Carney Complex with Adrenal Cortical Carcinoma
Emilie Morin, Ozgur Mete, Jonathan D. Wasserman, Anthony Michael Joshua, Sylvia L. Asa, and Shereen Ezzat
Departments of Medicine (E.M., A.M.J., S.E.) and Pathology (O.M., S.L.A.), University Health Network, and Hospital for Sick Children (J.D.W.), Toronto, Ontario, Canada M5G 2N2
Context: Carney complex is a genetically heterogenous multiple neoplasia syndrome. Adrenal cortical carcinoma is a rare malignancy with a poor prognosis that is not recognized to be associated with this syndrome.
Objective: We report a 22-yr-old female presenting with Carney complex who developed adrenal carcinoma. The response to adjunctive therapy is also described.
Methods: We performed a detailed pathology review of the adrenal tumor to examine morpho- logic changes, Ki-67 labeling, and p53 expression. We also performed genetic testing of candidate genes and describe the response to radiation and kinase inhibition therapy.
Results: The patient presented with an 8.5-cm adrenal mass with a MIB-1 labeling index of 20% and unequivocal angioinvasion classified as a T3NXM0 carcinoma. The nontumorous adrenal cortex revealed characteristic features of primary pigmented nodular adrenocortical disease. Genetic analysis revealed a novel PRKAR1 frame shift mutation resulting in a premature stop codon and a heterozygous p53 polymorphic substitution previously noted in other solid carcinomas. Disease recurrence in the liver showed partial response to combined stereotactic radiotherapy and sorafenib multikinase inhibition.
Conclusion: This represents an initial characterization of a malignancy among patients with Carney complex. Our findings have implications for disease surveillance and management of individuals with this genetic syndrome. (J Clin Endocrinol Metab 97: E202-E206, 2012)
C arney complex is a multiple neoplasia syndrome char- acterized by spotty skin pigmentation, cardiac and other myxomas, psammomatous melanotic schwanno- mas (PMS), endocrine tumors, and other tumors such as breast ductal adenomas (1). The endocrine lesions in Car- ney complex include testicular neoplasms, primary pig- mented nodular adrenocortical disease (PPNAD), GH- and prolactin-producing pituitary tumors, and thyroid cancer (2, 3). It is a genetically heterogenous autosomal- dominant disease. Mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene are found in nearly 60% of individuals with Carney complex, whereas an uncharacterized gene(s)
at the CNC2 locus on chromosome 2p16 is similarly im- plicated in disease pathogenesis (2, 4).
Adrenal cortical carcinoma (ACC) is a rare malignancy with a poor prognosis; epidemiological studies have re- ported a bimodal age distribution with a first peak in child- hood and a second in the fourth and fifth decades of life (5). Patients present with evidence of adrenal steroid hor- mone excess in approximately 60% of cases (5, 6). The molecular pathogenesis is still incompletely understood (7). Although associated with a number of genetic predis- position syndromes, ACC is not a finding in patients with Carney complex; rather hyperplastic lesions of the adrenal cortex are frequent.
Abbreviations: ACC, Adrenal cortical carcinoma; CT, computed tomography; GR, gluco- corticoid receptor; PKA, protein kinase A; PMS, psammomatous melanotic schwannoma; PPNAD, primary pigmented nodular adrenocortical disease; PRKAR1A, regulatory subunit type 1A of the cAMP-dependent protein kinase.
Copyright @ 2012 by The Endocrine Society
First Published Online November 23, 2011
Here we present the case of a young woman with es- tablished Carney complex who developed adrenocortical carcinoma arising in PPNAD.
Case reports
Adrenal carcinoma
In 2007, a 22-yr-old woman presented with Cushing’s syndrome with limited facial changes and secondary amen- orrhea. Laboratory examination revealed elevated urinary and serum cortisol, elevated dehydroepiandrosterone sul- fate, and elevated total testosterone. Computed tomographic (CT) imaging showed a 9-cm right adrenal mass and a nor- mal-appearing left adrenal gland. Laparoscopic right adre- nalectomy was performed. Her immediate postoperative CT and bone scans were negative for metastases. Her total tes- tosterone declined from 6.14 to 0.32 nmol/liter (normal < 3.7 nmol/liter), and imaging studies showed no residual dis- ease in the abdomen including the left adrenal or chest.
