Dia­gnostic Challenges and Extraordinary Treatment Response in Rare Malignant PEComa Tumor of the Kidney

Summary

Background:

Epithelioid angiomyolipoma (EAML) of the kidney, in contrast to classic benign renal angiomyolipoma, is a rare mesenchymal neoplasm with malignant potential. Represent­ing a member of the perivascular epithelioid cells (PEComa) tumor family aris­ing from the perivascular epithelioid cells, its accurate dia­gnosis and therapeutic approach remains challenging.

Methods:

We report a case of a patient with malignant EAML, initially treated as renal cell carcinoma (RCC) at our institution. In this paper, we briefly summarize current status of clinical and histopathological knowledge of renal PEComas with metastatic potential and reconsider the dia­gnostic and therapeutic approach in this particular case to highlight the risk of mis­dia­g­­­­nosis, malignant potential of renal PEComas and to demonstrate an unexpected treatment response.

Results:

The patient in our case was dia­gnosed with chromophobe RCC with sarcomatoid features. She underwent a radical nephrectomy and epinephrectomy with a satisfactory postoperative history. Local recurrence urged chemother­apy commencement with sunitinib in the first line, and shortly afterwards, the patient was enrolled in a clinical trial with everolimus, with an extraordinary favorable treatment response for 30 months. Follow­ing the extirpation of single abdominal nodularity after 36 months of treatment with mTOR inhibitor, and proceed­ing the everolimus administration, the dis­ease slowly progressed to the right liver lobe, result­ing in right hemihepatectomy in another 24 months. The immunoprofile of liver metastases with positive stain­ing of melanoma markers and smooth muscle markers induced the revaluation of the primary tumor and abdominal nodularity specimen to an invasive EAML of the kidney. Further dis­ease progression was unavoidable despite several chemother­apy regimens, and the patient died 104 months after primary dia­gnosis.

Conclusions:

Renal tumors with adverse radiographic and histopathological features should become candidates for immunohistochemical stain­ing as its omission frequently leads to a misdia­gnosis, as showed in our case report. Atypical treatment response might suggest a possibility of a diagnostic mistake and should lead to reevaluation of the diagnostic and treatment process in the particular patient.

Key words:

renal PEComa –  epithelioid angiomyolipoma –  dia­gnosis –  everolimus

Introduction

Epithelioid angiomyolipoma (EAML) of the kidney is a rarely dia­gnosed mesenchymal neoplasm with malignant potential, and it occurs sporadically or in association with tuberous sclerosis complex syndrome [1]. Renal angiomyolipomas (RAML) are considered a part of perivascular epithelioid cells (PEComa) tumor family, originat­ing from perivascular epithelioid cells (which have no recognized non-malignant counterpart) [2]. These infrequent tumours are dia­gnosed predominantly in females and arise from gastrointestinal, urinary tract, retroperitoneum, female reproductive organs, abdomino-pelvic sites and skin. RAML and pulmonary lymphangioleiomyomatosis represent 2 major findings within the PEComa group [3].

Dia­gnosis of the epithelioid RAML remains challeng­ing based upon its ra­diographic appearance and clinical pre­sentation. Renal EAML may easily be mis­dia­gnosed as renal cell carcinoma (RCC), renal sarcoma or medullary carcinoma. There is a strong evidence, support­ing the key role of immunohistochemical evaluation in accurate dia­gnosis –  PEComas typically stain for melanocyte (HMB45, Melan-A, MITF) and muscle cells markers (smooth muscle actin, myosin, calponin) and are negative for cytokeratins [4,5,6]. While most of the angiomyolipoma PEComas have be­nign nature, accord­ing to the literature, approximately 30% of all cases poten­tially develop into invasive renal EAMLs, characterized by aggressive growth and high risk of metastatic spread, re­sult­ing in poor prognosis. Current treatment approach for invasive EAML includes radical surgical procedure and mTOR signal­ing pathway targeted systemic ther­apy; however, optimal treatment strategy has not been estab­lished yet [7]. Herein, we present a case of patient with EAML of the kidney, initially dia­gnosed as RCC until dissemination, and treated with everolimus with unexpected positive response.

