Malignant perivascular epithelioid cell tumor of the colorectum: Clinicopathological characterization, diagnosis and treatment process of 7 cases

Abstract

BACKGROUND

Perivascular epithelioid cell tumor (PEComa) of the colorectum is exceedingly rare, with only a few published reports. It presents with a wide spectrum of biological behavior, ranging from benign to malignant. The prognosis for malignant PEComa is poor and there is little consensus on its treatment.

AIM

To fully characterize PEComa and standardize its diagnosis and treatment.

METHODS

Patients with colorectal malignant PEComa were identified from the First Affiliated Hospital, Zhejiang University School of Medicine and People's Hospital of Anji. Cases with controversial pathology and cases lost to follow-up were excluded, leaving seven remaining cases that formed the basis of the study. We collected relevant clinicopathological, therapeutic and followup details. Disease stage and progression were assessed by contrast-enhanced computed tomography at baseline and at 3-month intervals.

RESULTS

The mean age was 43 years, with a range of 5 years to 73 years. The average body mass index was 21.8 ± 3.0 kg/m², and 71.4% of cases occurred in the colon. The main symptoms of colorectal PEComas were abdominal mass and hematochezia. The most common microscopic finding of malignant behavior was infiltrative growth. Immunohistochemical analysis found that 6/7 cases were positive for HMB45, 5/7 were positive for melan-A, and 3/5 were positive for MiTF. The watch-and-wait approach to treatment was a risky option. Radical resection was preferable to systemic treatment. The median progression-free survival exceeded 38 months, longer than previously reported.

CONCLUSION

Radical or extended resection is the key to prolonged survival of malignant PEComa. More meaningful studies are urgently needed to establish the standardized diagnosis and treatment.

Key Words: Perivascular epithelioid cell tumor; Colorectum; Malignant; Resection; Mammalian target of rapamycin inhibitor

Core Tip: Perivascular epithelioid cell tumor (PEComa) of the colorectum is exceedingly rare, and inexperience in therapy and poor prognosis are obstacles to treatment. Here, we retrieved 7 cases censored at 3-month intervals with clinicopathological, therapeutic and follow-up details (median, 44 months). Patients benefited from R0 resection, which was superior to systemic therapy. There was a high risk of recurrence within 2 years postoperatively. The median progression-free survival exceeded 38 months, longer than previously reported. Therefore, radical or extended resection is the key to prolonging the survival of patients with colorectal malignant PEComa.

INTRODUCTION

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm composed of perivascular cells, which presents a significant diagnostic dilemma[1,2]. It does not present with any known typical clinical symptoms or signs, and the incidence is < 1 per million[3]. In 2002, the World Health Organization defined “mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells” as PEComas[4]. These include angiomyolipoma of liver and kidney, clear cell "sugar" tumor of lung, lymphangiomyomatosis, clear cell myomatosis of sickle ligament or round ligament, and not otherwise specified (PEComa-NOS). The most frequent sites of the latter subgroup are the uterus and retroperitoneum[5]. Since its first description, PEComa-NOS has been gradually reported in a wide variety of anatomical sites, including the colorectum[6-9]. As the clinicopathological features of this neoplasm may easily be confused with those of other more commonly encountered lesions, this poses difficulties in its diagnosis and treatment.

PEComa is a type of neoplasm with a range of biological behaviors, which can be classified as benign, borderline or malignant[10]. Benign means that the tumor is free of aggressive clinical behavior, such as tumor size > 5 cm, high nuclear grade, infiltrative growth, vascular invasion, necrosis, and mitotic rate > 1/50 high power field (HPF). Malignant refers to the presence of two or more aggressive features, and the rest are borderline PEComas. Schoolmeester et al[11] argued that this classification was inappropriate because patients without metastatic disease also fell into the malignant category. Metastasis of PEComas of the gastrointestinal tract occurred in occurred in 54% of women and 46% of men[12]. Clinically, malignant PEComa of the colorectum is easily misdiagnosed as adenoma, gastrointestinal stromal tumor or malignant melanoma[13]. Difficulty in diagnosis and inexperience in therapy are obstacles currently encountered. Reports of colorectal malignant PEComa remain infrequent. Furthermore, most reports have focused on diagnosis and pathology, and information on treatment and prognosis is limited.

MATERIALS AND METHODS

Patients diagnosed with malignant PEComa initially presenting in the colorectum were retrieved from the First Affiliated Hospital, Zhejiang University School of Medicine and People's Hospital of Anji, China. After each case was confirmed by two pathologists, relevant clinicopathological, therapeutic and followup details were collected. Cases with controversial pathology and those lost to follow-up were excluded. Disease stage and progression were assessed by contrast-enhanced computed tomography at baseline and at 3-month intervals. The time interval for progression-free survival (PFS) starts from initial diagnosis and ends at cancer progression, relapse or metastasis. Any progression-free patient was censored at the last follow-up (June 30, 2024). Empirical survival probability was calculated via the Kaplan-Meier method. Some data and images were obtained from referring clinicians. The study was approved by the Ethics Committees of the participating hospitals.

