Journal of Surgical Oncology 2005;90:31–35

Spontaneous Rupture of Adrenal Pheochromocytoma:Review and Analysis of Prognostic Factors

TAKASHI KOBAYASHI, MD,1* AKIRA IWAI, MD,2 RYO TAKAHASHI, MD,2 YOSHIHIRO IDE, MD,3

KOJI NISHIZAWA, MD,1 AND KENJI MITSUMORI, MD1

1Department of Urology, Hamamatsu Rosai Hospital, Hamamatsu, Japan2Department of Gastrointestinal Surgery, Hamamatsu Rosai Hospital, Hamamatsu, Japan

3Department of Surgical Pathology, Hamamatsu Rosai Hospital, Hamamatsu, Japan

Background and Objectives: Because of its rarity, the clinical characteristics of themanifestation of a ruptured pheochromocytoma and factors influencing on treatmentoutcomes in patients are still unclear.Methods: A comprehensive MEDLINE review of the literature on pheochromocytomas,rupture and hemorrhage was performed. Based on the review and one additional case ofour hospital, statistical analysis was undertaken to analyze the association of clinicaloutcome with clinical presentation, preoperative diagnosis, and treatment modality.Results: We identified 49 other cases of hemorrhagic pheochromocytoma in theliterature. After our case was added, a review of all 50 cases revealed that 17 of 38 thatcould not undergo adequately prepared (elective) surgery died, while all 12 patientswho underwent elective surgery survived (P¼ 0.004). An accurate preoperativediagnosis of pheochromocytoma was associated with elective surgery (P< 0.0001),and hemodynamic instability (shock status) was a significant factor for a faileddiagnosis and inadequate management, resulting in a poor prognosis (P¼ 0.023).Conclusions: Although it is a very rare condition, physicians should be aware that apheochromocytoma can bleed and present acutely in the abdomen with shock; anaccurate diagnosis and adequately prepared surgical removal are important for a goodpostoperative prognosis.J. Surg. Oncol. 2005;90:31–35. � 2005 Wiley-Liss, Inc.

KEY WORDS: pheochromocytoma; adrenal; rupture; hemorrhage; review

INTRODUCTION

Rupture of a pheochromocytoma is a rare, sometimeslethal, clinical condition, of which, to our knowledge,there have been 49 reported cases in the literature [1–45].Perioperative mortality would have resulted from bleed-ing, heart failure from excessive catecholamine, orpostoperative severe hypotension or pulmonary edema.Because of its rarity, factors for an unfavorable outcomehave not yet been elucidated. Here we reviewed theliterature with regard to clinical manifestation, diagnosis,treatment modality, and prognostic factors in cases of aruptured adrenal pheochromocytoma.

MATERIALS AND METHODS

Literature Review

The literature available in MEDLINE was reviewed forall cases of spontaneous hemorrhage from an adrenal

pheochromocytoma irrespective of whether bleedingoccurred inside the tumor or ruptured into the retro-peritoneum or intraperitoneum. Data regarding age,gender, tumor side, signs and symptoms, prior pheochro-mocytoma-associated history, preoperative diagnosis,treatment and outcome were collected.

Additional Case

In addition to cases in the literature, we included acase of a ruptured left adrenal pheochromocytoma in a37-year-old man who had presented prior hypertensionattack and hyperglycemia followed by acute onset pain

*Correspondence to: Takashi Kobayashi, MD, Department of Urology,Hamamatsu Rosai Hospital, Shogen-cho 25, Hamamatsu 430-8525, Japan.Fax: þ81-53-465-4380. E-mail: selecao@remus.dti.ne.jp

Accepted 18 January 2005

DOI 10.1002/jso.20234

Published online in Wiley InterScience (www.interscience.wiley.com).