Clinical case details

We present a case of 28-year-old Cau­casian female with recently dia­gnosed ulcerative colitis. The suspicion for an expansive process of the right abdomen was expressed by the gastroenterologist as an external oppression of ascend­ing colon and D3 (horizontal portion) duodenum was observed dur­ing the endoscopic examinations. CT and MRI scans revealed a multilocular capsulated tumor mass 11 × 15 × 14 cm (anterior-posterior dimension –  AP × laterolateral dimension –  LL × craniocaudal dimen­sion –  CC), encircl­ing the right kidney, richly vascularized, with necrotic parts and intratumoral hemorrhages. The tumor was in close contact with segment 6 of the liver, with no signs of infiltration, no lymph nodes or distant sites were affected. The patient underwent a right radical nephrectomy and epinephrec­tomy, and the pathological examination revealed chromophobe RCC with sarco­matous features, nuclear grade 4. Fol­low­ing surgery, the patient had been closely monitored and dis­ease-free for 15 months. Based on a CT-evidenced intra-abdominal recurrence, initial 6-month-period of treatment with sunitinib (50 mg/ day, 4 weeks on, 2 weeks off) had been commenced. Because of an early dis­ease progression, she was enrolled into a clinical trial with everolimus for advanced RCC. The dis­ease was stable for 36 months. Subsequently, she required a surgical extirpation of a single progress­ing omental metastasis. She continued everolimus ther­apy for another 24 months, when the dis­ease gradually spread to the right liver lobe, segment 6 and 7, and resulted in right hemihepatectomy. The tissue was microscopically evaluated as malignant melanoma, and the cells were immunohistochemically characterized –  CD10-, CK20-, RCC-, Hepatocyte-, TTF1-, S100+, Vimentin+, HMB45+, Melan A+, Ki67 30%. Regard­ing the unusual clinical behavior, treatment response to mTOR inhibitor and inconsistent histopathologic results, bio­psies from primary tumor, abdominal nodule and liver metastases were redefined to me­tastasiz­ing epithelioid RAML (Fig. 1, 2). The patient proceeded in treatment with everolimus for another 3 months; however, she experienced a severe dis­­ease dissemination to the lungs with pleural effusion as well as to the liver and intraabdominally. Subsequently, several lines of systemic ther­apy (5-fluro­uracil/ calcium leucovorine, gemcitabine, paclitaxel + carboplatin, vinorelbine) were administered without treatment response and the patient died 104 months after dia­gnosis.

Discussion

Perivascular epithelioid cell line was firstly described by Apitz in 1943, and it was designated as an abnormal myoblast in RAML [8]. In 2010, the World Health Organization introduced the definition of the PEComas as mesenchymal tu­mors composed of histologically and immunohistochemically distinctive pe­rivascular epithelioid cells [9].

Two major findings of the PEComa family are RAML and pulmonary lymph­angioleiomyomatosis. The first men­tio­ned represents a rare soft tissue tumor and may demonstrate malignant poten­tial. It occurs sporadically (50– 70% of all cases) or it is associated with genetic alterations of tuberous sclerosis complex, an autosomal dominant congenital dis­ease caused by the loss of heterozygosity in the TSC1 region (9q34) or TSC2 region (16p) [1,10,11]. It has been recognized that tuberous sclerosis complex genes are involved in mTOR signal­ing pathway [10]. Dur­ing the last 2 decades, more than 160 cases of angiomyolipoma PEComas have been published worldwide [6], identify­ing 3 major challenges of their management: dia­gnostic accuracy, necessity of risk stratification and determination of treatment strategies. Dia­gnostic process of EAML PEComa remains challenging. Given the histological evaluation, it may easily be confounded with RCC, renal sarcoma or melanoma [2,4]. The crucial role of immunohistochemistry in the differential dia­gnosis of renal EAML has been proven by numerous sources, includ­ing our clinical case, and should be considered especially in the presence of adverse features. Based on evidenced data, malignant PEComas should be considered in the differential dia­gnosis of large, well-circumscribed renal tumors with intratumoral hemorrhages and necrotic areas, predominantly if coagulative tumor necrosis, nuclear atypia and atypical mitosis are seen histologically [12,13]. The positivity of smooth muscle markers and melanoma markers are typical in most of renal PEComas. Moreover, current relevant data illustrate the need of EAMLs malignant potential assessment. EAMLs are extremely rare and account for approximately 5% of surgically removed angiomyolipomas [7]. The metastatic spread is observed among 20– 30% of patients, and most frequently af­fected sites are liver, lungs and perito­neum [11,14]. The criteria for malignant potential of EAML have not been established yet. Therapeutic approach includes radical surgical procedure; regard­ing systemic treatment, mTOR inhibitors administration has shown promis­ing results. Despite of primarily inaccurate dia­gnosis, the patient in this report benefited from mTOR inhibitor treatment and exhibited an extraordinary favorable response.

Conclusion

The tumors belong­ing to the PEComa family are not seen frequently, and their dia­gnostic and therapeutic management could be challenging. By report­ing our clinical case, we point at increas­ing awareness about the possibility of PEComa occurrence and misdia­gno­sis, and emphasize the role of immuno­histochemical examination in EAML. Secondly and equally important, we encourage the specialists to keep close attention to the clinical course of the dis­ease, and in case of extraordinary treat­ment response, reconsider the pri­mary find­ing and approach. Clinical evidence regard­ing renal EAML is emer­ging. Nevertheless, further inves­tiga­tion is needed to proceed in optimi­zation of the medical care standards for patients with rare PEComas of the kidney.

The authors declare they have no potential conflicts of interest concerning drugs, pro­ducts, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE recommendation for biomedical papers.

Submitted: 12. 09. 2018

Accepted: 17. 10. 2018

MUDr. Soňa Huľová

2nd Department of Oncology

Faculty of Medicine

Comenius University

National Cancer Institute

Klenová 1

833 10 Bratislava

Slovak Republic

e-mail: sonahulova@gmail.co