Perivascular Epithelioid Cell Tumor of the Cervix with Metastasis to the Brain ()
1. Introduction
PEComas are rare mesenchymal tumors distinguished by histologically and immunohistochemically peculiar perivascular epithelioid cells. Due to their heterogeneous clinical presentations and rarity, especially in the gynecological tract, these tumors pose a diagnostic challenge. PEComas may be found in the uterus, vulva, vagina, and retroperitoneum and are often associated with tuberous sclerosis complex [1]-[3].
These specific tumors include Angiomyolipomas (AMLs), clear cell sugar tumors, Primary Extrapulmonary Sugar Tumor (PEST), Lymphangioleiomyomatosis (LAM), Clear-Cell Myomelanocytic Tumor (CCMT) of the falciform ligament/ligamentum teres, primary cutaneous PEComa (CCCMT-Cutaneous Clear Cell Myomelanocytic Tumor) and PEComas not Otherwise Specified (NOS) [4]-[11].
In the gynecological field, uterine PEComas are particularly challenging to diagnose preoperatively. Studies have reported cases where these tumors were only identified postoperatively, highlighting the difficulties in clinical recognition and diagnosis [12].
We hereby report our findings to bolster the current knowledge concerning the clinicopathologic features, diagnostic pitfalls, and treatment strategies for PEComas within the gynecologic tract, owing to the yet-to-be settled controversies surrounding PEComas. Different previous articles will enable us to place an account on the fourth publication about PEComa with spread to central nervous system and the first one on cervical PEComa that tended to invade the brain. The patient has granted consent for publication of this case.
2. Case
A 65-year-old woman with a history of three pregnancies with three living children had postmenopausal bleeding and no history of fever, palpitation, chest tightness or abdominal pain. Her medical history included hypertension managed with amlodipine and she denied prior malignancies or TSC-associated symptoms like seizures or cognitive deficits. Family history revealed no neoplasm or genetic disorders. On gynecological examination, senile changes in the vulva, a small amount of dark brown vaginal secretion without a peculiar smell, atrophied and smooth cervix and forward tilted, atrophied uterus with no tenderness or mass. Cervical TCT and HPV tests were normal. A pelvic MRI showed a mass seen in the cervical canal (Figure 1). She underwent hysteroscopic surgery where two masses were resected, one from the cervix at 12 o’clock and the other from the proximal uterine wall. The first pathological results on the first mass of the cervix showed a heterotypic cell with an occasional mitotic Figure 1/50 hpf, and it was concluded in the immunohistochemical staining that they were finally excluded. epitheliogenic, neurogenic and lymphohematopoietic tumors while the second mass at the uterine wall was confirmed as an endometrial polyp. Considering the rarity of this malignancy and the high capacities for extreme complications, the current patient was vigilant about her condition. In view of the diagnosis of Perivascular Epitheliod Cell tumor (PEComa) with malignant potential unknown and tumor thrombus in the right iliac vein, the patient received laparoscopy-assisted abdominal hysterectomy and bilateral salpingioophorectomy. Histological examination revealed a tumor measuring 1 cm × 1 cm × 0.5 cm on the serosal surface and 1/3 < 2/3 infiltrating the cervical wall. In addition, 1 in 50 high-power fields exhibited mitotic figures. Definite neoplastic necrosis or lymphangiogenesis could not be identified. In addition, the cervical body junction, uterine and bilateral fallopian tubes were not affected by the tumor. Immunohistochemically, the tumor stained positive for MelanA, SMA and HMB45, focally positive for vimentin and Ki-67, but negative for CK7, S-100, CD99, Desmin, CKpan, CD38 and LCA. The patient was counseled for genetic testing, but she refused. The tumor thrombus as a result of immobilization in the right external iliac vein was removed. The D-dimer levels on the third postoperative day were 6171 ng/L. She was treated with enoxaparin and discharged from the hospital on the seventh postoperative day, once the pathology results were available. A review 2 weeks postoperative revealed slurred speech and right limb weakness without an obvious cause. She was able to grasp things by her right upper limb but was only able to walk slowly with her right foot dragging on the floor. The MRI of the brain (Figure 2) showed severe metastasis, a diameter of 4 cm
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Figure 1. Pelvic MRI showing a mass in the cervix pointed with the black arrows.
