Unusual Pediatric Sigmoid Perivascular Epithelioid Cell Tumor with Regional Lymph Node Metastasis Treated Using Gemcitabine and Docetaxel: A Case Report and Literature Review

Background Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm with distinctive morphology and specic expression of immunohistochemical markers. The lesion is typically diagnosed in middle-aged women, and few pediatric cases have been reported. However, standardized treatment for the tumor type remains unestablished. Herein, we report a case of a pediatric patient with gastrointestinal PEComa of the sigmoid colon with regional lymph node metastasis. The patient was successfully treated with complete tumor resection and gemcitabine/docetaxel combination chemotherapy without local or distant recurrence after 12 months postsurgery. Case presentation A 17-year-old female adolescent presented with gastrointestinal PEComa of the sigmoid colon with regional lymph node metastasis. She was treated with surgical resection of the tumor and cytotoxic chemotherapy with gemcitabine (900 mg/m2) and docetaxel (100 mg/m2) every 3 weeks. There was no recurrence of hematochezia stool, and complete response was achieved, with a progression-free survival of 12 months. Conclusion Surgical resection with adjuvant conventional cytotoxic chemotherapy can be considered as the rst-line treatment for early-stage gastrointestinal PEComa.

PEComas-not otherwise specified (PEComas NOS) are clear-cell tumors of other anatomic locations, those that do not qualify for the predominant assemblage of the PEComa family, such as the aforementioned tumor types [3]. PEComas NOS are typically diagnosed in women aged 38.9-56 years and are focused on the uterus and gastrointestinal (GI) tract, with the uterine corpus lesions accounting for 41% of the reported cases [1,[4][5][6][7][8]. Immunohistochemically, PEComas NOS typically exhibit positive melanocytic and myogenic markers, such as human melanoma black 45 (HMB45), melanoma antigen recognized by T cells (melan-A), and smooth muscle actin, and negative expressions of protein S100, cytokeratin, and desmin [9][10][11]. However, the histogenesis and corresponding normal cellular counterpart of PEComa remain unknown [1,3], and a standardized treatment strategy remains unestablished [2].
Because of their unpredictable histopathological manifestation, patients with aggressive PEComas have poor prognosis and do not respond well to chemotherapy [5,12,13]. The mammalian target of rapamycin (mTOR) inhibitor treatment remains controversial in patients lacking the tuberous sclerosis complex (TSC) gene mutation [5,9]. To date, radical surgical resection is an effective treatment for primary tumor and local recurrence prevention [2]. Herein, we report the case of an adolescent female patient with an unusual PEComa. The patient had regional lymph node metastasis presenting as a large bleeding rectosigmoid tumor, which was successfully treated with complete resection and gemcitabine/docetaxel chemotherapy. No local or distant recurrence was observed even after 12 months postsurgery.

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Case Report A 17- year-old female adolescent visited our emergency room with painless hematochezia stool for 2 days. The patient also had symptoms of dizziness and fainting, but did not have fever, other gastrointestinal symptoms or signs, trauma history, or recent weight loss. The laboratory ndings were as follows: hemoglobin level, 6.0 g/dL; white blood cell count, 8720 cells/mm3; and platelet count, 384,000 cells/mm3. The stool culture and laboratory test results were within the reference range, as were the tumor markers. Blood transfusion was performed for severe anemia. Tranexamic acid was also administered for massive bloody stool. Ultrasonography revealed a suspicious 2.9-cm ovoid mass in the pelvis region. Six cycles of cytotoxic chemotherapy with a combination of gemcitabine at 900 mg/m2 and docetaxel at 100 mg/m2 every 3 weeks were completed. A repeat abdominal CT scan 6 months after surgical resection revealed no local recurrence or distant metastasis. Colono beroscopy results performed 1 year after surgery were unremarkable. The patient's clinical condition remained stable after complete resection and treatment with gemcitabine/docetaxel without local or distant recurrence at the 12-month follow-up.