Pathology
The right adrenalectomy specimen was an 8.5-cm mass that replaced almost the entire gland. The tumor exhibited solid growth pattern (Fig. 1A) with areas of geographic necrosis (Fig. 1B) and increased mitotic activity including atypical mitotic figures. The MIB-1 labeling index was 20%. The tumor was composed of oncocytic epithelial cells that were positive for Melan-A (A103), inhibin, cal- retinin, and vimentin and were negative for pan-keratin, epithelial membrane antigen, and S-100 protein. There was unequivocal angioinvasion (Fig. 1C). The tumor sup-
A
B
C
D
pressor p53 was expressed in 20% of the tumor predom- inantly in the area of carcinoma (Fig. 1D). The nontumor- ous adrenal cortex revealed pigmented micronodules, often deep within the cortex in the zona reticularis or straddling the corticomedullary junction (Fig. 2). These nodules were composed mainly of compact cells with variable amounts of finely granular pigment, consistent morphologically with lipofuscin (Fig. 2 inset) charac- teristic of primary PPNAD. IGF-II and glucocorticoid receptor (GR) staining was also performed showing minimal reactivity in the normal cortex but strong pos- itivity in the benign hyperplastic nodules (Fig. 3), and
A
B
C
strong staining in the carcinoma (Fig. 3C). The initial tumor staging was T3NXM0.
Disease progression
Three months after the initial surgery, the patient re- ported pain in her right flank area. An abdominal CT scan demonstrated a low-attenuating lesion measuring 2.2 × 2.2 cm in the tumor bed just behind the vena cava and medial to the right kidney. Furthermore, serum dehydro- epiandrosterone sulfate had increased from 1.7 umol/liter postoperatively to 4.6 umol/liter (normal < 8.7 umol/ liter). Five months after the initial surgery, she underwent an open right radical nephrectomy with excision of the retroperitoneal mass and retroperitoneal lymphadenec- tomy and resection of part of the inferior vein cava. Pa- thology review confirmed metastatic adrenocortical car- cinoma with resection margins negative for malignancy.
Treatment with mitotane was initiated. Follow-up cross-sectional imaging remained clear of disease for 29 months until the summer of 2010 at which time CT scan- ning revealed new disease in the liver, a tumor deposit adjacent to the retrohepatic vena cava (Fig. 4) and in- trapulmonary metastases. Surgical consultation indicated that the patient was not a candidate for further resection.
Chemotherapy with cisplatin, etoposide, and doxoru- bicin was initiated. However, due to disease progression, the patient was enrolled in a clinical trial with hepatic stereotactic external-beam radiotherapy (42 Gy in six fractions) and the multikinase inhibitor sorafenib (600 mg daily). She tolerated this treatment with only a transient mild rash on her upper trunk and face that disappeared with conservative therapy. Over the course of 3 months, she had reduction in the size of her liver metastases in which the dominant lesion was reduced from 4.4 to 2.6
cm. The right adrenal bed remained stable with no evi- dence of new lesions. Unfortunately, her disease continues to progress in the lungs.
Carney complex
Clinical features
Evaluation of this patient’s presentation revealed sev- eral features consistent with the diagnosis of Carney com- plex. Notably, an atrial myxoma was diagnosed at 22 yr of age and doubled in size over 6 months, requiring sur- gical resection in October 2008. Also noted were multiple pigmented lentigines over the face, inner eye lids, and lips; there was no involvement of the external genitalia. Adre- nal pathology was also consistent with PPNAD. Thyroid examination has remained normal with no nodules de- tected to date. In addition, no PMS, no pancreatic, and no pituitary lesions have been identified in this patient on imaging and her related endocrine hormonal analyses have remained unremarkable.
Family history
The patient’s mother was also diagnosed with a right atrial myxoma requiring surgical resection at the age of 23 yr. She also has multiple pigmentary abnormalities, in- cluding dark lentigines over the trunk, implying a similar diagnosis to the index patient. There are no other individ- uals in the patient’s family who have been tested to date. Family history is otherwise negative for malignancies or endocrinopathies.
Genetic testing
Having met clinical criteria for a diagnosis of Carney complex, sequencing of the PRKAR1a gene from periph- eral blood lymphocytes was undertaken. This uncovered heterozygosity for a novel alteration, c.95_96delAA (8). This frame shift mutation results in a premature stop codon in exon 2 (p.Lys32Argfs*12). Expression of this truncated protein is anticipated to be abolished by non- sense mediated mRNA decay, resulting in haploinsuffi- ciency at the protein level (9), consequently leading to activation of downstream cellular processes. Although this specific mutation has not been previously identified, similar mutations resulting in premature stop codon con- stitute the majority (97 of 117) of mutations in PRKAR1a among individuals with Carney complex (8), supporting a causal association with the patient’s diagnosis of Carney complex.
