Aldosterone-Secreting Adrenal Cortical Carcinoma. A Case Report and Review of the Literature
Adrienne Carruth Griffin · Rachel Kelz . Virginia A. LiVolsi
C Springer Science+Business Media New York 2014
Abstract Adrenal cortical carcinomas (ACC) are rare, typi- cally aggressive malignant neoplasms with a reported inci- dence of 1-2 cases per 1 million population and account for 0.05-0.2 % of all malignancies. The majority of these tumors are functional with approximately 60 % of patients experienc- ing endocrine symptomatology typically characterized by Cushing’s syndrome (40 %) or a mixed hormonal picture of Cushing syndrome seen in association with virilization. Rare- ly, patients present with a pure hormonal syndrome of femi- nization or hyperaldosteronism, 6 and 2.5 %, respectively. We report a case of a 76-year-old woman presenting with recently diagnosed hypertension secondary to primary hyperaldosteronism. The patient underwent laparoscopic con- verted to an open adrenalectomy and a diagnosis of adreno- cortical carcinoma (aldosteronoma clinical) was rendered. This case and review of the literature highlight that while rare, aldosterone-secreting adrenal cortical carcinomas may occur. In this case report, we discuss the clinical presentation, path- ologic findings, and review the literature for adrenal cortical carcinomas and aldosterone-secreting adrenal cortical carcinomas.
A. C. Griffin ☒ Department of Pathology, Passavant Hospital, University of Pittsburgh Medical Center, 9100 Babcock Blvd, Pittsburgh, PA 15237, USA
e-mail: carruthgriffina@upmc.edu
R. Kelz
Department of Surgery, University of Pennsylvania Health System, 3400 Spruce Street, 4 Silverstien, Philadelphia, PA 19104, USA e-mail: rapaporr@uphs.upenn.edu
V. A. LiVolsi
Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, 3400 Spruce Street, Philadelphia, PA 19104, USA
e-mail: linus@mail.med.upenn.edu
Keywords Aldosterone · Hyperaldosteronism . Hypertension · Aldosteronoma · Carcinoma · Adrenocortical carcinoma · Adrenal cortical carcinoma
Introduction
Adrenal cortical carcinomas (ACC) are rare, typically aggres- sive malignant neoplasms with a reported incidence of 1-2 cases per 1 million population and account for 0.05-0.2 % of all malignancies [1, 2]. These tumors demonstrate an equal frequency in men and women and a bimodal age distribution with peaks in early childhood, under the age of 5 years, and in adults, 40-50 years of age [3]. The majority of these tumors are functional with approximately 60 % of patients experienc- ing endocrine symptomatology due to excess hormone pro- duction [1, 3]. The remaining patients are identified inciden- tally or present with complaints related to tumor growth and mass effect, such as abdominal or back pain, or metastatic disease. Most patients experiencing hormonal symptoms pres- ent with Cushing’s syndrome (40 %); however, in 24 % of patients, a mixed hormonal picture predominates with Cush- ing syndrome seen in association with virilization due to concurrent adrenal androgen production [3]. Rarely, patients present with a pure hormonal syndrome of feminization or hyperaldosteronism, 6 and 2.5 %, respectively [3]. Adreno- cortical carcinomas are noted manifestations of several hered- itary tumor syndromes including Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome and have rarely been seen in association with multiple endocrine neoplasia 1 (MEN1) and congenital adrenal hyperplasia (CAH) [4]. Overall, this ma- lignancy has a poor prognosis with a relapse or metastasis rate of 70-85 % [5], an average survival time from diagnosis of 14.5 months and a 5-year mortality rate of 75-90 % [6].
We are presenting a case report detailing the presentation, pathology, and follow-up of a patient with an aldosterone
secreting adrenal cortical carcinoma resected via laparoscopic converted to an open adrenalectomy.
Case Report
Clinical Findings
The patient was a 76-year old woman with a medical history of hypertension, heartburn, glaucoma, and depression. She presented to the Hospital of the University of Pennsylvania in January of 2009 with recently diagnosed hypertension secondary to primary hyperaldosteronism. Her outside medi- cal records, although not complete, revealed the following: She had initially presented with difficult to control hyperten- sion and mild, persistent hypokalemia and was found to have an elevated aldosterone level of 110 ng/dL (normal, 3-28 ng/ dL) and a low renin level of 0.1 ng ml h (normal range, 0.65-5.0 ng ml-1 h-1). Work-up for a pheochromocytoma with a 24-h urine collection of vanillylmandelic acid and metanephrine levels was negative. She did not report clinical symptoms suggestive of cortisol or androgen excess, and a dexamethasone suppression test and cortisol and ACTH levels were not evaluated. A CT of her abdomen and pelvis per- formed in April of 2008 revealed a heterogeneously enhanc- ing 3.7×2.7-cm right adrenal mass. This finding was followed and subsequent imaging in July of 2008 revealed that the mass had enlarged to 4.4×2.8 cm. A fine needle aspiration was performed at the outside hospital which was read as adreno- cortical neoplasm.
