 patients, 4 were female and 10 were male.
The presenting signs and symptoms included: upper abdominal pain in 6 patients, mental status changes and shock in 2 patients, and 1 with hypercortisolism (glucose intolerance, central obesity, and rounded face). Also, 5 patients were asymptomatic, and 4 of them had the lesion found incidentally during workup for a known nonadrenal malignancy.
In addition to the malignancy, in 5 patients other factors predisposing to AH were identified. At the time of diag- nosis, 3 patients were on anticoagulation (warfarin n = 2, subcutaneous heparin n = 1). Also, 1 patient had the onset of symptoms following blunt trauma, and 1 developed AH shortly after surgical resection of the bladder for treatment of transitional cell carcinoma of the bladder.
CT scans showed large heterogeneous masses suspicious for AH in 12 patients; 6 of 12 had objective measurements ranging from 6.8 to 11.0 cm (mean = 9.0 cm). Images were not available for review in the rest, and a measure- ment was not stated in the radiologist dictation. In 1 patient the diagnosis was made intraoperatively. A postmortem diagnosis was made in 1 case.
There were 9 patients managed by surgical resection: 4 had adrenalectomy, 2 had nephrectomy plus adrenalec- tomy, 1 had adrenalectomy with incidental splenectomy, 1 had adrenalectomy and bowel resection, and 1 had exploratory laparotomy and packing to control hemor- rhage. All 9 patient were operated on using an open technique; the mean surgical time was 136 min (range 62-210 min). The mean estimated blood loss was 1791 mL (median 425 mL, range 100-10,750 mL). There were 2 patients operated on emergently, with hypovolemic shock. Also, 2 patients developed intraoperative complications; 1 patient had a splenic injury requiring unplanned splenec- tomy and 1 massive hemorrhage and coagulopathy requiring packing and second-look laparotomy.
Adrenal metastasis was confirmed on percutaneous biopsies in 2 patients, and further therapy was not pursued because of the advanced stage of their disease (non-small- cell carcinoma of lung and chondrosarcoma). Also, 3 patients died prior to intervention (including 1 where the diagnosis was made at autopsy). None of these 3 patients died as a complication of hemorrhage.
Metastatic cancer to the adrenal gland was seen in 10 patients; the primary malignancy was lung (3), kidney (2), colon, thyroid, bladder, soft tissue, and bone (1 each). Adrenocortical carcinoma (ACC) were found in 4 patients: All patients with primary tumors had unilateral hemor- rhage, and 2 patients with metastatic lesions presented with bilateral hemorrhage. The 2 patients had known bilateral metastasis to the adrenal glands; 1 of the patients with bilateral hemorrhage presented with abdominal pain, and 1 presented with mental status changes and shock.
At the time of this review, all patients had died conse- quent to their malignancy. Actual survival time from the date of intervention ranged from 9 days to 7.8 years (mean = 675 days, median = 329 days). The 4 patients with ACC had a median survival of 21 months, mean survival 36 months (range 3 months to 5.5 years). Mean survival for 9 patients with metastatic tumors was 7 months, median survival 10 months (range 9 days to 7.8 years).
Autopsies were performed on 3 patients. Each had a known primary tumor, but only 2 had AH seen on a CT scan prior to death. In the remaining patient, the post- mortem diagnosis of AH was made incidentally. None of the tumors diagnosed during autopsy were primary adrenal cancer.
DISCUSSION
Adrenal hemorrhage associated with malignancy of the adrenal gland is uncommon. The majority of the literature consists of case reports in which AH alerted physicians to the presence of adrenal tumors.3-5 Only 6.4% of our patients (14 of 217) with adrenal hemorrhage had a con- comitant diagnosis of malignant adrenal neoplasm. Most of these neoplasms were metastatic lesions (71%) rather than primary malignancies of the adrenal gland. The most common primary malignancy causing AH was pulmonary, followed by renal tumors. Adrenocortical cancer may also cause AH.