Figure 2. Brain MRI showing a mass in the left posterior temporal lobe pointed by the black arrows.
in the right posterior temporal lobe. A craniotomy was performed under general anesthesia through a right temporal approach. A curvilinear incision was made over the right temporal region followed by elevation of a bone flap. The dura was opened in a cruciate manner, revealing a 4 cm lesion in the posterior temporal lobe. Gross total resection was achieved using microsurgical techniques and neuronavigation assistance, ensuring preservation of surrounding functional cortex. Hemostasis was secured and the dura closed primarily. The bone flap was replaced, and the wound was closed in anatomical layers. Histology confirmed the brain lesion as metastatic cervical PEComa.
Postoperative follow-up care included neurological monitoring, physiotherapy for right-sided weakness, and periodic imaging to assess for recurrence. The patient was referred for oncologic evaluation, including consideration of targeted therapy with mTOR inhibitors based on the known pathway involvement in PEComa. Although initial genetic testing was declined, repeat counseling was provided, emphasizing the potential benefits of identifying TSC1/TSC2 mutations for guiding systemic treatment options and familial risk assessment.
3. Discussion
The malignancy of PEComa is dependent on cellular characteristics irrespective of the site of origin. Sites of prominent metastasis include lung, bone, liver, intestine, and lymph nodes, whereas cases of isolated CNS metastases have been observed in only three instances due to the protective nature of the CNS, arising from the presence of the blood-brain barrier which restricts the unhindered transference of tumor cells [13]-[15]. Herein we discuss a case of metastatic malignant PEComa to the brain, being the fourth incident documented in a middle-aged female.
PEComas are a type of tumor that is characterized by the presence of genetic alterations constituting tuberous sclerosis complex (TSC); specifically, they show the loss of TSC1 and TSC2 gene functions in 27% and 73% of cases, respectively. The TSC genes are important in the regulation of the Rheb/mTOR/p70S6K pathway. Electron microscopy shows multiple granules with the ultrastructural characteristics of promelanosomes within a cytoplasm that displays features similar to those of smooth muscle cells [13].
PEComas are defined as tumors characterized by the presence of myoid markers (SMA, desmin, caldesmon) and the melanocytic markers (HMB-45, Melan-A, MiTF) by means of immunohistochemical coexpression. Their mode of expression is variable with morphology: tumors that are mainly spindle show strong muscle marker expression with limited melanocytic marker expression; predominantly epithelioid tumors may show strong expression of melanocytic markers with limited muscle marker expression [4] [5] [10] [11] [16] [17].
Immunohistochemical results showed positivity with Melan A, SMARCA4, HMB45 and negativity with CK7, S-100, CD99, Desmin, CKpan, CD 138, LCA work, showing the tumor showed much stronger expression of melanocytic markers than muscle markers which was consistent with studies reporting varied marker expression in cervical PEComas where HMB-45 was positive in all samples, Melan-A in 83%, and desmin in 66% [8].
PEComa occurring at “non-classic” anatomic distributions is known as PEComa-not otherwise specified (PEComa-NOS) and has been reported in gynecological, genitourinary, gastrointestinal, extremities, skin, heart, breast, oral cavity, and orbit with uterus as the most prevalent site. In our case report the patient had tumor size of 1 × 1 × 0.5 cm in diameter, with mitotic rate of 1/50 hpf, without nuclear pleomorphism, no neoplastic necrosis or lymphovascular invasion seen which is supportive of a benign/uncertain malignant classification of the PEComas as in (Table 1) [16]-[18].
Based on the risk stratification guidelines proposed by Bleeker et al., primary tumor size greater than 5 cm and a high mitotic rate of 1/50 hpf were identified as significant factors associated with recurrence in malignant PEComa cases [14]. For instance, a primary tumor exceeding 5 cm in size may indicate a more aggressive nature of the disease, leading to a higher likelihood of recurrence post-resection. Moreover, a high mitotic rate of 1/50 hpf, such as in our case with a 1.5 cm tumor, has been linked to an increased risk of metastasis. However, the exact timeline for recurrence or metastasis remains uncertain due to the rarity of such cases.
