Abstract
Background: Malignant mixed corticomedullary adrenal tumors (MCMTs) are extremely rare, with limited cases reported in the literature. The pathophysiology of malignant MCMTs is not well understood; the most prevailing theories are that it is a composite tumor of embryologically derived mesodermal (adrenal cortex) and neural crest (medulla) origin, perpetuating as two distinct cell lines forming a singular mass. Clinical features and laboratory diagnosis are associated with hypersecretions of the adrenal cortex and medulla. Surgical resection is curative in an isolated tumor. We reviewed and compared cases in the literature highlighting the pathogenesis and genetics of benign and malignant MCMT. Methods: Comprehensive literature analysis was conducted on PubMed and all the cases of mixed corticomedullary adrenal tumor published in English were included. Results: Most patients were female (73.1%) with a median age of 49 in women and 50 in men. Surgery was performed in all patients, and in four patients with malignant disease, chemotherapy was used as well. Clinically, most patients presented with hypertension (69%) followed by Cushing syndrome (42%) and diabetes (19%). Tumors often produced cortisol (74%), catecholamines (50%), and adrenocorticotrophic hormone (ACTH) (38%), with lower incidence of aldosterone- (7%) or dopamine (4%)-producing tumors. Immunohistochemical staining of 96% of cases showed Chromogranin-A (73%) and Synaptophysin (62%), followed by Inhibin-α (50%), Melan-A (31%), and S-100 (23%). Of the reported four cases with malignant disease, three showed a Ki-67 index of 40–50% with one showing less than 5%. Conclusion: Mixed corticomedullary adrenal tumors rarely present as a malignant disease requiring chemotherapy. Most MCMTs confer a good prognosis and respond well to surgical resection, though their pathogenesis is largely up to speculation because of limited data. Current theories regarding MCMT pathogenesis should be investigated further with genetic testing. Future research on MCMT may provide ways to guide physician diagnosis and subsequent treatment for refractory cases.
1. Introduction
Mixed corticomedullary tumors (MCMT) were first described by Mathison and Waterhouse in 1969 [1]. They are described as such due to their histological distinctions of adrenal cortical and medullary components. While patterns emerge as to the symptoms, they are non-pathognomic and not known to be associated with other underlying etiologies. The presenting symptoms are in form of Cushing syndrome, hypertension, hyperaldosteronism, hypokalemia, paroxysmal hypertension, and hypertension emergency [1,2,3,4,5]. It is difficult to obtain a preoperative diagnosis due to the rare nature, and various presenting multisystem symptoms.
Treatment consists of resection the tumor through adrenalectomy. Surgical resection results in symptomatic relief. Few cases in the literature demonstrate any malignant potential associated with MCMTs, although it has been seen in more recent decades. The etiology and mechanisms(pathophysiology) of these tumors is not well understood. Many proposed mechanisms have been cited such as “collision theory”, overproduction of adrenocorticotrophic hormone (ACTH) in a pheochromocytoma, pluripotent stem cells, or an underlying oncogene component [6,7,8,9]. Given the scarcity at which MCMT is seen, it is difficult to study these tumors in a full investigative fashion.
2. Materials and Methods
The review was conducted through PubMed with the search terms “corticomedullary”, “mixed”, and “adrenal”. Inclusion criteria were based on reports evaluated on having reported a case of mixed corticomedullary tumor(s). There were no exclusion criteria.
3. Results
Mixed corticomedullary tumors have a predilection in female patients (19/26), with mixed results between sides that would be expected for bilateral organs. The age range for all cases (male and female) was from 25 to 78. The median age for women (n = 19) and men (n = 7) was 49 and 50 years. The initial presenting symptoms were variable, with hypertension in 18/26 (69%) and Cushing syndrome in 11/26 (42%) being the most common (Table 1). Diabetes was present in 5/26 (19%) patients, and one patient presented with gestational diabetes. Four cases presented with flank pain, ipsilateral in three and contralateral in one patient. Tumor size is variable, with the smallest measuring 2.5 × 2.4 × 2.0, and the largest 22 cm.