The detection of AH requires a high index of suspicion. The clinical presentation of AH is variable, ranging from abdominal pain to symptoms related to hormone overpro- duction to symptoms of adrenal insufficiency, to completely asymptomatic patients. The most common symptom is upper abdominal pain localized to the side of
the lesion. In some patients the sudden onset of pain may even be mistaken for a ruptured abdominal aortic aneurysm or acute abdomen.1,6-12 In most of our patients, the diag- nosis depended entirely on CT findings. A study by Xiao et al. reported a 98% CT detection rate for AH and less than 10% false-positive and false-negative rate.13 While normal adrenal tissue has CT density of 0-20 Hounsfield Units (HU), the density of an acute hematoma can range from 50 to 90 HU and decreases within days to weeks. The gland may return to normal appearance or calcify within 8-12 weeks.14 Astute radiologists can accurately assess if the characteristics of the lesion suggest the presence of hematoma or an underlying malignancy.
Even though most patients with a hematoma and neo- plasm will have a metastatic lesion to the adrenal, all patients should be assessed for a functional adrenal neo- plasm prior to proceeding with surgical intervention. This evaluation should include a serum potassium, aldosterone, 24-hour urinary free cortisol level or a low-dose dexa- methasone suppression test, and plasma metanephrines or a 24-hour urine test for metanephrines and fractionated cat- echolamine levels. The use of synthetic corticotrophin analogs for testing adrenal function may help render the diagnosis of adrenal insufficiency with confidence if the patient shows signs and symptoms of adrenal insufficiency.
It has been reported that large ACCs commonly dem- onstrate necrosis or hemorrhage on CT imaging or pathologically.15 Harrison et al. found hemorrhage in 50% of ACC surgical specimens.16 Even though hemorrhage in metastatic tumors to the adrenal gland has been docu- mented by many case reports, the true incidence is unknown.3,11,17 Adrenal metastases are the most common malignant lesions to the adrenal gland. In patients with incidentally discovered adrenal tumors and no previous history of cancer, metastasis represents up to 21% of the masses. However, in patients with known cancer, up to 73% of these lesions are metastatic.18 Lung cancer is the primary tumor most commonly found to metastasize to the adrenal gland.9,19 While the exact mechanism for rupture and hemorrhage of adrenal tumors is unknown, it is pos- sible that rapid growth of the tumor combined with capsular and vascular invasion favors hemorrhage and rupture of the capsule. The unique vascular supply to the adrenal gland may also predispose to hemorrhage, as dur- ing stress the blood flow and cortisol production increase, making the gland susceptible to hemorrhage.
The poor outcomes of the majority of malignant adrenal neoplasms that have associated hemorrhage do not pre- clude a recommendation for surgery; however, it may define a patient cohort at risk for a poor prognosis. Despite the poor outcomes in patients with ACC, surgery remains the only effective treatment for ACC. A review by Kendrick et al. found curative resection was possible in
71%, with a perioperative mortality of 5%.20 However, 73% had recurrent disease. The report by Harrison et al. divides ACC into low- and high-risk groups based on pathologic features: tumor size, hemorrhage, and number of mitoses per high-power field. These features (large size, hemorrhage, and number of mitoses) have been shown to correlate with poor survival rates after curative resec- tion.16,21 A literature review of pheochromocytomas and hemorrhage performed by Kobayashi et al. found 50 cases of hemorrhagic pheochromocytoma and revealed that 45% of patients (17 of 38) that could not undergo elective sur- gery and premedication with alpha-antagonists died, while all patients who underwent elective surgery with proper preparation survived.22 The presence of hemorrhage should not change the management of incidentally discovered adrenal masses unless metastasis is suspected, or the patient is hemodynamically unstable at the time of pre- sentation. It is our current practice to rule out hormone production by the tumor and recommend surgical resection for patients with incidentally discovered adrenal lesions if they measure >4 cm, if the lesion is functional or has a worrisome appearance on CT scan.23
Highly selected patients with resectable solitary metas- tasis to the adrenal glands may have improved survival following adrenalectomy. Kim et al. examined surgical resection of isolated adrenal metastasis for selected patients with clinically solitary, resectable lesions. They showed that if resection can be performed safely, adrenalectomy can prolong survival of such patients.19 Other studies have shown prolonged survival in selected patients with meta- static lung carcinoma, renal cell carcinoma, colorectal carcinoma, and melanoma.24-27 A CT-guided fine-needle aspiration biopsy may help facilitate the diagnosis if metastasis needs to be ruled out, or if the patient is not a candidate for operation. All patients that are being con- sidered for a biopsy must be screened for a functional tumor prior to any elective intervention. In all patients with AH, adrenal insufficiency should be suspected and treated promptly. Adrenal insufficiency is dependent on the residual adrenal function; insufficiency becomes evident once 90% of adrenal tissue has been destroyed or when the residual adrenal tissue is “exhausted.”8,28 Adrenal insuf- ficiency should be suspected in patients presenting with the classic findings of hypotension, fever, low serum sodium, and high serum potassium; patients can also display altered mental status, shock, and need for inotropic support. If this condition is left untreated, it may lead to death.
