Adrenocortical Carcinoma Closely Mimicking a Pheochromocytoma: A Clinicopathologic Conundrum

SUMMARY

Adrenocortical carcinoma (ACC) is a rare neoplasm of the adrenal cortex that could be functioning or clinically silent, whereas pheochromocytoma is a tumor arising from the adrenal medulla which secretes catecholamines. Both are exceedingly rare tumors and the most common diagnostic dilemma is distinguishing one from the other. ACC typically presents with virilizing signs or clinical Cushing syndrome from excess androgen or cortisol production. It is exceptionally uncommon for ACC to clinically present as pheochromocytoma. Here we report a case of a 49-year old female who presented with resistant hypertension and paroxysms of headache. Further work up revealed elevated urine metanephrine levels, abdominal computed tomography (CT) scan found a large, heterogenous, left adrenal mass with renal vein extension. Left adrenalectomy with left renal vein thrombectomy was done. Histopathologic examination was consistent with a malignant adrenal tumor. Further immunohistochemistry studies were in favor of an ACC with neuroendocrine features which is an exceedingly rare entity. The handful of reported cases of ACC masquerading as pheochromocytoma was referred to as so-called pseudopheochromocytoma in literature. The difference in clinical presentation can be attributed to the presence of neuroendocrine features in ACC as documented by immunohistochemistry.

INTRODUCTION

Adrenocortical carcinomas (ACC) are rare malignant neoplasms of the adrenal cortex with a bimodal distribution in the first and fifth decades of life. The worldwide occurrence of adrenocortical carcinoma is extremely low with an approximate incidence of 1 to 2 cases per million adults each year with an estimated 5-year survival rate of 20-25%.1 They are most likely to be functional with a broad range of clinical presentations depending on the secreted hormone, and tend to be associated with virilizing signs and hyperadrenalism. The diagnosis of ACC requires a multidisciplinary team of experts often necessitating an extensive and exhaustive review of clinical history, laboratory and hormonal evaluations, multi-imaging modalities which are essential for tumor localization, and histopathology with concomitant immunohistochemistry for definitive diagnosis. It is extremely rare for ACC to present clinically as a tumor of the adrenal medulla, such as a pheochromocytoma. With such a presentation, clinical and imaging findings can be confounding to correlate, thereby consuming considerable time in arriving at the correct diagnosis, formulating treatment plans and ultimately impacting prognosis.2

Although there are some hereditary cancer syndromes associated with ACCs, most of the adrenocortical tumors diagnosed appear sporadically. One notable example is the Li-Fraumeni syndrome with inherited germline mutations in the TP53 gene and is known for its inherent increased risk for ACC. Lynch syndrome is also known to predispose patients to various malignancies because of DNA mismatch repair gene mutations. Classically, Lynch syndrome is frequently associated with right-sided colorectal carcinoma in 80%, as well as endometrial, biliary tract, small bowel, and urinary tract malignancies. A few case reports documented an association of ACC and Lynch syndrome with incidence at approximately 3%.3 Other predisposition syndromes associated with ACC include familial adenomatous polyposis as well as multiple endocrine neoplasia, type 1.4

Upon diagnosis of an adrenal mass, it is recommended to perform surgical resection when biopsy is not feasible. Pathologic examination of the resected specimen is important to document features such as adequate evaluation of the mitotic rate to aid in clinical decision-making regarding treatment.5 In the adjuvant chemotherapy for metastatic or unresectable disease, mitotane plays an important role in multidrug therapy. Mitotane acts by inhibiting select adrenocortical functions by binding to mitochondrial proteins. This results in tumor death and atrophy of the adrenal gland, particularly in the zona fasciculata and zona reticularis.6 The drug is usually given in combination with doxorubicin, etoposide, and cisplatin as standard for patients presenting with advanced disease.7

While there are several differential diagnoses of ACC including pheochromocytoma, adrenal adenoma, and other renal tumors, the final diagnosis is ultimately rendered by the pathologist. Here we present a case of adrenocortical carcinoma closely mimicking pheochromocytoma clinically, radiographically, and biochemically.

