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


Zriedkavý malígny PECom obličky –  dia­gnostická výzva a neobvyklá terapeutická odpoveď

Východiska:

Epiteloidný angiomyolipóm (EAML) obličky na rozdiel od benígneho renálneho angiomyolipómu predstavuje zriedkavý nádor mezenchymálneho pôvodu, ktorý disponuje malígnym potenciálom. Patrí do skupiny PEComov – tumorov vyvstávajúcich z perivaskulárnych epiteloidných buniek. Jeho dia­gnostika a terapeutický prístup zostávajú výzvou.

Metódy:

Autori prezentujú pa­cienta s malígnym EAML, ktorý bol iniciálne liečený ako renal cell karcinóm (RCC). Až neobvyklá terapeutická odpoveď vyústila k prehodnoteniu primárnej dia­gnózy. V príspevku je stručne sumarizovaný súčasný stav klinických a histopatologických poznatkov o renálnych PEComoch s dôrazom na ich metastatický potenciál a riziko dia­gnostického pochybenia.

Prípad:

Pa­cient s pôvodnou dia­gnózou chromofóbneho RCC so sarkomatoidnými črtami podstúpil radikálnu nefrektómiu a epinefrektómiu. Lokálna rekurencia ochorenia podnietila zahájenie prvej línie liečby sunitinibom a následné zaradenie pa­cienta do klinického skúšania s mTOR inhibítorom s neobvykle priaznivou odpoveďou v trvaní 30 mesiacov. Pomalá progresia ochorenia si vyžiadala extirpáciu solitárneho abdominálneho ložiska 36 mesiacov po zahájení liečby everolimom a napokon i pravostrannú hemihepatektómiu o ďalších 24 mesiacov. Imunoprofil pečeňových metastáz s pozitivitou melanómových a hladkosvalových markerov vyústil v rekvalifikáciu primárneho nálezu a metastatických ložísk na invazívny EAML obličky. Ďalšia progresia ochorenia bola napriek viacerým líniám systémovej liečby neodvratná a pa­cient 104 mesiacov po úvodnom stanovení dia­gnózy chorobe podľahol.

Záver:

Berúc do úvahy zriedkavosť a malígny potenciál PEComov obličiek, renálne nádory s nepriaznivými radiografickými a histopatologickými črtami sa stávajú kandidátom na imunohistochemické vyšetrenie. Neobvyklá odpoveď na liečbu upozorňuje na riziko dia­gnostického omylu a mala by viesť k prehodnoteniu dia­gnosticko-liečebného procesu u konkrétneho pa­cienta.

Kľúčové slová:

PECom obličky – epitelioidný angiomyolipóm – diagnostika – everolimus

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Obdržané: 12. 09. 2018

Prijaté: 17. 10. 2018


Authors: S. Huľová 1,3;  Z. Sycova-Mila 1;  D. Macák 2;  P. Janega 4;  M. Chovanec 1 ;  J. Mardiak 1;  M. Mego 1
Authors place of work: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovak Republic 1;  Department of Pathology, National Cancer Institute, Bratislava, Slovak Republic 2;  1st Department of Surgery, Pavol Jozef Šafárik University in Košice, Slovak Republic 3;  Department of Pathology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovak Republic 4
Published in the journal: Klin Onkol 2018; 31(6): 448-452
Category: Original Articles
doi: https://doi.org/10.14735/amko2018448

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 × 14cm (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 (50mg/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.

Fig. 1. Epithelioid angiomyolipoma of the kidney. The histological image was characterized by epithelioid morphology of tumor cells, with enlarged atypical nuclei and prominent nucleoli. HE, 200× (A), 400× (B).
Epithelioid angiomyolipoma of the kidney.
The histological image was characterized by epithelioid morphology of tumor cells, with enlarged atypical nuclei and prominent nucleoli.
HE, 200× (A), 400× (B).