In our study, the smallest tumor was 7 cm in diameter on CT imaging, and while tumor size is known to be a predictor of adrenal malignancy at the time of evaluating incidentally discovered lesions, it has not been reported as a predictor for AH, or metastasis.21,22,29 To date there is no evidence to recommend different management for patients
presenting with AH and cancer. If the patient is hemody- namically stable and shows no evidence of adrenal insufficiency, previous recommendations for management of adrenal incidentaloma and adrenal metastasis should be followed. The management of patients presenting after massive acute hemorrhage is different and may warrant emergent laparotomy to control the hemorrhage. There have also been reports of successful arterial embolization for AH as a consequence of adrenal tumors. 30,3 30,31
In conclusion, our study has shown that the majority of patients with AH and malignant neoplasm will have met- astatic tumors to the adrenal glands. These patients do not typically present in hemorrhagic shock, allowing for ade- quate preoperative evaluation for function and assessment for primary tumors that may be metastatic to the adrenal gland. While long-term survival was rare, patients with metastatic disease had a median survival of approximately 1 year. The effect of AH on survival of patients with malignant adrenal neoplasm is uncertain.
REFERENCES
1. Xarli VP, Steele AA, Davis PJ, Buescher Es, Rios CN, Garcia- Bunuel R. Adrenal hemorrhage in the adult. Medicine (Balti- more). 1978;57:211-21.
2. Vella A, Nippoldt TB Morris JC. Adrenal hemorrhage: a 25 year experience at the Mayo Clinic. Mayo Clin Proc. 2001;76:161-8.
3. Rodriguez Martinez JJ, Herreros Villaraiz M, Perez Garcia FJ, Fernandez Gomez JM, Martinez Gomez J, Regadera Sejas J, et al. Suprarenal hemorrhage as the first manifestation of a small cell pulmonary carcinoma. Presentation of a case. Arch Esp Urol. 2000;53:726-30.
4. Outwater E, Bankoff MS. Clinically significant adrenal hemor- rhage secondary to metastases. Computed tomography obser- vations. Clin Imaging. 1989;13:195-200.
5. Tanaka K, Noguchi S, Shuin T, Kinoshita Y, Kubota Y, Hosaka M. Spontaneous rupture of adrenal pheochromocytoma: a case report. J Urol. 1994;151:120-1.
6. Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage, early recognition and treatment. Ann Intern Med. 1989;110:227-35.
7. Thompson KE, Willard BT, Kuvshinoff, Teague JL. Adrenal hemorrhage mimicking an abdominal aortic aneurysm. Urology. 2003;61:1260xviii-1260xix.
8. Chen R. Adrenal crisis. Crit Care Clin. 1991;7:23-42.
9. Black RM, Daniels GH, Coggins CH, Mueller PR, Data RE, Lichtenstein N. Adrenal insufficiency from metastatic colonic carcinoma masquerading as isolated aldosterone deficiency. Report of a case and review of literature. Acta Endocrinol. 1981;98:586-91.
10. Lam KY, Lo CY. Metastatic tumors of the adrenal glands: a 30 year experience in a teaching hospital. Clin Endocrinol. 2002;56:95-101.