Table 1.
Characteristics of MCMT.
Hormone production varied slightly among tumors. The most common was cortisol production 73% (19/26) and catecholamines 50% (13/26). ACTH production was high in 38% (10/26), aldosterone in 7% (2/26), and dopamine in one case (4%). Immunohistochemical staining was performed in 25/26 cases (96%). Chromogranin-A and synaptophysin were the most commonly seen in 19/26 (73%) and 16/26 (62%) cases, respectively. Adrenal cortical staining was shown most often with Inhibin-α 13/26 (50%), Melan-A 8/26 (31%), S-100 6/26 (23%). Less common were calretinin and INMS1. In one case, CYP17, CYP11 β, TH, DBH, and PNMT were used (Table 2).
Malignant features were seen in 15% (4/26) of cases. Tumor necrosis was observed in these malignant cases. Three-fourths of cases showed a Ki-67 index, with one showing <5%, and the others 40–50%. Three studies had genetic sequencing performed to identify an underlying molecular alteration for these tumor presentations. Additionally included in this review were two studies where the tumors were seemingly “mixed” but were not described as the other tumors. Delevaux described it as a “dual tumor”, whereas Duan described the tumor as having a “distinct arrangement of cortical and medullary layers”.
Table 2.
Documented cases of mixed corticomedullary tumors (benign and malignant). TH (tyrosine hydroxylase); DBH (dopamine beta hydroxylase); PNMT (phenylethanolamine-N-methyltransferase; CYP17 (17 α -hydroxyl/17,20-lyase); 3β -HSD (3β-hydroxy-Δ5-steroid dehydrogenase).
Table 2.
Documented cases of mixed corticomedullary tumors (benign and malignant). TH (tyrosine hydroxylase); DBH (dopamine beta hydroxylase); PNMT (phenylethanolamine-N-methyltransferase; CYP17 (17 α -hydroxyl/17,20-lyase); 3β -HSD (3β-hydroxy-Δ5-steroid dehydrogenase).
| Reference | Age | Sex | Clinical Features | Size (cm) | Hormones | Immunohistochemistry (+) | Malignant | Genetic Analysis | Concurrent Pathological Findings | Treatment |
|---|---|---|---|---|---|---|---|---|---|---|
| Mathison and Waterhouse [1] | 39 | F | Cushing syndrome, hypertensive crisis | 4 × 3 × 3 | Cortisol, ACTH, catecholamines | N/A | N | N | None | Left adrenalectomy |
| Akai [7] | 61 | F | HTN | 3 × 3.5 | Cortisol, ACTH, catecholamines | N/A | N | N | None | Right adrenalectomy |
| Ohta [10] | 32 | M | Cushing syndrome, HTN | 4.5 | Cortisol, ACTH | N/A | N | N | None | |
| Michal and Havlicek [11] | 56 & 32 | F | 56—Cushing syndrome, hypertension 32—Cushing’s HTN | (56)—6 × 7 × 8 (32)—9 ×7 × 5 | Cortisol, ACTH, aldosterone | Synaptophysin, chromogranin, EMA, 113-1 | N | N | (56)—spindle cell carcinoma | Adrenalectomy |
| Delevaux [2] | 47 | M | HTN, diabetes | 9 | Aldosterone | NSE | N | N | None | Left adrenalectomy |
| Weinke [6] | 34 & 52 | F | 34—HTN, hair loss, amenorrhea 52—Cushing syndrome, flank pain | (34)—4.5 (52)—4.5 × 2.5 | (34)—Cortisol (52)—N/A | Synaptophysin, chromogranin, S-100, Inhibin-α | N | N | None | Right adrenalectomy |
| Chu [12] | 55 | F | Cushing syndrome | 2.5 × 2.4 × 2.0 | Cortisol, ATCH | Inhibin-α, Melan A, calretinin, chromogranin, synaptophysin | N | N | Ipsilateral myelolipidoma | Left adrenalectomy |
