Pheochromocytomatosis Treated By Radio-Guided Surgery

Abstract

Objective: Pheochromocytomatosis is a rare cause of recurrent pheochromocytoma due to seeding of tumor cells at the time of adrenalectomy. The diagnosis can be difficult and a high degree of suspicion is required pre-operatively. We present the case of a 57-year-old woman with a long history of symptoms suggestive of recurrent pheochromocytoma that evaded diagnosis for many years.

Methods: We describe the clinical course, diagnosis, and management. We also present a comprehensive review of the current literature.

Results: Pheochromocytomatosis in our patient presented as multiple recurrent episodes of tachycardia and hypertension 15 years after left adrenalectomy for pheochromocytoma. Diagnosis was evaded until complete hormonal evaluation confirmed biochemical evidence of catecholamine overproduction. Imaging revealed two sites of recurrence. Management included alpha-blockade followed by radio-guided surgery using ¹²³I-labeled metaiodobenzylguanidine scintigraphy and a gamma probe. At surgery, pheochromocytomatosis involved the spleen, omentum, and adrenal bed. A complete en bloc resection was performed, allowing normalization of the patient's blood pressure and heart rate postoperatively. Review of the literature identified 4 similar cases. Radio-guided surgery has been used in a few cases to localize pheochromocytoma, but has not been reported previously for intra-operative localization of pheochromocytomatosis.

Conclusion: Our case highlights the importance of life-long follow-up and thorough endocrine evaluation for patients with recurrent symptoms after initial surgical treatment for pheochromocytoma. It also describes the utility of radio-guided surgery in the treatment of pheochromocytomatosis.

Abbreviations: CPS = counts per second; CT = computed tomography; MIBG = 123I-labeled metaiodobenzylguanidine; SDH = succinate dehydrogenase

INTRODUCTION

Pheochromocytomas are rare, often benign, catecholamine-producing tumors of the adrenal gland that require surgical resection for definitive treatment (1). Rates of postoperative remission are excellent, but despite the apparently benign pathology of most pheochromocytomas, recurrence can occur following surgical resection with a reported frequency of 6 to 23% (2,3). The risk of recurrence is higher in hereditary syndromes, as well as with certain clinical features, such as primary tumor size (>5 cm) and primary tumor location (paraganglioma), which predict the possibility of malignancy and, therefore, a higher risk of recurrence (4–6). Hereditary syndromes associated with pheochromocytoma include multiple endocrine neoplasia type 2A, neurofibromatosis type 1, von Hippel-Lindau disease, and hereditary pheochromocytoma-paraganglioma syndrome due to mutations in the succinate dehydrogenase (SDH) subunit genes or other recently reported genes (6).

However, recurrence of pheochromocytoma can also be secondary to mechanical or surgical factors such as local seeding of benign tissue at the time of adrenalectomy, just as parathyromatosis can be caused by seeding of benign parathyroid tissue at the time of parathyroidectomy (7). We report a case of pheochromocytomatosis that presented more than a decade following adrenalectomy, and the use of radio-guided surgery to assist with aggressive en bloc resection of the benign tumor implants.

Case Report

Fifteen years prior to referral to our hospital, a 42-year-old woman presented on multiple occasions to the emergency department with headache, sweating, tachycardia, and hypertension. Fractionated urinary normetanephrine was elevated at 2,900 μg/24 hours (normal range, 82 to 500 μg/24 h; 110 to 1,050 μg/24 h in hypertensive patients) and a diagnosis of pheochromocytoma was made. A 4-cm left adrenal mass was identified and open left adrenalectomy was performed. The operative report described tumor disruption during surgery. Pathology confirmed a 4.6-cm encapsulated pheochromocytoma in multiple irregular fragments. There was mild nuclear atypia but no mitotic figures or angiolymphatic invasion. The patient's symptoms improved postoperatively.

Ten years postoperatively, the patient developed recurrent symptoms: initially “black-outs”, later tachycardia and fatigue, precipitating multiple visits to the emergency department. She developed congestive heart failure with dilated cardiomyopathy and an ejection fraction of 20%. She was started on beta-blockers and angiotensin inhibitors.

Five years later, at age 57, she was referred to our hospital with worsening fatigue, palpitations, sweating, constipation, nausea, and left upper abdominal and flank pain. Despite long-term treatment with metoprolol and losartan, the patient's blood pressure was not well controlled at 138/80 mm Hg. Work-up for recurrent symptoms revealed fractionated urinary normetanephrine and norepinephrine levels of 1,554 μg/24 hours (normal range, 110 to 1,050 μ/24 h) and 212 μg/24 hours (normal range, <135 μg/24 h), respectively, which biochemically confirmed recurrent pheochromocytoma.