CASE SUMMARY

The patient is a 49-year old female from Bicol who presented with a 3-year history of resistant hypertension, aquagenic pruritus, and paroxysms of headache. She has had episodes of elevated blood pressure since 17 years old. Medications were given, which she eventually discontinued. Consultation was initially done at a local hospital due to blood pressure spikes and headache, where work up revealed erythrocytosis. The patient underwent several phlebotomies to address the hematologic condition, and was eventually referred to the Philippine General Hospital (PGH) for further work-up and management. The patient consulted at the PGH Outpatient Department (OPD) last 2019 with persistently elevated blood pressure despite four different antihypertensive medications. She also presented with heart failure symptoms and plethora. Initial impression at the OPD was Polycythemia Vera. Bone marrow aspiration biopsy and JAK2 mutation assay were recommended for confirmation. With resistant hypertension and paroxysms of headache, palpitations and diaphoresis, pheochromocytoma was considered. Abdominal ultrasound was done revealing a heterogenous focus in the left suprarenal region measuring 9.5 x 7.3 x 8.0 cm. No doppler evidence of renal artery stenosis was noted. Additional diagnostic examinations were then requested.

However, due to the lockdowns brought about by the COVID-19 pandemic, diagnostic examinations were not done and the patient was not able to follow up for three months. In the interim, she continued to have uncontrolled hypertension along with aforementioned symptoms of pheochromocytoma. With the lifting of the community quarantine, work up was resumed, and once completed, the patient was subsequently prepared and admitted for surgery.

Investigation and Treatment

Mentioned in this report are the results of the diagnostic examinations employed. Hypercellular marrow with trilineage hematopoiesis was noted on bone marrow core biopsy and aspirate. Findings were compatible with a reactive marrow. Cytogenetic molecular studies with JAK2 and BCR-ABL were recommended for definitive classification.

Table 1. Preoperative laboratory work-up

Intermittent phlebotomy was done and the patient was maintained on hydroxyurea. JAK2 mutation was negative.

Initial biochemical work up for secondary hypertension revealed a slightly elevated urine metanephrine, normal aldosterone and renin levels. Cortisol was not suppressed after one milligram of dexamethasone was given, suggesting subclinical Cushing syndrome. With a high pretest probability of pheochromocytoma, urine metanephrine determination with  proper  urine  collection  was repeated twice, revealing 4.7 times and 3.9 times the upper limit of normal.

Chemistry studies showed adequate glucose control, renal function studies (BUN and Creatinine), and serum electrolytes within normal ranges. Liver enzymes were within normal limits whereas serum albumin was low. Deranged lipid profile was seen with elevated total cholesterol, LDL, triglycerides, and VLDL. Coagulation studies show prolonged prothrombin time as well as activated partial thromboplastin time. Arterial blood gas studies were unremarkable.

Complete blood counts revealed erythrocytosis, leukocytosis, and thrombocytosis with increased red cell distribution width. There was a trend towards normalization of blood counts throughout the length of hospital stay except for the red cell distribution width.

An abdominal computed tomography (CT) scan with adrenal protocol revealed a large, well- defined, mixed-attenuating, heterogenously-enhancing left adrenal mass with mass effects and extensions including left renal vein involvement. Radiologic findings were sug gestive of malignancy. Surgical intervention was then planned.

The CT image shows a large, well-defined, mixed- attenuating, heterogenously-enhancing mass (10.9 x 8.2 x 9.3 cm) with internal punctate calcifications in the left suprarenal region exhibiting avid arterial enhancement along with internal non-enhancing hypodense regions within the mass, likely representing areas of necrosis.

The patient was admitted to the intensive care unit for close monitoring and was managed by a multidisciplinary team. The patient subsequently underwent Left Adrenalectomy, Intraoperative Ultrasound, and Left Renal Vein Thrombectomy. Histopathology after wards showed m a l i g n a n t  a d r e n a l   t u m o r  with angiolymphatic and capsular invasion. A specimen labelled “thrombus” was noted to be positive for tumor cells. Surgical margins were assessed to be all negative for tumor cells. A chest CT was done for metastatic work up which revealed bilateral pulmonary nodules, likely metastatic.

Histopathology

Gross examination revealed an encapsulated, solid and tan- brown mass measuring 12.5 x 6 x

6 cm and weighing 480 grams. There are scant fibroadipose tissues adherent to the tan-white,

0.1 cm thick capsule. Cut sections show tan-brown, smooth, solid, variegated surfaces with pinpoint red-brown and cream-yellow areas. There is a separately submitted specimen labelled as “thrombus” which consists of a friable nodule (1 x 0.8 x 0.7 cm) with dark-brown granular surfaces.