She was referred to our institution for surgical consultation regarding her enlarging adrenal mass. At the time of presen- tation to us, she was medicated with Aldactone (50 mg), Benicar (40 mg), Lasix (40 mg), and Plendil (5 mg) and had a blood pressure of 136/69, sodium level of 138 mmol/L (normal, 136-144 mmol/L), and potassium level of 3.8 mmol/L (normal, 3.6-5.1 mmol/L). On review of systems, she reported leg swelling, palpitations, and anxiety. Physical exam was notable for a systolic ejection murmur and trace ankle swelling bilaterally. Due to the size of the tumor (4.4 cm) and recent growth (0.7 cm in 3 months), a laparo- scopic adrenalectomy was scheduled in February of 2009 to exclude a diagnosis of carcinoma and for treatment of proba- ble aldosterone-secreting adenoma.
Intraoperatively, the mass was noted to be densely adherent to the inferior vena cava, and the case was converted to an open resection. The tumor was removed through a flank incision. A small capsular rupture occurred while removing the specimen from the body. Additional soft tissue was sent following removal of the tumor from the inferior resection bed. Final pathologic diagnosis revealed adrenocortical carci- noma stage II (pT2, N0, M0) with extracapsular and vascular invasion. The additional margin revealed fibroadipose tissue
without definitive tumor present. Her postoperative course was notable for a prolonged ileus while on narcotics. She was weaned off narcotics and was able to be discharged home on postoperative day 8. She was started on mitotane, 2 g per day for 1 year and replacement hydrocortisone, 20 mg per day. A PET scan performed in April of 2009 demonstrated in- creased uptake in an area of her sigmoid colon without evi- dence of metastatic disease or recurrence in the resection bed. She was directed to obtain a colonoscopy, and biopsies dem- onstrated colonic adenocarcinoma. Subsequent colonic resec- tion revealed a 5.4-cm invasive moderately differentiated adenocarcinoma with metastasis to one of ten sampled lymph nodes. She was treated with systemic 5-fluorouracil, leucovorin and Avastin and completed therapy in December of 2009.
She completed her course of mitotane in May of 2010. In July 2010, a repeat PET scan study demonstrated new focal nodular areas in the liver, confirmed by CT scan to be suspi- cious for metastatic disease. Attempts to biopsy the liver masses in August of 2010 failed. Repeat imaging in January of 2011 revealed an increase in size and number of liver lesions as well as a hypermetabolic soft tissue mass in the left mid-abdomen, anterior to the descending colon and increased activity in the left iliac bone suggestive of metastasis. Biopsies performed at an outside institution of a representative liver lesion in January of 2011 demonstrated metastatic adrenocor- tical carcinoma. She subsequently developed intractable asci- tes and recurrent pleural effusions. Palliative care was initiated and she expired in June of 2011.
Pathological Findings
Gross inspection revealed a 49.5-g adrenalectomy specimen with a mass lesion measuring 5.5×4.5×3.6 cm. The surface of the mass was noted to be ruptured through the capsule in an area measuring 2.5×1.5 cm. Sectioning revealed a well- circumscribed, multilobular, tan-brown to tan-yellow cut sur- face with central necrosis. Residual unremarkable adrenal parenchyma measuring 5×1.6×0.3 cm was compressed by the mass.
Microscopically, the tumor was encapsulated and hetero- geneous and composed of both low nuclear to cytoplasmic ratio cells with pale finely granular cytoplasm as well as cuboidal cells with scant to moderate granular eosinophilic cytoplasm, round nuclei with coarse chromatin, and incon- spicuous to prominent nucleoli (Fig. 1). Cells were arranged in variably sized trabeculae, nests, and sheets and accompanied by a fine vascular network (Fig. 2). Scattered cells with marked random nuclear atypia were identified (Fig. 2c). Areas of the tumor were notable for small cell morphology and composed of sheets of high nuclear to cytoplasmic ratio cells with coarse chromatin and inconspicuous nucleoli (Fig. 3). Multiple foci of capsular and vascular invasion as well as
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adrenal cortical invasion (Fig. 4a, b), and scattered microscop- ic foci of coagulative necrosis, were seen (Fig. 1b). The tumor was mitotically active with a rate of 45 mitoses/50 high-power field. No spironolactone bodies were seen. The residual adre- nal parenchyma was thinned and focally fibrotic with evi- dence of vascular dilation, likely secondary to mass effect from the tumor. The tip of the adrenal, distant from the tumor, was histologically unremarkable.