� 2005 Wiley-Liss, Inc.

of the chest and left upper abdomen and hypertensionwith systolic pressure up to 170 mmHg. During anemergency surgery based on the preoperative diagnosisof spontaneous bleeding into pancreatic cyst, left adrenalpheochromocytoma was diagnosed by frozen sectionpathology. The tumor was completely removed and pos-toperative course was uneventful except mild, transientcongestive heart failure managed by catecholamine anddiuretics. Final pathological diagnosis was ruptured pheo-chromocytoma without marked atypia and the patientare in good health without tumor associated symptoms12 months after surgery.

Statistical Analysis

Statistical analysis was done using Chi-square test,Fisher’s exact test, Mann–Whitney’s U-test, and logisticregression analysis with commercial available software.All tests were two-sided and statistical significance wasapplied to P values of <0.05.

RESULTS

We identified 49 other cases with spontaneous hemor-rhage from an adrenal pheochromocytoma. A summaryof the 50 cases is shown in Table I.

Presentation

Age, gender, and side of the cases with rupturedpheochromocytoma are not quite different from overalldemographic features of pheochromocytoma. Accordingto the literature, 80% of the patients presented abdominalpain of acute onset, while some patients complainedlumbar or chest pain. Although majority of the cases werehypertensive at presentation, there were 13 patients whocame into shock status with systolic pressure less than90 mmHg. Although there have been over 200 reportedcases of pheochromocytoma associated with pregnancy[46], there has been best to our knowledge no report thatrupture of pheochromocytoma occurred during preg-nancy. Prior history of pheochromocytoma-associatedsymptoms including hypertensive attack, headache,palpitation, or hidrosis was observed in 21 (42%) cases.

Preoperative Diagnosis

Seven of the patients had already been diagnosed tohave a pheochromocytoma when the hemorrhage occur-red (Table I). Adequate diagnosis of pheochromocytomawas obtained in 13 (30.2%) of the remaining 43 cases.Eighteen patients were diagnosed to have a differentdisease majority of which were aortic aneurysms, whilethe origin of bleeding was not diagnosed in 10 cases.In most cases after 1985, computerized tomography wasused for diagnosis. Rate of accurate diagnosis was 38.1%(8 of 21) after 1985 compared with the rate of 22.7% (5 of22) in the cases reported in 1985 or earlier (P¼ 0.332,Fisher’s exact test).

Treatment, Outcome, and Prognostic Factors

Surgical removal was performed in 41 cases including29 cases undergoing emergent surgery. Mortality rate is34%, and hypovolemia from hemorrhage, respiratorydisorder from pulmonary edema, and heart failure fromcatecholamine cardiomyopathy were the major causes ofperioperative mortality.Although about one-third of patients died of the

disease, there was no mortality in the 12 patients whounderwent elective surgery in which total body water waswell controlled with a-adorenoblockade and fluid infu-sion therapy, while 17 (44.7%) of the 38 patients who didnot undergo elective surgery, with appropriate medicalpreparation, died (Table II, P¼ 0.004, Fisher’s exact test).In addition, hemodynamic instability, cases reportedbefore 1985, and incorrect preoperative diagnosis wereassociated with mortality. Since there was a strongcorrelation between elective surgery and preoperativediagnosis of a pheochromocytoma (Table III, P< 0.0001,Fisher’s exact test); logistic regression multivariateanalysis incorporating hemodynamic instability, reported

TABLE I. Clinical Characteristics of 50 Patients WithSpontaneous Hemorrhage From a Pheochromocytoma

Median (range) age (years) 50 (15–80)

Gender (men:women) 25:25

Tumor side (right:left:bilateral) 27:22:1

Symptom (%)

Acute abdomen 40 (80)

Shock 30 (60)

Lumbar pain 13 (26)

Chest pain 9 (18)

Prior history of tumor associated symptom 21 (42)

Preoperative diagnosis (%)

Known pheochromocytoma 7 (14)

Pheochromocytoma 13 (26)

Abdominal aortic aneurysm 8 (16)

Other misdiagnosis 10 (20)

Bleeding from unknown origin 12 (24)

Surgical settings (%)

Emergency 29a (58)

Elective 12 (24)

Not performed 9 (18)

Hemorrhage site (%)

Inside tumor 12 (24)

Rupture

Retroperitoneum 25 (50)

Intraperitoneum 13 (26)

Outcome (%)

Survived 33 (66)

Dead 17 (34)

aIncluding one case with secondary elective surgery performed after an

exploratory emergency operation in which a pheochromocytoma was

confirmed.