Microscopic examination shows the tumor to be composed of a heterogenous population of sheets of cells surrounding blood vessels. Cytologic features include variably-sized, round, hyperchromatic nuclei with prominent, multiple nucleoli. The cytoplasm is predominantly eosinophillic with discrete, vacuolated areas and indistinct cytoplasmic borders (Fig. 3 A, B, and C). There are occasional giant cells with abundant eosinophillic cytoplasm and bizarre hyperchromatic nuclei. Some focal areas show tumor cells breaking through the capsule (Fig. 3. D) and into the surrounding adipose tissue. Further scrutiny show pericapsular areas with lymphovascular space invasion (Fig. 3, E and F). The case was initially signed out as malignant adrenal tumor.

Immunohistochemistry studies for synaptophysin, chromogranin, S100, inhibin, calretinin, neuron-specific enolase (NSE), CD56, TTF-1, and Ki-67 were recommended.

Immunohistochemistry Studies

Immunohistochemistry results showed positive staining for inhibin, synaptophysin, NSE, CD56, and calretinin. Chromogranin, S100, and TTF-1 were negative. Ki-67 staining revealed fifteen to twenty percent (15-20%) proliferative index. The immunohistomorphologic features favor an adrenocortical carcinoma with neuroendocrine features.

Outcome and Follow-up

Postoperatively, the patient had adrenal insufficiency, which was managed accordingly. Urine metanephrine level was normal two weeks after surgery. Blood pressure was controlled and  alpha  blockade  was successfully discontinued. Close follow at the outpatient department is currently under the care of endocrinology and medical oncology. During her latest follow-up, there was no note of recurrence of symptoms. Close monitoring of blood pressure trends and symptoms related to both pheochromocytoma and adrenal insufficiency was instituted. The patient is for chemotherapy and is currently on corticosteroids and a single antihypertensive agent.

DISCUSSION

Cases in literature on the approach to diagnosis and management of ACC found it a remarkably rare aggressive disease in adults. It has an annual incidence of 1-2 cases per million. ACC has a very limited selection of treatment plans especially with metastatic disease wherein the five- year survival rate declines to 0-17%.1 Thus, accurate diagnosis is critically important.

More often the diagnosis of ACC is supplemented by noting its functioninrg status with excess production of various steroid hormones, the most common of which are cortisol and androgens, thus causing clinical Cushing syndrome and overt signs of virilization.8 ACC can be diagnosed biochemically through a standard 24-hr urinary cortisol excretion test and a dexamethasone suppression test.9 The prognosis of ACC tends to be poor, especially with metastatic disease. It is exceptionally rare to encounter an ACC to clinically present as a pheochromocytoma.

Pheochromocytoma is a catecholamine secreting tumor of the adrenal medulla. It has an annual incidence of 2-8 cases per million and tends to present in the third to fourth decade of life.10 The typical clinical course of pheochromocytoma consists of episodes of palpitation, diaphoresis, uncontrolled hypertensive spikes, and headaches attributed to an excess catecholamine secretion. Hypertension is rarely absent and whether it presents as paroxysmal or persistent would depend upon the catecholamine secreted. Biochemical diagnosis of pheochromocytoma can be established by measuring metabolites of catecholamines which include plasma metanephrines, 24-hr urine catecholamines or their metabolites (VMA and metanephrines).11  In our case, patient had hypertensive spikes, sudden headaches, and elevated urine metanephrines on serial determination which clinically suggested a pheochromocytoma.

Radiologic imaging helps narrow down the differential diagnosis of a suprarenal mass. CT scan features suggestive of ACC include margin irregularity, inhomogenous appearance, areas of necrosis, calcification, low fat content, and high attenuation with irregular enhancement after contrast administration.12 In our present case, contrast-enhanced CT findings showed a large, well- defined, mixed-attenuating, heterogenously-enhancing mass with punctate calcifications in the left suprarenal region showing arterial enhancement admixed with non-enhancing hypodense regions within the mass, likely representing areas of necrosis. These radiologic features coupled with presence of multiple, bilateral discrete nodules within the lungs on chest CT are highly suggestive of malignancy. Apart from having increased sensitivity compared to CT scan, MRI has an advantage of being able to examine the fat planes adjacent to the tumor as well as to exclude metastases.13 In terms of detecting adrenal masses, ultrasound was found to have less sensitivity and tends to be highly user dependent.

