Unusual paediatric sigmoid perivascular epithelioid cell tumour with regional lymph node metastasis treated using gemcitabine and docetaxel: a case report and literature review.

Perivascular epithelioid cell tumour (PEComa) is an extremely rare neoplasm with distinctive morphology and specific expression of immunohistochemical markers. The lesion is typically diagnosed in middle-aged women, with few reports of paediatric cases, and there is no standardized treatment for the tumour type. Here, the case of a 17-year-old female, who presented with painless haematochezia for 2 days and was diagnosed with gastrointestinal PEComa of the sigmoid colon with regional lymph node metastasis after serial examination, is presented. She was treated by surgical resection of the tumour and cytotoxic chemotherapy comprising 900 mg/m2 gemcitabine and 100 mg/m2 docetaxel every 3 weeks for six cycles. Haematochezia did not recur, and complete response was achieved, with progression-free survival at the 24-month follow-up examination. Surgical resection with adjuvant conventional cytotoxic chemotherapy may be considered as an option for treating gastrointestinal PEComa.

Introduction

Perivascular epithelioid cell tumours (PEComas) are extremely rare neoplasms of mesenchymal origin, featuring distinctive morphology, immunohistochemistry and ultrastructure, and include angiomyolipomas, lymphangioleiomyomatosis, and clear-cell sugar tumours.[1,2] PEComa–not otherwise specified (PEComa–NOS) refers to clear-cell tumours of anatomic locations that do not qualify for the predominant assemblage of the PEComa family, such as the aforementioned tumour 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 uterine corpus lesions accounting for 41% of reported cases.[1,4-8]

Immunohistochemically, PEComa–NOS typically exhibits positive melanocytic and myogenic markers, such as human melanoma black-45 (HMB-45), melanoma antigen recognized by T-cells 1 (melan-A), and smooth muscle actin, and is negative for protein S100, cytokeratin, and desmin.[9-11] However, the histogenesis and corresponding normal cellular counterpart of PEComa remain unknown.[1,3]

There is currently no standardized treatment strategy for PEComa,[2] and due to the unpredictable histopathological manifestation, patients with aggressive PEComas have a poor prognosis and do not respond well to chemotherapy.[5,12,13] In addition, 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 shown to be an effective treatment for the primary tumour and for local recurrence prevention.[2] Herein, the case of a 17-year-old female patient with an unusual PEComa is described. She presented at Kaohsiung Medical University Hospital with painless haematochezia for 2 days. Colonofibreoscopy and pathology analysis revealed a perivascular PEComa of the rectosigmoid colon with regional metastatic lymph nodes that were successfully treated with complete resection and gemcitabine/docetaxel chemotherapy. No local or distant recurrence was observed at 24 months following surgery.

Case report

Written informed consent was obtained from the patient and her parents for publication of the case report and accompanying images, and all details have been deidentified to protect the patient’s identity. Ethics approval was obtained from the Institutional Review Board of Kaohsiung Medical University Hospital (IRB No.: KMUHIRB-E(I)-20200366). The manuscript was prepared and revised according to the CARE Checklist (2016), and the reporting of this study conforms to CARE guidelines.[14]

A 17-year-old female patient visited the emergency room of Kaohsiung Medical University Hospital in May 2019 with painless haematochezia for the previous 2 days. She also had symptoms of dizziness and fainting, but did not present with headache, blurred vision, fever, nausea or vomiting, abdominal pain, chest pain, tachycardia, trauma history, recent weight loss, general numbness or weakness.

The patient had a previous medical history of anaemia, which was diagnosed at a school health examination, but she did not receive further examination or treatment. She reported no history of other gastrointestinal symptoms or signs, or trauma.

At the Kaohsiung Medical University Hospital emergency room, the patient’s temperature was 37.2 °C, heart rate was 80 beats per min, respiratory rate was 18 breaths per min, blood pressure was 93/57 mmHg and oxygen saturation in room air was 100%. Consciousness was clear and she scored 15/15 on the Glasgow Coma scale. Her conjunctiva was pale. The clinical abdominal examination showed normoactive bowel sound, no muscle guarding, no tenderness, no rebound pain and tympanic sound to percussion.