| Lee [3] | 25 | F | Weight gain, bitemporal headache, postpartum diabetes | 3.2 | Cortisol, ACTH, catecholamines | Inhibin-α, Melan A, chromogranin | N | N | Contralateral pheochromocytoma and ganglioneuroma | Right adrenalectomy |
| Ma [4] | 41 | F | Cushing syndrome, amenorrhea, weight gain, HTN | 4 × 4 | Cortisol, ACTH (catecholamines not measured) | Synaptophysin, chromagranin, Melan A, Inhibin-α | N | N | None | Left adrenalectomy |
| Kimura [5] | 54 | F | HTN, diabetes | 5.3 × 4.9 | Cortisol, catecholamines | Chromogranin A, P450c21 | N | N | None | Left adrenalectomy |
| Ajmi [13] | 34 | F | Hirsutism, weight gain, amenorrhea | 6 × 4 | Cortisol | Chromogranin A | N | N | None | Right adrenalectomy |
| Alexadraki [14] | 66 | F | Mild HTN, subclinical Cushing syndrome | 4.2 × 3.7 × 3.4 | Cortisol, ACTH, catecholamines | Synaptophysin, chromogranin | N | N | None | Left adrenalectomy |
| Singh [15] | 48 | F | Weight gain, edema | 8 × 7 × 9 | Catecholamines | Synaptophysin, chromogranin, S-100, Inhibin-α | N | None | Right adrenalectomy | |
| Lau [16] | 64 | F | HTN | 3.6 | Catecholamines | Synaptophysin, Melan A, Inhibin-α | N | N | None | Right adrenalectomy |
| Michalopoulos [17] | 63 | F | Weight loss, abdominal pain | 8 × 7.5 × 4.5 | Cortisol, ACTH, catecholamine | Synaptophysin, chromogranin, NSE, Vimentin, S-100, calretinin, CKAE1/AE3 | Y | N | Ki67 <5% Microvascular and capsular invasion | Right adrenalectomy Chemotherapy: carboplatin and etoposide |
| Kaneko [18] | 63 | M | HTN, diabetes | 3.5 × 2.6 × 2.6 | Dopamine | Synaptophysin, chromogranin | N | N | None | Left adrenalectomy, partial nephrectomy |
| Donatini [19] | 53 | M | Right flank pain | 5.5 × 4 × 3.5 | Catecholamines | Synaptophysin, Melan-A, Inhibin-α | N | N | None | Left adrenalectomy |
| Turk [20] | 78 | F | HTN, dizziness | 10 | Androgens, catecholamines | Synaptophysin, chromogranin, Melan-A, Inhibin-α | Y | N | Ki67, 40–50%, tumor necrosis, vascular invasion Stage III with Stage IV metastasis in liver at day 121 postop | Left adrenalectomy Chemotherapy: carboplatin and etoposide |
| Thinzar [21] | 48 | M | Fatigue, HTN, bruising | 3.9 | Cortisol, catecholamines | Synaptophysin, chromogranin, S1-100, Melan-A, Inhibin-α | N | N | Ki-67, <1% | Left adrenalectomy |
| Alsabek [22] | 50 | M | Left flank pain, anorexia, weakness, weight loss | 22 | Cortisol | Chromogranin, S-100, Inhibin-α, calretinin | Y | N | Tumor necrosis, focal but no capsular invasion | Left adrenalectomy |
| Duan [23] | 58 | M | Subclinical Cushing syndrome, HTN, diabetes | 3 × 3.8 | Cortisol, catecholamines | SF-1, chromogranin | N | N | Spindle positive cells | Right adrenalectomy |
| Kanzawa [24] | 31 | F | Gestational HTN | 3.8 × 2.4 | Cortisol, catecholamines | Synaptophysin, chromogranin, 3B-HSD, CYP17, CYP11β 1, TH, DBH, PNMT, Inhibin-α, INSM1 | N | Y | Ki-67 <1% | Right adrenalectomy |
| Chiou [9] | 32 | F | Cushing syndrome, hypertension | 8.8 | Cortisol | Chromogranin, SOX2, CD44, OCT4 | N | Y | None | Right adrenalectomy |
| Ramírez-Rentería [8] | 16 | F | Cushing syndrome, HTN | 9.3 × 7.6 × 10.4 | ACTH, cortisol | Inhibin A, Melin A, calretinin, ACTH, chromogranin A, synaptophysin, PS-100 | Y | Y | Metastasis, Ki-67: 40% | Right adrenalectomy |
+ (positive) N/A (not available), N (no), Y (yes), NSE (neuron specific enolase), () corresponds to age of the patient, & (and).