11. Karanikiotis C, Tentes AA, Markakidis S, Vafiadis K. Large bilateral adrenal metastases in non-small cell lung cancer. World J Surg Oncol. 2004;2:37.
12. Landen S, Delugeau V. Adrenal hemorrhage mimicking an acute abdomen. Am J Emerg Med. 2005;23:219-20.
13. Xiao XR, Ye LY, Shi LX, Cheng GF, Li YT Zhou BM. Diagnosis and treatment of adrenal tumours: a review of 35 years’ experi- ence. Br J Urol. 1998;82:199-205.
14. Lockhart ME, Smith JK, Kenney PJ. Imaging of adrenal masses. Eur J Radiol. 2002;41:95-112.
15. Dunnick NR, Heaston D, Halvorsen R, Moore AV, Korobkin M. CT appearance of adrenal cortical carcinoma. J Comput Assist Tomogr. 1982;6:978-82.
16. Harrison LE, Gaudin PB, Brennan MF. Pathologic features of prognostic significance for adrenocortical carcinoma after cura- tive resection. Arch Surg. 1999;134:181-5.
17. Oo TH, Martin L, Hesketh PJ. Adrenal hemorrhage secondary to metastasis from lung cancer. Clin Lung Cancer. 2002;4:183-5.
18. Brunt LM, Moley JF, Adrenal incidentaloma. World J Surg. 2001;25:905-13.
19. Kim SH, Brennan MF, Russo P, Burt ME, Coit DG. The role of surgery in the treatment of clinically isolated adrenal metastasis. Cancer. 1998;82:389-94.
20. Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS, Thompson GB, et al. Adrenocortical carcinoma surgical progress or status quo? Arch Surg. 2001;136:543-9.
21. Lenert JT, Barnett CC, Kudella AP, Sellin RV, Gagel RF, Prieto VG, et al .; Evaluation and surgical resection of adrenal masses in patients with extra-adrenal malignancy. Surgery. 2001;130:1060-7.
22. Kobayashi T, Iwai A, Takahashi R, Ide Y, Nishizawa K, Mitsumori K, et al. Spontaneous rupture of adrenal pheochromocytoma: review and analysis of prognostic factors. J Surg Oncol. 2005;90: 31-5.
23. Herrera MF, Grant CS, van Heerden JA, Sheedy PF, Ilstrup DM. Incidentally discovered adrenal tumors: an institutional experi- ence. Surgery. 1991;110:1014.
24. Mercier O, Fadel E, de Perrot M, Mussot S, Stella F, Chapelier A, et al. Surgical treatment of solitary adrenal metastasis from non- small cell lung cancer. J Thorac Cardiovasc Surg. 2005;130:136- 40.
25. Moudouni SM, En-nia I, Manunta A, Guille F, Lobel B. Factors influencing adrenal metastasis in renal cell carcinoma. Int Urol Nephrol. 2003;35:141-7.
26. Murakami S, Terakado M, Hashimoto T, Tsuji Y, Okubo K, Hirayama R. Adrenal metastasis from rectal cancer: report of a case. Surg Today. 2003;33:126-30.
27. Haigh PI, Essner R, Wardlaw JC, Stern SL, Morton DL. Long- term survival after complete resection of melanoma metastatic to the adrenal gland. Ann Surg Oncol. 1999;6:633-9.
28. Knight B. Sudden unexpected death from adrenal hemorrhage. Forensic Sci Int. 1980;16:227-29.
29. Shen WT, Sturgeon C, Duh QY. From incidentaloma to adre- nocortical carcinoma: the surgical management of adrenal tumors. J Surg Oncol. 2005;89:186-92.
30. Nakajo M, Onohara S, Shinmura K, Fujiyoshi F, Nakajo M. Embolization for spontaneous retroperitoneal hemorrhage from adrenal myelolipoma. Radiat Med. 2003;21:214-9.
31. Hendrickson RJ, Katzman PJ, Queiroz R, Sitzmann JV, Koniaris LG. Management of massive retroperitoneal hemorrhage from an adrenal tumor. Endocr J. 2001;48:691-6.