32 Kobayashi et al.

year and preoperative diagnosis, finding that casesreported before 1985 (P¼ 0.028, 95% confidence interval0.023–0.0802) and failed preoperative correct diagnosisof pheochromocytoma (P¼ 0.013, 95% confidence interval0.014–0.603) were independent factors for poor prognosis.

After excluding 7 patients who had already beendiagnosed to have pheochromocytoma prior to rupture,analysis of the remaining 43 patients whose diagnosiswas not obtained at presentation showed that hemody-namic instability had a significant influence on the correctdiagnosis of a pheochromocytoma (Table III).

DISCUSSION

Although the rate of mortality with misdiagnosis and/or inadequate management has lowered over time, hemor-rhagic pheochromocytoma can still be lethal, as shownduring the last decade [45]. Since its first description byCahill in 1944 [1], there have been, to our knowledge,50 cases of hemorrhagic pheochromocytomas includingour case, with 17 (34%) patients dying of the disease.

Our literature review revealed that being a casereported before 1985 was an independent factor for poorprognosis. Similar findings have been reported in series

of elective surgery for non-ruptured cases [47]. Althoughthere was no significant difference, the rate of correctdiagnosis has been improved beyond 1985, when com-puted tomography began to widely used in clinicalsettings (22.7% vs. 38.1%, P¼ 0.332, Fisher’s exact test).In addition to improvements in the intensive managementof cardiopulmonary complications induced by excessivecatecholamine, this advance in diagnosis seems to lead tothe improved prognosis beyond 1985.

In fact, a correct diagnosis also has an independentimpact on the prognosis of a patient with hemorrhagicpheochromocytoma; leading the physician to adequatelyprepare the patient for surgical removal of the tumor.Elective surgery with preoperative medical treatmentimproved outcomes in pheochromocytoma surgery [47]in contrast, poorly controlled preoperative blood pressureis a risk factor for perioperative morbidity [48]. Correctdiagnosis is therefore essential for adequate preparationfor surgery in safe (Tables II and III).

Hemodynamic instability seems to play an importantrole in the management of hemorrhagic pheochro-mocytoma. Shock has been considered to be either purehemorrhagic shock, or due to a massive release of cate-cholamine associated with bleeding in the tumor, or to asudden fall in the blood catecholamine level. In ourliterature review, the bleeding site such as inside thetumor, retroperitoneum or intraperitoneum showed nosignificant impact on the patient’s existent state of shock(P¼ 0.811, Chi-square test). Hemodynamic instabilityindicates that bleeding actively occurs and obligessurgeons to perform emergency exploration, which issignificantly associated with postoperative mortality(Tables II and III). Particularly, intraperitoneal bleedingis an absolute indication for emergency exploratorylaparotomy. However, hemorrhage into the retroperito-neal space rarely causes mortality from bleeding if thepatient concomitantly receives adequate management.Therefore, provisional conservative management and aquest for endocrinological diagnosis is recommended inpatients presenting acute abdomen and retroperitoneal

TABLE II. Factors for Poor Clinical Outcome

Survived (n¼ 33) Dead (n¼ 17) P value

Median age (range) 48 (15–80) 52 (23–80) 0.894*

Presenting shock status (%) 15 (45) 14 (82) 0.016**

Rupture (%) 24 (73) 13 (76) >0.99**

Intraperitoneal bleeding 5 (15) 7 (41) 0.077**

Median tumor size (range)a 8 (3–15) 10 (3–25) 0.137*

Reported before 1985 (%) 14 (42) 14 (82) 0.008**

Preoperative correct diagnosis (%) 18 (55) 2 (12) 0.005**

Elective surgery (%) 12 (36) 0 (0) 0.004**

Statistical methods: *Mann–Whitney’s U-test; **Fisher’s exact test.aEleven cases with tumor size not stated.