Imaging was then performed for tumor localization and to determine whether the excess catecholamine production arose from local tumor recurrence, a new pheochromocytoma, or metastatic disease. A ¹²³I-labeled metaiodobenzylguanidine (MIBG) scan of the abdomen was performed first to confirm the site(s) of excess catecholamine production, demonstrating 2 foci of increased activity: the left adrenalectomy bed (Fig. 1 A) and the left paracolic gutter (Fig. 1 B). A computed tomography (CT) scan was then performed to more accurately localize the areas of tumor recurrence. CT confirmed multiple foci of irregular, nodular soft tissue corresponding to the same areas observed on the MIBG scan (Fig. 2). A total of 5 soft tissue densities were identified on CT, the largest of which was directly adjacent to surgical clips in the adrenal bed and measured 3.1 × 1.6 cm.

Fig. 1.

¹²³I-labeled metaiodobenzylguanidine – single photon emission computed tomography scan of the abdomen demonstrating foci of increased activity (arrows) in (A) the left adrenal bed and (B) the left paracolic gutter.

Fig. 2.

Computed tomography scan demonstrating multiple foci of irregular, nodular soft tissue deposits (arrows), corresponding to (A) the left adrenal bed, adjacent to metal surgical clips (arrowheads), with normal right adrenal gland (thin arrow), (B) an area just inferolateral to the left adrenal bed, and (C) the left paracolic gutter, directly adjacent to the descending colon.

The patient was started on alpha-blockade (terazosin 1 mg daily) and her ejection fraction subsequently improved to 50%. Beta-blockade (metoprolol 12.5 mg twice daily) and angiotensin blockade (losartan 25 mg daily) were continued, with dose adjustments to induce postural hypotension that could be tolerated by the patient while being prepared for surgery. The pre-operative heart rate was 75 beats per minute and blood pressure was 103/68 mm Hg.

Re-operative radio-guided surgery was performed using ¹²³I-MIBG injection pre-operatively on the morning of surgery, and a hand-held gamma probe in the operating room. Exploratory laparotomy and adhesiolysis was performed, revealing multiple tumor implants. Using the gamma probe, pheochromocytomatosis was identified in the left paracolic gutter, left adrenal bed, spleen, and omentum. Tumor implant counts per second (CPS) were over 4 times that of background counts (i.e., 200 to 400 CPS compared with background of 20 to 50 CPS). The suspected tumor implants were sent for frozen section, which confirmed pheochromocytomatosis. En bloc resection was performed of all pheochromocytoma implants, which required splenectomy and omentectomy (Fig. 3 and 4). Pathology confirmed recurrent pheochromocytoma consisting of numerous (>6) tan-white, firm, encapsulated nodular implants measuring 0.5 to 1.5 cm throughout the adipose tissue abutting a remnant (3.4 cm) of adrenal gland (Fig. 3 A). There were also 9 nodules of pheochromocytoma measuring 0.2 to 1.4 cm infiltrating the omentum and covering the spleen (Fig. 3 A through C). The adrenal cortex and medulla were unremarkable and not involved by tumor. The tumor had typical zellballen architecture, with no vascular invasion or necrosis, minimal nuclear pleomorphism and hyperchromasia, and no increased mitotic activity. Microscopic clustering of chromaffin cells was seen associated with arteries, nerves, and the peri-adrenal retroperitoneal tissue. Screening immunohistochemistry for SDH subunits was negative, with normal expression of SDHB (SDH complex iron-sulfur subunit, mitochondrial) protein in tumor cells. Postoperatively, antihypertensive medications were tapered off and the patient experienced an excellent recovery, with normotension (blood pressure 105/72 mm Hg) and resolution of symptoms. Follow-up free plasma metanephrines at 6-months post-surgery were normal.

Fig. 3.

Surgical specimens showing (A) en bloc resections of multiple nodules of pheochromocytomatosis infiltrating the left adrenal bed and left paracolic gutter, and the spleen and omentum. (B,C) Closer view of nodules of pheochromocytomatosis infiltrating the omentum and spleen. Metal surgical clips are seen in areas where tumor nodules were biopsied for frozen section.

Fig. 4.

View of surgical bed following en bloc resection of pheochromocytomatosis deposits.

DISCUSSION

Iatrogenic pheochromocytomatosis is a rare cause of recurrent pheochromocytoma. Overall, recurrence of pheochromocytoma following open adrenalectomy has been estimated at 6 to 8% (8). Data on recurrence rates following minimally invasive, including retroperitoneoscopic, adrenalectomy are limited; however, emerging results suggest increased recurrence following laparoscopic adrenalectomy (9). The main risk factors for recurrence are genetic predisposition or malignancy (10,11). However, recurrence may also result from intra-operative disruption of a tumor leading to implantation and eventual pheochromocytomatosis (12). Brennan and Keiser (12) describe one case of pheochromocytomatosis following open adrenalectomy due to seeding of tumor cells at the operative site. Three cases of pheochromocytomatosis have been described following laparoscopic transabdominal adrenalectomy (13). As in our patient, the diagnosis was firmly established in these 3 cases with biochemical and ¹²³I-MIBG evidence of recurrence, and there was no personal or family history of endocrine disorders. Importantly, imaging confirmed recurrence in the initially-operated adrenal bed, with no evidence of visceral metastasis, contralateral adrenal tumor, or tumor in other extra-adrenal locations. As in our patient, the original operative reports of these 3 cases described tumor “spillage”, “friability”, and “extensive dissection and late ligation of adrenal vein”, respectively; the authors suggested these as possible methods of local seeding (13).