4. Discussion
Mixed corticomedullary tumors are a rare subset of adrenal tumors that display an appearance and clinical signs of adrenal cortical adenoma and pheochromocytoma. Seldomly they can be seen with other adrenal tumors, ipsilaterally and contralaterally. Most of the tumors reviewed were diagnosed postoperatively upon histological and immunohistochemical analysis. While there is a variation among the clinical presentations with these tumors, macroscopically the variation is not as broad. First termed “mixed corticomedullary tumors” by Weinke [6], due to their interspersed and mixed histological appearance in a single tumor, there are reports of a single tumor representing distinctly separate histological cortical and pheochromocytoma elements in the same encapsulated tumor in two cases [2,23]. We have included them in this review while not fitting the classic definition, as they were not macroscopically distinct and in a single encapsulation.
Diagnosis and Associated Features
Preoperative diagnosis is limited in these tumors due to their rarity and symptoms mimicking adrenal cortical, pheochromocytoma, or neither. The most common symptoms at presentation were Cushing syndrome, hypertension, and diabetes, of which many resolved completely after adrenalectomy. Postoperative cortisol and catecholamine levels in many cases returned to normal limits. A majority of cases were described as incidentalomas, in which the patient may have had hypertension and diabetes. Other concurrent tumors were found in some cases such as myelolipoma, spindle cell carcinoma, and ganglioneuroma. It is unclear if there is any association, or if this is a coincidental finding. In the case reported by Lau [16], the patient was noted to have a history of neurofibromatosis and breast cancer. Interestingly, this is the only case to have described a previous diagnosis of cancer in someone with MCMT. Kanzawa et al. [24] speculated there may be a potential underlying oncogenic mutation that could be understood between the two cancers, but this is difficult to interpret with a few cases [25,26].
The radiological findings are nonspecific, such as heterogeneously enhancing lesions and overlap with findings of pheochromocytoma. However, 123I-meta-iodobenzylguanidine (MIBG) scintigraphy show increased focal uptake [16,24,27,28].
5. Conclusions
This is the largest review of all cases in the literature to date and the only one to compare benign and malignant MCMTs. It is also the first to report this specific tumor type in a child. The authors propose to group cases such as Dele Vaux and Duan as mixed corticomedullary tumors due to the nature of both histological subsets being demonstrated in a single encapsulated tumor. As the pathogenesis of the disease state is uncertain, it is unclear why these tumors developed in discreet histological entities rather than truly mixed as seen in others. As genetic sequencing becomes readily available, there may be more cases reported to help elucidate any underlying genomic target for these tumors, specifically those with malignant potential. To better understand any genetic component that may be targeted, we recommend casting a wide array and comparing it to other adrenal and renal tumors in adults and children for further clarity and additions to the literature. Most MCMTs are benign and have a good prognosis after surgical intervention. Only a few cases were described with malignant features and metastasis requiring chemotherapy. Further investigation should be performed when these seldom-seen tumors are discovered to elucidate further information on pathogenesis and possible treatment for those that may recur despite resection.
Author Contributions
Conceptualization, A.U., S.H. and N.A.K.; methodology, A.U.; software A.Q.K.Y.; validation, J.K.; formal analysis, M.K.; investigation, A.U.; resources, K.B.; data curation, A.U.; writing—original draft preparation, P.T.S., A.U., K.T., S.M., F.A.E.M. and K.B.; writing—review and editing, N.A.K. and S.H.; visualization, A.U.; supervision, N.A.K. and S.H.; project administration, A.U.; funding acquisition, No funding. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
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