In our patient’s case, the diagnosis of PEComa of the cervix was established through Hysteroscopic and MRI evaluations prompted by postmenopausal bleeding symptoms. Interestingly, there were no initial signs of CNS involvement until several weeks after the initial surgery, which involved a total abdominal hysterectomy and bilateral salpingectomy. This delay in CNS manifestation highlights the challenge in detecting brain lesions early, especially since many patients with brain metastasis may not exhibit symptoms initially. Detecting brain metastasis promptly is
Table 1. Showing worrisome features predictive of outcome in patient with PECOmas refference from Gadduci and Zannoni 2020.
Folpe et al. |
|
Schoolmaster et al. |
|
Bennet
et al. |
|
Category |
Histologic criteria |
category |
Histologic criteria |
category |
Histologic criteria |
Benign |
No worrisome features: less than 5 cm in diameter, non high nuclear grade and cellularity, mitotic rate <1/50 hpf, no necrosis, no vascular invasion |
Bening/ uncertain malignant potential |
Less than 4 worrisome features: size > 5 cm, high grade atypia(excluding degenerative atypia), mitosis > 1/50 hpf, necrosis, lymphovascular invasion |
Uncertain malignant potential |
Less than 3 worrisome features: size > 5 cm, high grade atypia(excluding degenerative atypia), mitosis > 1/50 hpf, necrosis, lymphovascular invasion |
Uncertain malignant potential |
One or both of the following features: nuclear pleomorphism,multinucleated giant cell only or size > 5 cm |
|
|
|
|
Malignant |
Two or more worrisome features: Size > 5 cm in diameter, infiltrative, high nuclear grade and cellularity, mitotic rate> 1/50 hpf, necrosis, vascular invasion |
Malignant |
4 or more worrisome features: size > 5 cm, high grade atypia(excluding degenerative atypia), mitosis >1/50 hpf, necrosis, lymphovascular invasion |
Malignant |
3 or more worrisome features: Less than 3 worrisome features: size > 5 cm, high grade atypia(excluding degenerative atypia), mitosis> 1/50 hpf, necrosis, lymphovascular invasion |
|
Hpf:High power field |
|
|
|
|
crucial as it can significantly impact treatment outcomes, particularly in determining the need for adjuvant therapy post-resection.
The malignancy of PEComa is dependent on cellular characteristics irrespective of the site of origin. Prominent sites of metastasis include lung, bone, liver, intestine, and lymph nodes, with isolated CNS metastases documented in only three prior cases due to the protective nature of the blood-brain barrier [13]-[15].
Management strategies for PEComas are evolving with increasing focus on targeted therapies and risk-based stratification. Surgical resection remains the cornerstone for localized disease, and complete resection of metastases is pursued where feasible. Several case reports and small series have demonstrated efficacy of mTOR inhibitors such as sirolimus and everolimus, which act downstream of TSC1/TSC2 mutations, particularly in recurrent or metastatic disease [5] [10]. In our case, we did not give any chemotherapy since our patient declined genetic testing which could help to identify the TSC1/TSC2 mutations.
Surgical strategies for such tumors typically involve surgical resection of the brain lesions. A successful example can be seen in a study by Parfitt et al., where a temporal craniotomy was performed, resulting in improved patient outcomes. Similarly, Jayapalan et al. conducted a dual lesion resection using intraoperative CT image guidance, showcasing the importance of precise surgical techniques. Additionally, Bharadwaj et al. opted for a right occipital craniotomy coupled with tumor decompression and mTOR pathway inhibitor therapy, demonstrating the evolving landscape of treatment options in managing PEComa metastasis. Regular follow-ups, as seen in the 6-month monitoring plan, are crucial in monitoring the patient’s response to therapy and detecting any recurrence early on. The reluctant use of neoadjuvant and adjuvant radio- and chemotherapy is attributed to the fact that PEComas are considered resistant to those treatments and, apart from several reports, there were no clear benefits of such an approach noted.
4. Conclusion
In conclusion, this case report sheds light on the very nature of including PEComas in differential diagnoses of post-menopausal bleeding, especially in the gynecological tract. The diagnosis of PEComa with brain metastasis in this patient challenges a more exigent discovery and relatively swifter intervention for such a rare tumor and the sustaining multidisciplinary approach in its management. The case further reiterates the importance of routine follow-ups assessing the patient’s treatment response and the early detection of any recurrence. Finally, this case report adds to the literature regarding PEComas and shares the much-needed impetus for awakening awareness and recognition of this rare tumor in the gynecological tract.