The biological behavior of a pheochromocytoma contributes to eventual recurrence, but it is exceedingly difficult to distinguish benign from malignant tumors using initial clinical and pathological information (11,14). Nonetheless, there was no evidence of aggressive behavior in the initial pathology or presentation of our patient. In addition, the pathology report stated that the tumor was present in multiple fragments with disrupted soft tissue, indicating that spillage during the initial surgery was highly likely. In the 3 laparoscopic cases resulting in pheochromocytomatosis, initial pathology reports confirmed no features of malignancy in 2 of the 3 cases; invasion into blood vessels and fibrous capsule was reported in the third case but with insufficient evidence to establish a diagnosis of malignancy. True malignant disease can only be diagnosed if pheochromocytoma cells are identified in a location distant from the primary tumor, such as a lymph node or the liver (15,16). In our patient, final pathology after re-operation demonstrated no evidence of nuclear atypia or invasion, and the cortical and medullary tissue did not involve tumor; thus, the recurrent nodules did not appear to be malignant or metastatic, but rather to be benign tumor implants as a result of prior seeding. However, morphology does not predict tumor behavior, and though a scaled score has been described to distinguish benign from malignant neoplasms (pheochromocytoma of the adrenal gland scaled score), it has been found to be unreliable in predicting tumor behavior (17,18). The presence of extra-adrenal pheochromocytoma and microscopic tumor deposits in the peri-adrenal retroperitoneal tissue raised the possibility of paragangliomatosis; however, screening by immunohistochemistry for SDH subunits was negative with normal expression of SDHB, which makes this less likely.

In our patient and in the 3 laparoscopic cases, ¹²³I-MIBG identified strings of increased tracer uptake correlating with multiple separate nodules and nodular clusters of recurrent pheochromocytoma in the retroperitoneum. In one case, the pattern of recurrence was very similar to that of our patient (i.e., the left adrenal bed, upper abdomen, and paracolic gutter) and required a similar surgical approach (i.e., en bloc resection of the spleen, left kidney, part of the left hemidiaphragm, and tail of the pancreas) (13).

It can be difficult to diagnose primary or recurrent pheochromocytoma, as symptoms and signs may mimic other conditions. In our patient, recurrent symptoms were present for over 5 years before the diagnosis was confirmed, despite the clinical presentation being similar to the patient's original presentation of pheochromocytoma. Likewise, the 3 cases described by Li et al (13) had classical signs and symptoms (i.e., headache with either episodic hypertension or sweats, pallor, and palpitations) that presented between 18 and 40 months following initial surgery. In our patient, recurrent symptoms began 10 years postoperatively. As in our patient, symptoms completely resolved after initial surgery in each of the 3 cases, with normal fractionated urinary metanephrines during the first postoperative year. Hence, pheochromocytomatosis may present many years after initial surgery; life-long follow-up with annual biochemical investigation (e.g., measurement of plasma free metanephrines) would allow for timely diagnosis and surgical treatment, and prevent the detrimental long-term effects of high circulating catecholamine levels.

Radioisotope-guided surgery is commonly used in certain surgical specialties such as sentinel lymph node mapping in melanoma and breast cancer, radioimmuno-guided surgery in colon cancer, and localization of parathyroid adenoma (19). Radio-guided localization of pheochromocytoma using ¹²³I-MIBG scintigraphy and intra-operative gamma probe has been reported in a few cases (20–22); however, to our knowledge, this is the first case to describe its use in pheochromocytomatosis. A decision was made to use this technique in our patient due to the suspicion that there could be numerous small tumor nodules that could not be identified by the pre-operative CT and MIBG scans. The pre-operative scans did alert the surgeons to the fact that a tumor was present outside the adrenal bed, in the left paracolic gutter. However, the extent of tumor spread or spillage was unknown. At surgery, the radio-guided technique allowed the surgeons to locate the inferior extent of the tumor implants in the left paracolic gutter, which would not have been evident without the gamma probe. Also, many of the tumor nodules in the greater omentum could be identified only with the use of the probe. Thus, the use of ¹²³I-MIBG scintigraphy and intra-operative gamma probe enabled the surgeons to perform complete resection of all tumor-containing tissue, which would otherwise not have been possible. Despite complete resection of the pheochromocytoma, our patient is at risk of further recurrence. We recommend a follow-up MIBG scan at 6 months post-surgery and repeat annual measurement of plasma metanephrines.

CONCLUSION

Recurrence of pheochromocytoma due to pheochromocytomatosis can occur after open or laparoscopic adrenalectomy. Symptoms often resemble the initial presentation with pheochromocytoma; a high degree of suspicion and a thorough endocrine evaluation are required for diagnosis. Genetic predisposition should be excluded with mutational analysis for susceptibility genes. However, annual life-long follow-up is warranted after initial resection of pheochromocytoma, even in sporadic cases, as recurrence may occur many years after initial surgery.