RESULTS

Clinical features

Seven colorectal malignant PEComa cases were finally included in our study. The clinical features are summarized in Table 1. Their age at diagnosis ranged from 5 years to 73 years, with a mean of 43 years. Four patients were men and three patients were women. The average body mass index was 21.8 ± 3.0 kg/m², including two overweight, one underweight and four healthy weight. None of the patients had features of tuberous sclerosis. One patient had high blood pressure and another had viral hepatitis; the remaining patients did not have any underlying disease. Initial presentation was abdominal mass in 3 cases (2, 5 and 6), one of which was accompanied with abdominal pain, and hematochezia in 2 cases (4 and 7). Case 3 had no clinical symptoms and PEComa was found by health screening. We found that 71.4% of PEComas occurred in the colon. In our medical records, the largest tumor had a volume of 10.5 cm × 6.5 cm × 2.5 cm.

Table 1 Clinical features of seven malignant perivascular epithelioid cell tumors in the colorectum.

Case No.	Age in years	Sex	BMI in kg/m2	Basic disease	Family history	TSC	Initial site	Size in cm	Clinical presentation
1	49	Male	27.6	None	None	None	Sigmoid colon	5.5 × 4.5 × 2.5	Difficulty in defecation
2	73	Female	19.4	Hypertension	None	None	Descending colon	10.5 × 6.5 × 2.5	Palpable abdominal mass
3	30	Male	22.5	None	None	None	Ascending colon	3.0 × 2.5 × 2.0	None2
4	67	Female	21.4	Viral hepatitis	None	None	Rectum	4.0 × 2.5 × 2.0	Hematochezia
5	5	Female	18.1	None	None	None	Ascending colon	4.0 × 3.0 × 2.5	Abdominal mass and pain
6	48	Male	24.0	None	Carcinoma1	None	Transverse colon	7.7 × 6.3 × 4.0	Palpable abdominal mass
7	28	Male	19.9	None	None	None	Middle rectum	6.5 × 6.5 × 4.5	Hematochezia

¹Mother had lung carcinoma.

²The patient had no clinical presentation.

BMI: Body mass index; TSC: Tuberous sclerosis complex.

Pathological findings

We discovered that tumor cells were surrounded by vessels with angiomyolipoma-like features. Microscopically, tumors were composed of epithelioid and spindle cells with eosinophilic, granular to clear cytoplasm (Figure 1A). Tumor cell nuclei were round, spindled or ovoid, vesicular, and usually had prominent nucleoli. The pathological results all met the malignant criteria. Details are shown in Table 2. The proportion of high nuclear grade and vascular invasion was 42.9% and 57.1%, respectively. Three were predominantly infiltrative and two had focally infiltrative edges. We also found mitosis > 1/50 HPF in 3/7 cases. Necrosis was present in only 2 cases. By immunohistochemistry, 6/7 were positive for HMB45, 5/7 for melan-A, 3/6 for SMA, 3/5 for MiTF and 3/7 for desmin. None was positive for pan-cytokeratin, and 1 case each was positive for TFE3, S100, CD117 and MyoD1. Fluorescence in situ hybridization for Ewing Sarcoma protein RNA binding protein 1 was also negative (Figure 1B).

Figure 1 Pathological results of colorectal malignant perivascular epithelioid cell tumor. A: High magnification view showing epithelioid and spindly tumor cells (hematoxylin and eosin stain); B: Ewing Sarcoma protein RNA binding protein 1 detected by fluorescence in situ hybridization.

Table 2 Microscopic and immunohistochemical findings of the 7 cases.

Findings	Positive/total	Percentage	Findings	Positive/total	Percentage
Tumor size > 5 cm	4/7	57.1	SMA	3/6	50.0
High nuclear grade	3/7	42.9	MiTF	3/5	60.0
Infiltrative growth	5/7	71.4	TFE3	1/7	14.3
Vascular invasion	4/7	57.1	Desmin	3/7	42.9
Necrosis	2/7	28.6	S100	1/6	16.7
Mitosis > 1/50 HPF	3/7	42.9	CD117	1/7	14.3
Pan-cytokeratin	0/5	0	CD34	0/5	0
HMB45	6/7	85.7	CD10	0/5	0
Melan A	5/7	71.4	Myo D1	1/7	14.3

HPF: High power field.

Treatment

According to preoperative imaging, most tumors cannot be identified as mesenchymal sarcoma. For example, as shown in Figure 2, colorectal PEComa was difficult to distinguish from adenocarcinoma. We performed puncture biopsy to aid diagnosis of suspected PEComa. Except for case 3, which chose the watch-and-wait approach, and case 7, which received preoperative chemotherapy, the others first underwent radical resection, as shown in Figure 3. This was related to the tumor characteristics. As we anticipated, the mass of case 3 did not exhibit malignant behavior at the initial diagnosis, and the PEComa of case 7 infiltrated adjacent tissues and was difficult to perform R0 resection. Both had surgery 6 months later due to disease progression. All of the masses were confirmed to be malignant PEComas by postoperative pathology. Two of the patients underwent adjuvant therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus, but recurrence still occurred at 12 months and 21 months, respectively. For recurrence, mTOR inhibitor, tyrosine kinase inhibitor targeted therapy and immunotherapy had little effect. Nevertheless, there was no evidence of tumor after re-R0 resection in cases 2 and 6 (Figure 3).

