Key-words:
Adrenocortical carcinoma - brain neoplasms - myoepithelioma
Introduction
Myoepithelial tumors are rare neoplasms that develop from myoepithelial cells in glandular structures such as salivary glands, mammary glands, and secretory glands in dermis. It may also arise from soft tissue, but these two subtypes may have different genetic profiles.[[1]] Based on the degree of cellular atypia and mitotic activity, it can be classified into myoepithelioma with a benign course or myoepithelial carcinoma that is highly malignant.[[2]],[[3]],[[4]] Primary intracranial myoepithelial neoplasms are even rarer with only around nine cases reported [[Table 1]].[[1]],[[3]],[[4]],[[5]],[[6]],[[7]],[[8]],[[9]] Extra-axial tumors contributed to the majority in this cohort. Due to the rarity of such a condition, it has been considered as an independent disease without association with other diseases.
Table 1: Summary of primary intracranial myoepithelioma reported in literature
Adrenocortical carcinoma (ACC) is also uncommon with an annual incidence of 0.7–2 per million and carries a poor prognosis.[[10]],[[11]] Sporadic cases are more common, but it is known to have an association with familial cancer syndromes such as Li-Fraumeni syndrome, multiple endocrine neoplasia type 1, Beckwith–Wiedemann syndrome, familial adenomatous polyposis, Lynch syndrome, Carney complex, and neurofibromatosis type 1.[[10]],[[12]],[[13]],[[14]],[[15]],[[16]],[[17]] These conditions are not typically associated with myoepithelial neoplasms. On the other hand, 11.5% of nonfamilial cancer syndromes patients with ACC had other malignancy before or after their diagnosis of ACC.[[11]]
Despite the low incidence of each disease, we encountered a patient with both intracranial myoepithelioma and ACC which is the first known case report in the English literature.
Case Report
Our patient is a 34-year-old gentleman who enjoyed good past health. His grandparents died of terminal malignancies that were common locally at the age of above sixties. His parents have remained healthy. There is no suspicion of familial cancer syndrome. Just more than 1 year ago, he complained of lower abdominal discomfort. Computer tomography (CT) of the abdomen showed a huge mass at the hepatorenal fossa that arose from the right adrenal gland [[Figure 1]]a. The hormonal profile was unremarkable. Laparotomy for tumor excision was performed, and histopathology confirmed that it was an ACC. The tumor also invaded into the diaphragm, which showed capsular and venous invasion. The resection margin was clear. He received adjuvant radiotherapy uneventfully followed by long-term mitotane with hydrocortisone replacement. Two positron-emission topographies (PETs)-CT using 14F-fluorodeoxyglucose were performed at 1 month and 6 month after surgery. Both the studies showed neither local recurrence nor distant metastasis.
Figure 1: (a) Coronal image of computer tomography of the abdomen with contrast. Arrows marked the huge tumor in the hepatorenal fossa. (b) Axial plain computer tomography brain showed a hypodense lesion with calcification (arrow). (c) Coronal magnetic resonance imaging T1 sequence showed that the nodule had gadolinium contrast enhancement and was in contact with the tentorium (arrow). (d) Axial plain magnetic resonance imaging T2 sequence showed the cystic portion of the tumor (arrow)
He remained well till 12 months after operation when he complained of nonspecific headache associated with dizziness. The patient had no other symptoms and was neurologically intact. CT of the brain showed a hypodense lesion at the right occipital lobe with speckles of calcification [[Figure 1]]b. In retrospective review, the lesion had been present in prior PET-CTs without serial change. Magnetic resonance imaging (MRI) of the brain showed a right occipital cystic lesion with a gadolinium-enhancing mural nodule [[Figure 1]]c and [[Figure 1]]d. Given the diagnosis of ACC, the preliminary diagnosis was brain metastasis and stereotactic radiosurgery was contemplated. However, his treating oncologist opinioned that a biopsy should be taken, as the lesion did not look like metastasis. Craniotomy for tumor excision was performed. The lesion was found to be rubbery in consistency, had a calcified nodule that adhered to the tentorial surface, and contained clear cystic fluid. A gross total excision was achieved. The patient remained well after surgery.
Histopathological examination showed a partially calcified and extensively fibrotic nodular lesion adhered to the superficial brain cortex [[Figure 2]]a. The lesion comprises irregular nests and clusters of tumor cells in a hyalinized background, which focally (not extensively) infiltrates the cortex [[Figure 2]]b, [[Figure 2]]c, [[Figure 2]]d, [[Figure 2]]e. There is no cellular whorl formation. The cells possess oval nuclei containing dispersed chromatin and pale eosinophilic cytoplasm with indistinct cell borders. Their nuclei are mildly pleomorphic with dispersed chromatin. Mitotic figures are not identified. Neither necrosis nor vascular invasion is seen. Occasional cells display pseudonuclear inclusions; these are reminiscent of those seen in meningiomas, although nonspecific. In view of the clinical history, immunohistochemistry was pursued, which revealed the absence of convincing expression of meningothelial markers such as epithelial membrane antigen (EMA) and SSTR2A [[Figure 3]]a and [[Figure 3]]b. Instead, there are expressions of cytokeratins, glial fibrillary acidic protein (GFAP), S-100 protein, and focally smooth muscle actin [[Figure 3]]c, [[Figure 3]]d, [[Figure 3]]e, [[Figure 3]]f. The nuclear expression of INI1 is retained [Figure 3g]. They are negative for p63, glial markers (Olig2 and SOX10), neuroendocrine markers (melan A, inhibin, SF-1, chromogranin, synaptophysin, and calretinin), and TTF-1 (not shown). The Ki-67 proliferative index is low (1%) [Figure 3h]. This tumor is therefore morphologically different from the previously excised ACC, and the combination of expression of cytokeratin, GFAP, S-100 protein, and SMA is supportive of myoepithelial differentiation. Morphologically, the tumor is bland looking and shows low proliferation. However, it is difficult to accurately predict the biological behavior of this tumor since there have been no specific histopathological criteria for malignant myoepithelioma in the central nervous system nonetheless except for the focal cortical infiltration.