Results of blood analyses were as follows: haemoglobin level, 6.0 g/dl (normal range, 11.1–15.1 g/dl); white blood cell count, 5720 cells/mm3 (normal range, 4140–10 520 cells/mm3); and platelet count, 384 000 cells/mm3 (normal range, 160 000–370 000 cells/mm3). Gross appearance of the stool was bloody, and the faecal occult blood test result was 4+. No Salmonella or Shigella species were isolated in the stool culture, and stool tests for enteric adenovirus and rotavirus antigen were negative. Laboratory tests showed the following: C-reactive protein, 0.35 mg/l (normal range, <5.0 mg/l); aspartate aminotransferase (serum glutamic-oxaloacetic transaminase), 17 IU/l (normal range, 10–42 IU/l); alanine aminotransferase (serum glutamic pyruvic transaminase), 12 IU/l (normal range, 10–40 IU/l); and tumour markers carbohydrate antigen 19-9, <16.1 U/ml (normal range, <37 U/ml) and carcinoembryonic antigen, <0.3 ng/ml (normal range, <5 ng/ml). Blood transfusion was performed for severe anaemia. Tranexamic acid (500 mg/5 ml ampoule), 1 ampoule by intravenous drip every 8 h, for 6 days, was also administered for massive bloody stool.

Ultrasonography revealed a suspicious 2.9-cm ovoid mass in the pelvis region. Further abdominal computed tomography (CT) revealed a large pedunculated polypoid lesion measuring 3.5 × 3.1 × 2.8 cm, with heterogenous enhancement in the rectosigmoid colon and metastatic lymphadenopathy of approximately 0.6 cm in the paracolic region (Figure 1A–D).

Figure 1.

Representative images from abdominal computed tomography (CT) of the primary tumour in the sigmoid colon, showing a large pedunculated polypoid lesion measuring 3.5 × 3.1 × 2.8 cm, with heterogenous enhancement in the rectosigmoid colon (arrow) and metastatic lymphadenopathy of approximately 0.6 cm in the paracolic region: (a) plain CT axial plane; (b) arterial phase axial plane; (c) sagittal plane; and (d) coronal plane.

Colonofibreoscopy indicated a large submucosal tumour with ulcerations and a large stalk at 10 cm from the anus (Figure 2A and B). The patient received robotic-assisted low anterior resection of the rectosigmoid colon tumour at Kaohsiung Medical University Hospital, with an uneventful postoperative course. Pathology of the resected tumour tissue (Figure 3A) revealed a perivascular epithelioid cell tumour of the rectosigmoid colon with regional metastatic lymph nodes, classified as pT1N1 (American Joint Committee on Cancer staging manual, 8th edition, 2017). The circumferential resection and surgical resection margins were free of tumour cells. Immunohistochemical staining of the tumour cells revealed strong diffuse positivity for HMB-45 (Figure 3B) and negative results for melan-A, cytokeratins (multicytokeratin antibody AE1/AE3), paired box protein Pax-8 (PAX8), discovered on gastrointestinal stromal tumours protein 1 (DOG-1; also known as anoctamin-1), and synaptophysin.

Figure 2.

Representative colonofibreoscopy images showing a large submucosal tumour with ulcerations and a large stalk at 10 cm from the anus.

Figure 3.

Representative tissue sections of the primary tumour in the sigmoid colon: (a) haematoxylin and eosin-stained section showing nests and sheets of plump round to polygonal cells with a clear cytoplasm, and large vessels with perivascular growth; and (b) cytoplasmic pigmentation and HMB-45 positive immunostaining of the tumour cells (both original magnification, × 400).

The final diagnosis of the presented case was sigmoid PEComa, cT1N1M0, stage IIIA, pT1N1. Adjuvant conventional cytotoxic chemotherapy was initiated at 1 month following complete resection, comprising six cycles of 900 mg/m2 gemcitabine, combined with 100 mg/m2 docetaxel, every 3 weeks (delivered between August and November 2019).

Repeat abdominal CT scans at 6, 12 and 18 months after surgical resection revealed no local recurrence or distant metastasis. Results of colonofibreoscopy, performed 1 year after surgery, were unremarkable. An abdominal ultrasound scan also showed no specific finding. The patient’s clinical condition remained stable after complete resection and treatment with gemcitabine/docetaxel without local or distant recurrence at the 24-month follow-up.