Figure 2 Contrast-enhanced abdominal CT scan showed an invasive lesion (orange arrow) located in the anterior wall of the rectum (case 7). A: Non contrast; B: Arterial phase; C: Venous phase.

Figure 3 Treatment process and efficacy evaluation of the 7 cases. NED: No evidence of disease; PD: Progressive disease; Re: Relapse.

Follow-up

PEComa patients require rigorous follow-up. The median follow-up was 44 months, with the longest being 77 months and the shortest 28 months. Abdominal recurrence occurred in cases 2 and 6, and case 7 developed liver metastasis, retroperitoneal lymph node metastasis and pelvic implantation. After further treatments, only case 7 showed disease progression; the remaining patients had no evidence of disease. The 3-year PFS for operation was 57.1% (Figure 4). Although the median survival period has not yet been reached, it exceeded 38 months. The high-risk time for recurrence and metastasis of colorectal PEComa was within 2 years postoperatively.

Figure 4 Kaplan–Meier curve for progression-free survival of patients with colorectal malignant perivascular epithelioid cell tumor treated by operation. PFS: Progression-free survival.

DISCUSSION

Guidelines for PEComa have not yet been established. Surgical resection is the most commonly chosen therapy. For recurrence or metastasis of malignant PEComa, systemic therapy is the mainstay, but its effectiveness remains unclear. Angiomyolipoma and other tumors within the PEComa family occur at increased frequency in patients with tuberous sclerosis complex (TSC), which results from germline mutations in the tumor-suppressor genes TSC1 or TSC2[14]. Mutations in either gene provide the basis for the use of mTOR inhibitors, such as sirolimus or everolimus[15]. Colorectal PEComa-NOS seems independent of TSC, but requires further verification through more cases and genetic studies. A study by Sanfilippo et al[16] demonstrated that patients with PEComas may be responsive to gemcitabine, anthracyclines and antiangiogenic agents. In addition to surgery and systemic therapy, radiotherapy is another option worth considering[17]. There is still a lack of case reports and sharing of experience on various therapeutic effects until now. The therapy and prognosis of < 20 PEComas of the colorectum have been reported. Therefore, case reports on therapy and prognosis of malignant PEComa are urgently needed. Doyle et al[12] found that in 5 patients with colorectal malignant PEComa, the median time from diagnosis to death was only 22 months (range, 2-48 months). This was inconsistent with the results of our study, in which the median PFS was more than 38 months after radical surgery. This discrepancy may be due to differences in treatment approaches. Our center favors that radical or extended resection over current chemotherapy, targeted therapy and immunotherapy.

There is insufficient evidence to demonstrate that surgery combined with adjuvant therapy can achieve a survival benefit. The diagnostic and therapeutic procedures for 7 cases and the literature review in this study provides valuable experience and reference for subsequent patients. We report that 2 cases receiving postoperative adjuvant therapy with mTOR inhibitors experienced recurrence within 2 years. Coincidentally, Doyle et al[12] found that patients who received mTOR inhibitors still had disease progression and subsequently received doxorubicin and ifosfamide, but the clinical effect was transient. Chiang et al[18] suggested that that TSC2 mutant PEComa with a JAZF1-SUZ12 fusion might direct effective treatment. Whether to use mTOR inhibitors as first-line therapy, especially for advanced and metastatic PEComas, remains controversial. Some clinicians have reported high survival rates without therapy for up to 1 year after diagnosis[3]. We do not agree with this viewpoint because of the rapid progression in case 3 during the watch-and-wait period. Most patients with poor prognosis did not receive proper diagnosis and treatment. Different strategies were adopted in some cases with varying effects. The addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors, resulted in a marked clinical benefit[19]. Djerroudi et al[20] reported the first case of metastatic malignant PEComa that developed in a patient with Lynch syndrome, who showed complete response to anti-PD1 pembrolizumab. AMPECT, a phase II, single-arm, registration trial, investigated the safety and efficacy of the rapamycin inhibitor nab-sirolimus. The study showed an overall response rate of 39%, which might make nab-sirolimus an important novel drug[21]. Although there have been some reports of systematic treatment for PEComas, none of them was highly effective, consistent with our data. Therefore, these drugs should not be widely used.

CONCLUSION

In the study, the morbidity of colorectal PEComas in males and females is similar, and most cases commonly involve the colon. They exhibit variable clinical behavior, from benign to malignant. The presence of nuclear atypia, infiltrative growth, vascular invasion and mitotic activity are the strongest predictors of malignant behavior. PEComas occurring in the colorectum have been reported in small numbers, but most of them lack therapeutic and prognostic data. Difficulties in diagnosis and inexperience in treatment are responsible for poor prognosis. We believe that radical or extended resection is the key to prolonging survival. In addition, most patients do not benefit from existing drugs used for systemic therapy. More meaningful samples and key data are urgently needed to promote the standardized diagnosis and treatment of malignant colorectal PEComas.