Figure 2: (a) The lesion displays a nodular configuration on low power, which is adhered to a rim of superficial brain cortex (to the right of the black line). Heavy calcification is focally noted (arrow) (H and E, ×20). (b and c) The tumor cells are arranged in irregular nests and clusters in a hyalinized background. They infiltrate into the superficial cortex in (b) (beyond the dotted line) (H and E, ×200). (d) Rare cells contain pseudonuclear inclusions (arrow; H and E, ×400). (e) Tumor nests in the brain cortex, associated with calcification (H and E, ×200)
Figure 3: By immunohistochemistry, the tumor cells do not show genuine staining for meningothelial markers such as epithelial membrane antigen (a) and SSTR2A (b). Some of them express cytokeratin (MNF-116) (c). They are diffusely positive for GFAP (d). They express S-100 protein diffusely (e) and smooth muscle actin focally (f). INI1 expression is retained (g). Their Ki-67 proliferation index is very low (h) (immunoperoxidase method, ×400)
This lesion had no alarming histological features; we therefore decided to observe without adjuvant treatment. CT of the abdomen performed 1 week after craniotomy showed no evidence of recurrent ACC. The patient was on his prior treatment for ACC with mitotane. MRI of the brain performed 4months after craniotomy showed no recurrent tumor.
Discussion
The origin of intracranial myoepithelial neoplasms has remained unknown. They have been postulated to be developed from salivary gland rest in the sellar region, middle cranial fossa, and cerebellopontine angle during embryonic development.[[1]],[[4]],[[18]] While these proposed mechanisms may explain extra-axial myoepithelial neoplasms located at the skull base, they cannot readily explain those occurring in intra-axial location, falx, high convexity dura, and in our patient, the occipital lobe.[[6]],[[8]] Apart from the heterogeneity in location, the reported cases had a variable spectrum of protein expression as shown by immunohistochemistry. The diagnoses, besides morphology, relied heavily on different combinations of cytokeratin, S-100 protein, EMA, SMA and GFAP, p63 and calponin expression.
The presence of focal cortical infiltration did raise some concern for its potential biological behavior despite the bland morphology and low proliferative index. However, an infiltrative border may not always herald an aggressive clinical course at least in the setting of soft-tissue myoepithelial tumors. In a study of 101 of such tumors in soft tissues, it was found that invasive growth cannot be relied upon as a useful prognostic finding since none of the infiltrative tumors recurred or metastasized.[[19]]
For a young patient like ours, the development of ACC and myoepithelioma, both being rare, led us to wonder if he had a germline predisposition to tumors or cancers. To the best of our knowledge, there has only been a single case report of myoepithelial carcinoma occurring in association with a hereditary cancer syndrome.[[20]] Although biallelic inactivation of the APC gene was demonstrated, myoepithelial carcinoma is not conventionally regarded as part of the tumor spectrum of FAP. On the other hand, most cases of ACC are sporadic, and as previously discussed, none of the associated hereditary syndromes are known to confer an increased risk of myoepithelial tumors.
Furthermore, the two tumors are not known to share common oncogenic pathways. Rearrangements of the EWSR1 gene have been reported to be associated with myoepithelial tumors in soft tissue and other nonsalivary gland locations.[[2]],[[5]],[[21]] A subset of skin and soft-tissue myoepithelial tumors display frequent PLAG1 gene rearrangements and therefore appear to be genetically linked to their salivary gland counterparts.[[21]],[[22]] For sporadic ACC, several comprehensive genomic studies have identified IGF2 overexpression, WNT pathway perturbations (CTNNB1 and ZNRF3 mutations), TP53 mutations, copy-number alterations including massive DNA loss and whole-genome doubling, and decreased telomere length.[[23]],[[24]],[[25]],[[26]] Overall, it appears that ACC and myoepithelial tumors show distinctly different mechanisms leading to their respectively genetic lesions.
With the available evidence, it is probably a coincidence that our unfortunate patient developed two rare tumors at a young age. Nonetheless, in the era of next-generation sequencing, whole-exome or whole-genome sequencing of germline and tumor DNA may hold the answer to our question of whether there is a hereditary predisposition to tumor development in this patient. Even so, it is anticipated that interpretation will not be straightforward, as this is the first known report of co-occurrence of two rare tumors and the complexities in demonstrating the pathogenicity of the many variants that will likely be identified.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