TABLE III. Factors for Correct Preoperative Diagnosis of aPheochromocytoma, and the Association Between a CorrectDiagnosis and Elective Surgery

Correct

(n¼ 13)

Incorrect

(n¼ 30) P value

Presenting acute abdomen (%) 12 (92) 25 (83) 0.649

Presenting shock status (%) 4 (31) 21 (70) 0.023

Presenting uncommon symptoma (%) 4 (31) 13 (43) 0.513

Prior tumor-associated history (%) 7 (54) 13 (43) 0.740

Reported before 1985 (%) 5 (38) 17 (57) 0.332

Elective surgery (%) 9 (69) 0 (0) <0.0001

Fisher’s exact test.aA symptom that seems uncommon for a pheochromocytoma, such as

chest pain, indigestion, convulsion, and syncope.

Rupture of Pheochromocytoma 33

hematoma suspected of being a ruptured pheochromo-cytoma, even if the patient is in shock.Although this review clearly shows the importance

of having the correct diagnosis of pheochromocytoma,there seems to be some difficulties to obtain it in the acutesettings. Biochemical and endocrinological evaluations,which are sensitive and specific tests for pheochro-mocytoma allowing enough time for the diagnosis, aresometimes time-consuming and inaccurate in variousacute events which may increase urinary metanephrinesand plasma catecholamines to the level that occurs withtumors [49].When a ruptured pheochromocytoma is suspected,

abdominal CT scan is the study of choice as in non-ruptured cases [50]. Indeed, CT scan was performed in 18of 24 cases reported in 1985 or later. Typically, hetero-geneously enhanced mass and hematoma in the suprar-enal region of the retroperitoneum is obtained. Quickscanning and imaging of CT is more feasible in theemergency setting compared with magnetic resonanceimaging (MRI). CT seems to have some advantages overMRI in the discrimination of ruptured pheochromocy-toma from the differential diagnoses resulting in similarsymptoms including leaked aortic dissection and bleed-ing from intraperitoneal organs.In the case we experienced, surgical extirpation would

have been performed after medical treatment if we hadobtained a prior diagnosis of pheochromocytoma. How-ever, as the diagnosis was obtained intraoperatively,we carried out tumor removal in a single procedure.There is a report that exploration revealed hemorrhagefrom a pheochromocytoma that was successfully re-moved in a secondary, elective procedure [30]. However,current series regarding surgical removal of pheochro-mocytoma demonstrated high morbidity rates for repeatoperations for pheochromocytoma [48,51].Although our case fortunately achieved the uneventful

recovery from an emergency operation, the correct pre-operative diagnosis and adequate medical treatment seemto be the prerequisites for a successful outcome in themanagement of hemorrhagic pheochromocytomas. Fromthis literature review, awareness that patients with ahemorrhagic pheochromocytoma can present acute ab-domen or chest pains with hemodynamic shock is animportant consideration for diagnosis of this rare butlethal condition. This knowledge should assist in arrivingat a correct diagnosis and providing adequate manage-ment, facilitating a good outcome.

CONCLUSIONS

Patients with hemorrhagic pheochromocytoma oftenpresent acute abdomen and, sometimes, chest pains, orhemodynamic shock, which can lead to an incorrect

diagnosis. Misdiagnosis and consequent inadequatemanagement can result in an unfavorable outcome evenin the modern medical era. Awareness of the possiblemanifestation of a hemorrhagic pheochromocytoma isvery important for the management of this rare but lethalcondition.

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