There are similar overlapping clinical and histopathologic features found in both adrenocortical carcinoma and pheochromocytoma which preclude obtaining an accurate diagnosis. An aldosterone or cortisol-secreting ACC and pheochromocytoma could present with hypertension. A review comprising 300 ACC cases found that discriminating between ACC and pheochromocytoma is the most common obstacle in obtaining an accurate diagnosis although they have strikingly different biochemical profile in that pheochromocytomas primarily secrete catecholamines and in ACC the primary products are steroid hormones such as cortisol and aldosterone.15 In our case, we noted prominent clinical features that suggest a clinical impression of pheochromocytoma. This is further supported by laboratory findings of elevated 24-hr urine metanephrines. We have very few reported cases in literature documenting an ACC which presented with a clinical course similar to a pheochromocytoma.

Gross examination of adrenocortical tumors strongly favors malignancy on the basis of metastases, direct invasion of contiguous structures, or tumor size.14 Unfortunately, pathologically malignant adrenal tumors have similar average sizes. On microscopic examination, both can appear as a cellular proliferation composed of large, pleomorphic cells with enlarged nuclei.15

Pathologic evaluation of adrenocortical tumors is made simpler with the wide adaptation of the Weiss criteria¹⁶, first introduced in 1984 and is now considered standard for determining malignancy in tumors of the adrenal cortex, which outlines specific criteria according to histologic features. These include high nuclear grade, mitotic rate >5 per 50 HPF, atypical mitotic figures, eosinophillic tumor cells (>75% of tumor), diffuse architecture (>33% of tumor), necrosis, venous invasion, sinusoidal invasion, and capsular invasion. Adrenocortical carcinoma is highly likely with three or more of the nine criteria, while less is in keeping with an adenoma. In our case, histopathologic evaluation of the tumor revealed the following: Fuhrman nuclear grade IV, Mitotic rate of 21/50 HPF with atypical mitotic figures, a predominantly eosinophillic tumor cell cytoplasm (70%), diffuse architecture, venous, and capsular invasion. In our case, histopathologic examination showed a malignant adrenal tumor with capsular and lymphovascular invasion.

Since the clinical course of the patient documented a pheochromocytoma-like behavior, subsequent testing for neuroendocrine markers was pursued to explain the hypertensive spikes. Markers of neuroendocrine differentiation were added which consisted of NSE, synaptophysin, chromogranin, CD56, and TTF-1. Among these additional markers, we found the tumor to have positive staining for synaptophysin, CD56, and NSE. It would appear that the tumor cells also have cytoplasmic neuroendocrine granules that could account for the clinical behavior described earlier. Hence, we revised the histopathologic diagnosis to an adrenocortical carcinoma with neuroendocrine features. An adrenal tumor with histopathologic features consistent with an ACC with evidence of neuroendocrine differentiation is compatible with a very rare entity described as so-called pseudopheochromocytoma in literature.21

The paucity of reports reviewed termed these tumors as so-called pseudopheochromocytoma and suggested that the clinical findings can be explained by the presence of neuroendocrine features in these adrenal tumors.18  Other reported cases showed coexistence of both adrenocortical tumors and pheochromocytoma.20 The confounding behavior seen in our adrenocortical tumor is related to its neuroendocrine differentiation, consistent with the so-called pseudopheochromocytoma.21 The scant number of case reports seen in current literature found that these tumors show positive immunohistochemistry staining for markers such as NSE (80% of cases) and synaptophysin (100% of cases), and consistently negative staining for chromogranin,22 the staining pattern of which is also observed in our case. Increased sensitivity and specificity in differentiating adrenocortical carcinoma from pheochromocytoma is achieved by testing for calretinin (96% reactivity) and inhibin (92% reactivity), 23 both of which are also positive in our case. In a series reviewing sensitivity and specificity of calretinin and inhibin for adrenocortical tumors, a correlative analysis showed that combination of calretinin and inhibin yielded sensitivities and specificities of 94% and 100%, respectively.24 So far, only a handful of cases 25, 26, 27, 28 have been reported worldwide thereby making this tumor an exceedingly rare entity causing clinical, radiologic, and pathologic confusion and hindering prompt initiation of appropriate treatment. As far as we are aware, this case is the first ever reported from the Philippines.

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