Discussion

Studies on treatments and outcomes specific to PEComa are limited to institutional series and anecdotal case reports. Review of an article by Chen et al,[3] and a PubMed search of articles published up to July 2020, using the following search terms: (“perivascular epithelioid cell tumor” or “PEComa”) and (“gastrointestinal tract” or “GI” or “oral ” or “mouth” or “esophagus” or “gullet” or “gastric” or “stomach” or “duodenum” or “jejunum” or “ileum” or “cecum” or “colon” or “colorectal” or “sigmoid” or “rectum” or “anus” or “mesentery”), revealed 62 cases of gastrointestinal PEComa–NOS in the literature.[3,12,15-23] the colon was the most commonly affected part of the abdominal cavity, followed by the mesentery, rectum, stomach, duodenum, ileum, cecum, and other locations.[3] The GI tract is the second most frequent location of PEComa, preceded only by the gynaecological tract.[8] In addition, polypoid tumours centred in the mucosa and submucosa principally occur in the cecum and rectum.[24] GI PEComas have a conspicuous female tendency,[11,25] along with an incidence peak in the fourth or fifth decade of life.[3] However, there are limited previous reports of GI PEComas in children.[24,26-28] The first reported paediatric case of metastatic PEComa of the colon was published in 2008,[27] and described an 11-year-old prepubertal Caucasian boy who underwent resection of a 5.5-cm-long section of the sigmoid colon. At the 5-month follow-up, the results of repeat CT were unremarkable and the boy was asymptomatic.[27] In 2009, a case report similar to the present patient, published in 2009, described a 15-year-old female patient with rectal PEComa and lymph node involvement that was successfully treated with surgical resection and adjuvant chemotherapy (doxorubicin, ifosfamide, and mesna) without recurrence at 9 months following surgery. Regardless of the affected age group, prognostic pathologic markers of GI PEComas are few, due to the rare nature of the neoplasm.[24]

Distinguishing GI PEComa from GI stromal tumour (GIST) or other sarcoma is challenging because PEComa generally presents a biphasic GIST-compatible morphology.[12] The clinical manifestation of PEComa is variable and with little discrimination, and may include abdominal pain or rectal bleeding, or may be asymptomatic.[3,28] Haematochezia was observed in the present patient, whereas intermittent rectal bleeding has been observed in several previously described paediatric patients.[24,26,29] Imaging studies assist in identifying the lesion to a certain degree.[30,31] 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.[31] Endoscopy may facilitate the detection of a polypoid tumour or fungating mass with irregular ulceration, and tumours are generally observed as a rich vascularization with a hyaline wall or even necrosis.[4,32]

Immunohistochemical discernment of melanocytic differentiation is the most effective approach to differentiating GI PEComa-NOS from other tumours, such as GIST, angiomyolipoma, paraganglioma, malignant melanoma, and alveolar soft part sarcoma.[2] Although the precursor or normal counterpart of PEComa-NOS remains undefined,[12] HMB-45 continues to be the most sensitive and frequent melanocytic marker in 92–100% of reports.[1,2,33] Other potential melanocytic and myogenic markers are melan-A, smooth muscle actin, and microphthalmia transcription factor, which have been described in 23–88%, 59–93%, and 50–92% of reports, respectively, as well as desmin and caldesmon.[1,2,8,10,24,33] PEComa-NOS is negative for expression of chromogranin A, synaptophysin and protein S100, and thus, may be differentiated from paraganglioma.[2] Diagnosis of GIST can be excluded if either perivascular concentric proliferation or representative granular cytoplasm is present.[3] Less than 50% of GISTs are strongly CD117 positive and GISTs completely lack expression of melanocytic markers, especially HMB-45.[12]

Folpe et al.[11] established a series of criteria to distinguish the pathological behaviour of aggressive PEComa, namely high-risk features such as a size of ≥5 cm, a mitotic rate of ≥1 cells/high power field, an infiltrative growth pattern, high nuclear grade and cellularity, necrosis, and vascular invasion. Another study proposed that a tumour size of ≥5 cm and a mitotic rate of ≥1 cells/ high power field are crucially associated with prognosis and recurrence.[1,5,30,34] Tumours with ≥2 high-risk characteristics are categorized as malignant PEComa, and 81.6% of such lesions may relapse within 23 months.[2,33] The present case involved a pedunculated polypoid lesion in the sigmoid colon that was approximately 3.5 × 3.1 × 2.8 cm, with no evidence of necrosis, and the tumour was well limited in the submucosa, with no further infiltration.

According to National Comprehensive Cancer Network (NCCN) guidlines,[35,36] removing the sarcoma with a cancer-free surgical margin (R0) is the goal, and additional neoadjuvant or adjuvant treatments, such as radiation therapy, chemoradiation and systemic therapy, might be combined with surgery. Systemic therapies including sirolimus, everolimus and temsirolimus have been suggested for use in cases of PEComa, recurrent angiomyolipoma and lymphangioleiomyomatosis. The guideline concluded that not everyone will receive the same treatment, and treatment options should depend on the location and type of soft tissue sarcoma. Other publications have also shown surgical resection to be the preferred treatment for primary GI PEComa tumours, particularly in benign and chemoradio-resistant groups.[3,4,7,24] Surgical resection is also adopted to manage local recurrence after initial therapy, enabling long-term control of metastatic foci.[12,37]