Consistent with recent recommendations for testing of p53 germline status in individuals diagnosed with adre- nocortical carcinoma (10), genetic analysis was performed but revealed no pathogenic mutations in the p53 gene. Instead, heterozygosity for the Pro72Arg polymorphism,
which had previously been associated with increased risk for multiple malignancies including osteosarcoma (11) and pancreatic cancer (12), was noted in the patient’s pe- ripheral blood DNA.
Although these molecular findings do not specifically explain the development of ACC in this patient, a model for progressive accumulation of genetic lesions leading to adrenal malignancies has previously been proposed (13). According to this model, alterations in protein kinase A (PKA) signaling (most commonly through mutations of PRKAR1a) represent an early event, whereas subsequent genetic events lead to neoplastic transformation. We thus speculate that this patient’s adrenal carcinoma resulted from p53 polymorphic changes superimposed on the ac- tivated PKA pathway.
Discussion
This is an unusual case of a patient with Carney complex and ACC. To our knowledge, it is the first documented case of ACC arising in a background of PPNAD.
Carney complex is a clinically and molecular hetero- geneous disorder. A subgroup of patients are PRKAR1A mutation carriers and have at least two of the classic triad of abnormalities: myxomas, skin abnormalities, and en- docrinopathy. A clear genotype-phenotype association seems to determine the spectrum of disease in individual patients (14). Mutations located in exons are more often associated with acromegaly, myxomas, lentigines, and schwannomas (14). The Carney complex adrenal tumors are typically histologically benign lesions. However, in this syndrome, PMS may be malignant and metastasize, and thyroid neoplasms may also become malignant. Case reports have also included malignancies of the breast, tes- ticles, and ovaries in patients with Carney complex (15- 17). Thus far, however, only benign adrenal cortical pro- liferations such as PPNAD have been reported in the setting of Carney complex (18).
Adrenocortical neoplasms are thought to be associated with aberrations in the adrenocorticotropic hormone- cAMP-PKA and Wnt/B-catenin pathways (19). Inactivat- ing mutations of genes including the p53 tumor suppressor gene and alterations of the 11p15 locus leading to IGF-II overexpression seem to be frequently observed in the pathogenesis of ACC (20, 21). ACC are overrepresented among individuals with hereditary cancer predisposition syndromes compared with their frequency in the general population. For example, ACC represent 11.9% of tu- mors in patients with germline p53 mutations [associated with the Li-Fraumeni syndrome (22, 23)] but less than 1% of all cancers in all individuals (24) (International Agency
for Research on Cancer, TP53 database, http://www- p53.iarc.fr). Adrenocortical tumors, although not neces- sarily carcinomas, are also reported among patients with the Beckwith-Wiedeman syndrome (25) (implicat- ing the IGF-2 gene), familial adenomatous polyposis (26, 27), and rarely in multiple endocrine neoplasia 1 (28). To our knowledge, no ACC has been previously reported among patients with the Carney complex. In the context of the p53 P72R polymorphism, this may represent a novel biological predisposition to adreno- cortical tumorigenesis and may reflect functional inter- actions between the p53 and PKA pathways.
Sorafenib, a novel oral multikinase inhibitor that tar- gets multiple receptor tyrosine kinase pathways such as vascular endothelial growth factor and RAS-RAF, was approved Food and Drug Administration for the treat- ment of advanced renal cell carcinoma and hepatocellular carcinoma. Clinical trials revealed also good response in thyroid carcinomas. In one previous report of the use of sorafenib in sporadic ACC, a sustained remission with this kinase inhibitor in a female patient with stage 4 disease was described (29). Our patient’s disease response in the abdomen, particularly in the liver, was probably attribut- able to the concomitant stereotactic radiation therapy to this organ.
This patient presented with two rare conditions. Al- though the presentation may be coincidental, it is also possible that this represents an initial characterization of an additional tumor type among individuals with Carney complex, potentially related to the specific PRKAR1A novel mutation described here. These observations may have implications for disease surveillance in this and other patients with Carney complex.
Acknowledgments
The authors thank Drs. Amir Hanna and Ken Pace (St. Michael’s Hospital, Toronto, Ontario, Canada) for diagnosis and referral of this patient.
Address all correspondence and requests for reprints to: Sher- een Ezzat, M.D., Princess Margaret Hospital, 610 University Avenue, no. 8-327, Toronto, Ontario, Canada M5G-2M9. E-mail: shereen.ezzat@utoronto.ca.
Disclosure Summary: The authors have nothing to disclose.
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