Discussion
Studies on treatments and outcomes speci c to PEComa are limited to institutional series and anecdotal case reports. A PubMed search (accessed in July, 2020) revealed 62 cases of gastrointestinal PEComa NOS in the literature; the colon was the most commonly affected part in the abdominal cavity, followed by the mesentery, rectum, stomach, duodenum, ileum, cecum, and other locations [3]. The GI tract is the subfrequent location, preceded only by gynecological tract [8]. In addition, polypoid tumors centered in the mucosa and submucosa principally occur in the cecum and rectum [14]. Folpe et al. [11,15] indicated that GI PEComas have a conspicuous female tendency, along with an incidence peak in the fourth or fth decade of life [3]. However, some GI PEComas have previously been reported in children [14,[16][17][18]. The rst pediatric case of metastatic PEComa of the colon was recorded in 2008 [17]. An 11-year-old prepubertal Caucasian boy received resection of a 5.5-cm-long sigmoid colon. At the 5-month follow-up, the results of repeat CT were unremarkable and the boy was asymptomatic [17]. In 2009, another report similar to our case was published. A girl aged 15 years with rectal PEComa and lymph node involvement was successfully treated with surgical resection and adjuvant chemotherapy (doxorubicin, ifosfamide, and mesna) without recurrence at 9 months postsurgery. Regardless of the affected age group, prognostic pathologic markers of the GI PEComas are few because of the rare nature of the neoplasm [14].
Differentiating GI PEComa from GI stromal tumor (GIST) or other sarcoma is challenging because PEComa generally presents a biphasic GIST-compatible morphology [12]. PEComa's clinical manifestation is variable and with little discrimination, including abdominal pain, rectal bleeding, or asymptomatic [3,18]. Hematochezia stool was observed in our patient, whereas intermittent rectal bleeding was observed in several pediatric patients [14,16,19]. Imaging studies assist in identifying the lesion to a certain degree [20,21]. Arteriovenous hypervascularity may be observed in contrast-enhanced CT, but most areas are seen as homogeneous and well-demarcated masses with clear boundaries in plain CT [21]. Endoscopy can facilitate the detection of a polypoid tumor or fungating mass with irregular ulceration, and tumors are generally observed as a rich vascularization with a hyaline wall or even necrosis [4,22].
Folpe et al. [11] established a series of criteria to distinguish the pathological behavior of aggressive PEComa, namely high-risk features such as a size of ≥5 cm, a mitotic rate of ≥1 cells/ high power eld (HPF), an in ltrative growth pattern, high nuclear grade and cellularity, necrosis, and vascular invasion.
Another study proposed that a tumor size of ≥5 cm and a mitotic rate of ≥1 cells/ HPF are crucially associated with prognosis and recurrence [1,5,20,24]. Tumors with ≥2 high-risk characteristics are categorized as malignant PEComa, and 81.6% of such lesions may relapse within 23 months [2,23]. In our patient, pedunculated polypoid lesion in the sigmoid colon was approximately 3.5 × 3.1 × 2.8 cm3, with no evidence of necrosis. The tumor was well limited in the submucosa, with no further in ltration.
Surgical resection is the preferred treatment for primary tumor GI PEComas, especially in the benign and chemoradioresistant groups [3,4,7,14]. It is also adopted to manage local recurrence after initial therapy, enabling long-term control of metastatic foci [12,25]. Most tumors are eradicated at the size of 4-6 cm when excision is performed [12,18]. Cheng et al. [24] successfully treated patients with recurrent PEComas of the sigmoid colon with pancreatic metastasis by surgical resection alone. In 2018, a patient with rectum PEComa with recurrent liver metastases was cured through surgery. However, 37.1% of patients treated with surgical resection without adjuvant therapy can develop distant metastases after 6 months [26]. All of the pediatric patients [14,[16][17][18] were treated with surgery as an initial management strategy. However, the preferred adjuvant therapy, including doxorubicin, paclitaxel, gemcitabine, and oxaliplatin alone or in combinations, is a matter of contention [5,9,13,14,27,28]. For benign PEComa, no standardized regimen has been provided to avoid recurrence after surgery [3,4]. Clinical outcomes in the published literature are varied. Ryan et al. reported the case of a patient aged 15 years with rectum PEComa and lymph node involvement. The patient was successfully treated with surgical resection and adjuvant chemotherapy with a combination of doxorubicin, ifosfamide, and mesna, with no recurrence at 9 months postsurgery. [14] In 2010, another report described a patient aged 7 years with ascending colon PEComa who was treated with adjuvant IFN-α2b immunotherapy after resection, with a good prognosis [27]. Bleeker et al. [4] demonstrated that conventional cytotoxic chemotherapy is not effective in malignant PEComas and emphasized the superiority of mammalian target of rapamycin (mTOR) inhibitor therapy. The mTOR pathway regulates cell growth and is associated with the inactivation of tuberous sclerosis complex 1 (TSC1) and TSC2 genes [1,12]. Characterization of TSC1 and TSC2, along with their downstream products [2,13], could help develop targeted therapeutic agents, such as sirolimus or tacrolimus. However, contrary results were observed when a female patient aged 58 years with metastatic PEComa was treated with a combination of topotecan, temsirolimus (mTOR inhibitor), and bortezomib [28]. Moreover, a male patient aged 23 years with colon PEComa demonstrated resistance to mTOR inhibitor therapy but maintained stable prognosis when treated with a combination of doxorubicin and ifosfamide for 9 months [13]. In accordance with the published literature and our institutional experience, we suggest surgical resection with adjuvant conventional cytotoxic chemotherapy as the rstline treatment for early-stage GI PEComas. For tumors manifesting ≥2 aggressive pathological behaviors [5,11], the TSC gene should be identi ed to evaluate the need for mTOR inhibitor therapy.
Metastases may not be observed in some patients even up to 10 years after tumor resection. Thus, such patients especially with tumors measuring >8 cm require monitoring for several years after surgical treatment [2,12]. Freeman et al. documented the longest follow-up of 180 months in a patient with PEComa of the sigmoid colon measuring 6 cm who was successfully treated with radical excision [29]. Pisharody et al. suggested that physical examination and CT scans must be performed every 6 months and endoscopy should be conducted every year after surgery to monitor local recurrence and distant metastasis. [3,17] Conclusion Studies on PEComas are few and demonstrate high heterogeneity. Therefore, a comparative study to determine the optimal treatment is challenging. This study suggests surgical resection with adjuvant conventional cytotoxic chemotherapy as a treatment option for early-stage GI PEComas. However, well-documented clinical trials should be performed to accumulate immunohistochemical evidence and suggest empirical therapy. The ndings can be extrapolated to practice procedures. Declarations Ethics approval and consent to participate: As this study is a case report, ethics approval was not necessary after consulting the Institutional Review Board of Kaohsiung Medical University Hospital Consent for publication: Written informed consent was obtained from the patient and the parents for publication of the case report and the accompanying images.
Availability of data and material: The datasets supporting this manuscript are included within the article. All raw data can be acquired from the corresponding author.