LETTER TO THE EDITOR
Concurrent Pheochromocytoma and Cortical Carcinoma of the Adrenal Gland
AMBROGIO FASSINA, MD,1* ROCCO CAPPELLESSO, MD,1 FRANCESCA SCHIAVI, BD, PhD,2 MATTEO FASSAN, MD1
1 Department of Diagnostic Medical Sciences and Special Therapies, University of Padova, Padova, Italy 2 Familial Cancer Clinic, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
Dear Editor:
We report the case of a 46-year-old Caucasian woman who was admitted in June 2009 to Padova University Hospital for pain in the left flank. In her medical history, the patient had undergone laparotomic excision of a pheochromocytoma (Pheo) in the left adrenal gland (November 2008).
A laparoscopic biopsy from the left kidney (inferior pole) revealed a monomorphic population of small cells with round nuclei and inconspicuous nucleoli, with no cellular atypia, nor tumor necrosis. The cytology findings were suggestive of an adrenal cortical origin.
The histological slides of the 2008 adrenal mass were re-evaluated. Adjacent to the originally diagnosed Pheo (rare nuclear atypia; scant spindle cells; low Ki-67 index [MIB-1 <1%; 1:100, Dako, Carpinteria, CA]; PASS score <4) [1] a concurrent second cell population was
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observed (Fig. 1). This neoplasm was composed by small cells with oval nuclei, occasional nucleoli, dispersed chromatin, and eosinophilic cytoplasm reminiscent of zona reticularis cells. There was neither necrosis nor broad collagen bands. Immunostaining of this second cell population was positive for inhibin a (1:25, Dako) and CD56 (1:100, Novocastra, Newcastle-upon-Tyne, UK), and negative for chromo- granin A (1:100, Dako), synaptophysin (1:200, Dako), S100 (1:1,000, Dako), serotonin (1:100, Dako), somatostatin (1:800, Dako), CK7 (1:100, Novocastra), and CK20 (1:50, Dako) [2]. The Ki-67 index was high (>4%; Fig. 1) [2]. Capsular and vascular invasion could not be assessed due to sample fragmentation. The final diagnosis was concurrent Pheo and adrenal cortical carcinoma (ACC).
In July 2009, the patient underwent surgery for a nodule in the left flank that appeared to be a subcutaneous metastasis of the ACC, with large areas of necrosis, pseudo-capsule invasion, and infiltration of the surrounding tissues.
Although several authors reported the association of Pheo with benign adrenal gland cortical conditions (i.e., hyperplasia or adenoma), this is the first report, to the best of our knowledge, of the concurrent occurrence with an ACC [3-10].
The coexistence of the two conditions may have different possible explanations. The simultaneous presence of Pheo and an adrenal cortical proliferation might only be an incidental event, or the manifestation of a genetic predisposition to endocrine dysplasia and tumor. On the other hand, factors secreted by the Pheo may stimulate adrenal cortex hyperfunction/proliferation in an unknown paracrine way. Indeed, Pheo are able to produce and secrete a variety of peptides, including adrenocorticotropic hormone (ACTH), insulin-like growth factor II (IGF2), somatostatin, growth-hormone-releasing hormone (GHRH), corticotropin-releasing hormone (CRH), oxytocin, antidiure- tic hormone (ADH), parathyroid hormone-like (PTH) factor, calcito- nin-like factor, vasoactive intestinal peptide (VIP), and interleukin-6 (IL-6) [3]. Therefore, those and other still unknown substances might explain an interaction between the contiguous medullary and cortical tissues.
In our patient, the research of germ-line mutations of VHL, RET, SDHB, SDHC, SDHD, and TMEM127 by direct sequencing of exons and multiplex ligation-dependent probe amplification on DNA
*Correspondence to: Ambrogio Fassina, MD, Department of Diagnostic Medical Sciences and Special Therapies, University of Padova, Via Gabelli 61, 35100 Padova, Italy. Fax: +39-049-8213782
E-mail: ambrogio.fassina@unipd.it
Received 22 August 2010; Accepted 27 August 2010
DOI 10.1002/jso.21759
Published online 28 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
extracted from peripheral blood leukocytes resulted negative, confirming the sporadic nature of the Pheo and excluding a genetic predisposition to develop this endocrine tumor. Thus, the remaining possible explanations of the coexistence of the two tumors are that it was an incidental event or that substances secreted by the Pheo caused the development of the ACC. We follow the opinion that factors secreted by the Pheo may stimulate adrenal cortex proliferation in paracrine way. Indeed, as suggested in the elegant case report on the coexistence of bilateral adrenal Pheo and idiopathic hyperaldosteron- ism by Tan et al. [3], the occurrence of Pheo with adrenal cortical abnormalities in so many patients, including ours, would make incidental occurrence improbable. However, hormonal products causing the neoplastic transformation in the cortex remain to be investigated.
ACKNOWLEDGMENTS
The authors thank Dr. Vincenza Guzzardo for the skilled execution of the immunohistochemical staining. The manuscript has been seen and approved by all authors who gave permission for the publication of the letter.
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