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.
