Studies on treatments and outcomes specific 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. The GI tract is the subfrequent location, preceded only by gynecological tract. In addition, polypoid tumors centered in the mucosa and submucosa principally occur in the cecum and rectum. Folpe et al.[11, 15] indicated that GI PEComas have a conspicuous female tendency, along with an incidence peak in the fourth or fifth decade of life. However, some GI PEComas have previously been reported in children[14, 16-18]. The first pediatric case of metastatic PEComa of the colon was recorded in 2008. 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. 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.
Differentiating GI PEComa from GI stromal tumor (GIST) or other sarcoma is challenging because PEComa generally presents a biphasic GIST-compatible morphology. 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. 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].
Immunohistochemical discernment of melanocytic differentiation is the most effective approach to differentiating GI PEComa from other tumors, such as GIST, angiomyolipoma, paraganglioma, malignant melanoma, and alveolar soft part sarcoma. Although the precursor or normal counterpart of PEComa remains undefined, HMB-45 continues to be the most sensitive and frequent melanocytic marker in 92%–100% of reports[1, 2, 23]. Other potential melanocytic markers are melan-A, smooth muscle actin, and microphthalmia transcription factor, which were indicated in 23%–88%, 59%–93%, and 50%–92% of reports, respectively, as well as desmin and caldesmon[1, 2, 8, 10, 14, 23]. PEComa has negative expression for chromogranin A, synaptophysin and protein S100, which can divergent from paraganglioma. Diagnosis of GIST can be precluded if either perivascular concentric proliferation or representative granular cytoplasm is present and <50% of GISTs are strongly CD117 positive and completely lack expressions of melanocytic markers, especially HMB-45.
Folpe et al. 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 field (HPF), an infiltrative 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 infiltration.
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. 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. All of the pediatric patients[14, 16-18] 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. 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. Bleeker et al. 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. 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. In accordance with the published literature and our institutional experience, we suggest surgical resection with adjuvant conventional cytotoxic chemotherapy as the first-line treatment for early-stage GI PEComas. For tumors manifesting ≥2 aggressive pathological behaviors[5, 11], the TSC gene should be identified 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. 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]