The tumor was present at the resection margin as well as at the area of capsular disruption. Immunohistochemical stains revealed positivity for inhibin, focal staining for calretinin, and negative staining for S-100, supporting a cortically de- rived neoplasm. The focal areas with small cell morphology were negative for LCA, inhibin, and calretinin, suggesting a more poorly differentiated region of the tumor. Foci of vascu- lar invasion and intravascular tumor emboli were highlighted with CD31 (Fig. 4c). Ki67 revealed 10 % staining in the majority of the tumor mass with focally increased staining (20 %) in the areas of small cell differentiation. Overall, the features favoring carcinoma in this case include the increased mitotic rate, capsular and vascular invasion, necrosis, diffuse architecture and small cell differentiation with differential staining from the large cell areas of more typical aldosteronoma, and high Ki67 staining. A diagnosis of adre- nocortical carcinoma (aldosteronoma clinical), 5.5 cm, with
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multifocal capsular and vascular invasion and tumor present at margin of resection was rendered.
Discussion
Adrenocortical neoplasms arise from the one of the three zones of the adrenal cortex, zona glomerulosa, fasciculate, or reticularis and are not uncommon with a reported prevalence of around 3 % [1]. While distinction from adrenal cortical adenomas is of paramount importance given the disparate management strategies and prognoses, this distinction repre- sents one of the major diagnostic dilemmas within the field of endocrine pathology. A variety of approaches for assessing
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adrenocortical neoplasms have been proposed; however, these criteria are not infallible and are somewhat subjective in their application.
Adrenal cortical adenomas are typically incidentally discov- ered, nonfunctioning neoplasms which are generally small (<4 cm and <60 g), well-circumscribed, solid, and solitary masses located within the adrenal cortex. Grossly, the cut surface of these lesions is typically yellow to brown and without necro- sis. Microscopically, these tumors are classically composed of trabeculae or nests of clear vacuolated cells which generally possess low nuclear to cytoplasmic ratio but may demonstrate endocrine atypia characterized by randomly enlarged, bizarre, and hyperchromatic nuclei. Mitoses are rare to absent.
Alternatively, overtly malignant adrenal cortical carcino- mas are typically large and bulky tumors usually, but not always, weighing over 100 g [2]. These tumors are typically nodular in appearance with a variegated cut surface, ranging from pink-yellow to red brown with foci of hemorrhage, necrosis, and calcification not infrequently noted. Microscop- ically, much like the adrenal cortical adenoma, carcinomas may be composed of variably differentiated cells arranged in solid sheets, trabeculae, or nested arrangements. Cells them- selves may range from the cytologically bland with clear, vacuolated cytoplasm to small- to medium-sized eosinophilic cells. In some cases, tumors demonstrate pleomorphic, mark- edly atypical giant cells. Mitotic activity, with atypical mito- ses, is common. These tumors typically stain positively for vimentin, melanA, calretinin, inhibin, and SF-1 and are neg- ative for EMA and CEA. While the aforementioned immuno- histochemical stains may be used to help support adrenal cortical origin, they are by no means site specific and may also stain positively in potentially morphologically similar metastatic lesions such as melanoma, mesothelioma, and tu- mors of gonadal and pancreatic origin. Adrenocortical carci- nomas may metastasize widely to lungs, retroperitoneal lymph nodes, and liver and bone [2] and demonstrate large and small caliber vessel vascular invasion and also locally invade adjacent organs.