Most tumours are eradicated at the size of 4–6  cm when excision is performed.[12,28] Cheng et al.[34] described the successful treatment of patients with recurrent PEComas of the sigmoid colon and pancreatic metastasis using surgical resection alone, and a 2018 publication reported a patient with rectal PEComa with recurrent liver metastases who was cured through surgery.[38] However, 37.1% of patients treated with surgical resection without adjuvant therapy may develop distant metastases after 6 months.[38] Most of the previously reported paediatric patients were treated with surgery as an initial management strategy.[24,26-28] However, the preferred adjuvant therapy, including doxorubicin, paclitaxel, gemcitabine, and oxaliplatin alone or in combinations, is a matter of contention.[5,9,13,24,39,40] For benign PEComa, no standardized regimen to avoid recurrence after surgery has been described.[3,4] Clinical outcomes in the published literature are varied. Ryan et al.[24] reported the case of a 15-year-old patient with rectal PEComa and lymph node involvement. The patient was successfully treated with surgical resection and adjuvant chemotherapy that comprised a combination of doxorubicin, ifosfamide, and mesna, with no recurrence at 9 months postsurgery. Another report, published in 2010, described a patient aged 7 years with ascending colon PEComa who was treated with adjuvant interferon-α2b immunotherapy after resection, with a favourable outcome.[39]

Bleeker et al.[5] demonstrated that conventional cytotoxic chemotherapy is not effective in malignant PEComas and emphasized the superiority of mTOR inhibitor therapy. The mTOR pathway regulates cell growth and is associated with inactivation of the TSC1 and TSC2 genes.[1,12] Deletions or loss of heterozygosity (LOH) are observed at locus TSC2 in some PEComa cases, leading to the loss of tuberin activity.[1,2,41] LOH at the TSC1 locus, encoding hamartin, has been less described.[5] However, both proteins regulate the activation state of GTPase, acting as an inhibitor of the mTOR signalling pathway.[41] The loss of tuberin and hamartin function leads to excessive activity of mTOR serine/threonine kinase, which is a target for mTOR inhibitors in treating patients with advanced PEComa.[5] Compared with TSC1 or TSC2 somatic mutations in PEComa–NOS and malignant PEComa, the germ-line mutation inactivating the TSC1 or TSC2 genes in tuberous sclerosis showed a closer association with lymphangioleiomyomatosis or angiomyolipomas.[2] Tuberous sclerosis has been shown to occur in only 0–6.25% of patients with PEComa.[2,5,11] Characterization of TSC1 and TSC2, along with their downstream products,[2,13] may help develop targeted therapeutic agents, such as sirolimus or tacrolimus. However, contradictory results were observed when a 58-year-old female patient with metastatic PEComa was treated with a combination of topotecan, temsirolimus (mTOR inhibitor), and bortezomib.[40] Moreover, a 23-year-old male patient 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] The reported experience utilizing mTOR inhibition in PEComa-NOS is limited, and the responses are shown to be inconsistent.[11] The present authors suggest maintaining a conservative evaluation and appraisal of the research results in these published articles. Additionally, in accordance with the published literature and the authors’ own experience at Kaohsiung Medical University Hospital, the authors suggest surgical resection with adjuvant conventional cytotoxic chemotherapy as the first-line treatment for early-stage GI PEComa. For tumours manifesting ≥2 aggressive pathological behaviors,[5,11] the TSC gene might be considered, to identify and evaluate the need for mTOR inhibitor therapy.

Metastasis may be observed even 10 years following tumour resection in some patients. Thus, such patients, and particularly those with tumours measuring >8 cm, require monitoring for several years after surgical treatment.[2,12] The NCCN 2020 guidelines recommend the following in cases of soft tissue sarcoma: (1) re-imaging after surgery using magnetic resonance imaging or CT with contrast to assess primary tumour and rule out metastatic disease; and (2) chest imaging using x-ray or CT every 3–6 months for 2–3 years, then every 6 months for the next 2 years.[35] Freeman et al.[42] 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. Other studies have suggested physical examination and CT scans every 6 months, and endoscopy every year after surgery, to monitor local recurrence and distant metastasis.[3,27]

Conclusion

Studies on PEComas are few and demonstrate high heterogeneity, thus, a comparative study to determine the optimal treatment remains challenging. The present study suggests surgical resection with adjuvant conventional cytotoxic chemotherapy as a treatment option for early-stage GI PEComa. However, well-documented clinical trials should be performed to accumulate immunohistochemical evidence and suggest empirical therapy. The current findings may be extrapolated to practice procedures.