A definitive diagnosis of adrenocortical carcinoma is con- tingent upon the identification of local tumor invasion or distant metastasis. In 1984, with subsequent revisions in 1989, Dr. Lawrence Weiss proposed a set of nine histologic criteria for the evaluation of adrenocortical neoplasms to distinguish benign from malignant lesions (Table 1) [7-9]. To date, these criteria are still generally held as the most specific and reliable. A modification of the Weiss system was proposed by Aubert et al. in 2002 which proposed using five of the original nine criteria and assigning higher point values to some criteria [9]. The threshold for malignancy for both schema is ≥3. Our patient’s tumor met eight of the nine original Weiss criteria (Table 1). In 1989, Weiss and col- leagues performed additional investigations which resulted in the proposal that adrenocortical carcinomas with mitotic
| Weiss system [7] | Modified Weiss system [9] | Patient's Weiss/modified Weiss |
|---|---|---|
| Nuclear grade Furhman II/IV (1 point) | 1 point/0 points | |
| Mitotic rate >5/50 HPF (1 point) | Mitotic rate >5/50 HPF (2 point) | 1 point/2 points |
| Abnormal mitoses (1 point) | Abnormal mitoses (1 point) | 0 point/0 points |
| ≤25 % Clear cells (1 point) | ≤25 % Clear cells (2 point) | 1 point/2 points |
| >1/3 Diffuse architecture (1 point) | 1 point/0 points | |
| Necrosis (1 point) | Necrosis (1 point) | 1 point/1 point |
| Venous invasion (1 point) | 1 point/0 points | |
| Sinusoid invasion (1 point) | 1 point/0 points | |
| Capsular invasion (1 point) | Capsular invasion (1 point) | 1 point/1 point |
| Threshold for malignancy, >3 | Threshold for malignancy, >3 | Weiss system, 8 points |
| Modified Weiss system, 6 points |
indices >20 mitoses/50 high-power fields were deemed high grade and noted to be poor outcome tumors with median survival times of 14 months [8]. By these criteria, our patient’s tumor could be considered high grade; however, her survival time was ultimately 28 months. A variety of other approaches have been proposed and used over the years, including one by Hough et al. in 1979 [10] and another by Van Slooten et al. in 1985 [11]. Other laboratory modalities including immunohis- tochemistry and molecular analysis are currently being inves- tigated and applied with varying degrees of success. Studies have demonstrated that markers of proliferation such as Ki67 are predictive of malignancy with suggested cutoff levels for malignancy of >2.5-4 % [9, 12]. This patient’s tumor had a Ki67 index of 20 %, compatible with carcinoma.
While ACCs are occasionally discovered incidentally, clin- ically, patients with adrenal cortical carcinomas typically pres- ent with symptoms related either to hormone excess or mass effect. In general, hyperaldosteronism is most frequently sec- ondary to an aldosterone-producing adrenal adenoma or ad- renal hyperplasia. Few case reports of aldosterone-secreting adrenal cortical carcinomas exist as these represent exceed- ingly rare tumors comprising approximately 2.5 % of adrenal cortical carcinomas overall [3, 13-18]. A recent study pub- lished by Seccia et al. reviewed the literature for published cases of aldosterone-producing adrenocortical carcinomas and summarized the features for 60 published cases. Their demo- graphic findings were compatible with those of ACC with a reported average age of patients of 44 years (17-79 years), maximum tumor diameter of 7.0 cm (2.5-15.0 cm), and tumor mass weight of 248 g (6.3-1,250 g). All but three patients presented with symptoms of Conn’s syndrome, and they found an average increase of aldosterone 14 times the normal range and suppressed renin levels in more than half of reported cases. Many of the patients were further evaluated for elevated levels of other steroids; approximately 10 % of the reported cases had elevated levels of plasma cortisol.
Surgical resection represents the mainstay of management of ACC, though the use of laparoscopic surgery is controver- sial. While concerns regarding the use of laparoscopy for the resection of suspected adrenal cortical carcinomas have been raised [6, 19-21], some contend that, in the appropriate patient and with an experienced surgeon, laparoscopic resection of ACC may be safely performed [22, 23]. However, it has been shown that the chances of both positive margins or intraoper- ative tumor seeding as well as more rapid tumor recurrence are higher in laparoscopically resected tumors than those per- formed open [19, 23]. In the absence of a robust prospective study examining open resection versus laparoscopic adrenal- ectomy, it seems that open adrenalectomy is most advisable for the resection of adrenocortical carcinomas [20].
Conclusion
Adrenal cortical carcinoma is a rare aggressive tumor of the adrenal cortex with a roughly equivalent gender distribution and a bimodal age at presentation. While the majority of these tumors are functional, sole overproduction of aldosterone is rare. We presented a case of a woman with hyperaldosteronism who was found after surgery to have an aldosterone-secreting adrenal cortical carcinoma. The initial clinical impression in our case was that the patient’s tumor was most likely an adenoma and thus resectable via a laparo- scopic approach. Intraoperatively, the tumor was noted to be adherent to the inferior vena cava, and the case was converted to an open adrenalectomy prior to disruption of the tumor capsule; the specimen was received in pathology with evident capsular rupture. She was managed with adjuvant mitotane and replacement hydrocortisone therapy and was found to have recurrent disease 17 months after her initial surgery. At the time of recurrence, our patient was evaluated outside of our hospital system, so the true extent of her disease at
representation is not entirely clear. While she had documented visceral metastases, pleural and peritoneal effusions, in the absence of a tissue diagnosis, it is impossible to be certain if the findings represented metastatic adrenal carcinoma, if her effusions were malignant or if her recurrence was related to intraperitoneal spread secondary to tumor seeding. She re- ceived palliative management and expired 28 months after her initial diagnosis.
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