Fig. 2. Immunohistochemical profi le of the tumor. Tumor cells were negative for cytokeratins AE1/3 (A) and CD10 (B), focally positive for vimentin (C), and showed typical cytoplasmic positivity for Melan A (D) and HMB45 (E). The cells showed also cytoplasmic MyoD1 (F) positivity reported in these tumors [15]. IHC-Px-DAB, 400×.
Immunohistochemical profi le of the tumor.
Tumor cells were negative for cytokeratins AE1/3 (A) and CD10 (B), focally positive for vimentin (C), and showed typical cytoplasmic positivity
for Melan A (D) and HMB45 (E). The cells showed also cytoplasmic MyoD1 (F) positivity reported in these tumors [15]. IHC-Px-DAB, 400×.

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


Zdroje

1. Kuroda N, Pan CC. Renal angiomyolipomas: clinical and histological spectrum. Urol Sci 2011; 22(1): 40–42.

2. Esheba Gel S, Esheba Nel S. Angiomyolipoma of the kidney: clinicopathological and immunohistochemical study. J Egypt Natl Canc Inst 2013; 25(3): 125–134. doi: 10.1016/j.jnci.2013.05.002.

3. Hwang HC, Hwang, JI, Hung SW et al. Epithelioid angiomyolipoma: an overview of five cases with the concept of PEComa. Chin J Radiol 2008; 33: 253–260.

4. Grant C, Lacy JM, Strup SE. A 22-year-old female with invasive epithelioid angiomyolipoma and tumor thrombus into the inferior vena cava: case report and literature review. Case Rep Urol 2013; 2013: 730369. doi: 10.1155/2013/730369.

5. Cao QH, Liu F, Xiao P et al. Coexistence of renal epithelioid angiomyolipoma and clear cell carcinoma in patients without tuberous sclerosis. Int J Surg Pathol 2015; 20(2): 196–200. doi: 10.1177/1066896911413576.

6. Singer E, Yau S, Johnson M. Retroperitoneal PEComa: case report and review of literature. Urol Case Rep 2018; 19: 9–10. doi: 10.1016/j.eucr.2018.03.012

7. He W, Cheville JC, Sadow PM et al. Epithelioid angiomyolipoma of the kidney: pathological features and clinical outcome in a series of consecutively resected tumours. Mod Pathol 2013; 26(10): 1355–1364. doi: 10.1038/modpathol.2013.72.

8. Apitz K. Die geschwulste und Gewebsmissbildungen Nierenrinde. II Midteilung Die mesenchymalen Neubildungen. Virchows Arch 1943; 31: 306–327.

9. Wildgruber M, Becker K, Feith M et al. Perivascular epitheloid cell tumor (PEComa) mimick­ing retroperitonea liposarcoma. World J Surg Oncol 2014; 12: 3. doi: 10.1186/1477-7819-12-3.

10. Pan CC, Chung MY, Ng KF et al. Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol 2008; 214(3): 387–393. 10.1002/path.2289.

11. Jayaprakash PG, Mathews S, Azariah MB et al. Pure epithelioid perivascular cell tumour (epithelioid angiomyolipoma) of kidney: case report and literature review. J Cancer Res Ther 2014; 10(2): 404–406. doi: 10.4103/0973-1482.136672.

12. Kenerson H, Folpe AL, Takayama TK et al. Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol 2007; 38(9): 1361–1371. doi: 10.1016/j.humpath.2007.01.028.

13. Tirumani SH, Shinagare AB, Hargreaves J et al. Imag­ing features of primary and metastatic malignant epithelioid cell tumors. AJR Am J Roentgenol 2014; 202(2): 252–258. doi: 10.2214/AJR.13.10909.

14. Chuang CK, Lin HC, Tasi HY et al. Clinical presentations and molecular studies of invasive renal epithelioid angiomyolipoma. Int Urol Nephrol 2017; 49(9): 1527–1536. doi: 10.1007/s11255-017-1629-4.

15. Panizo-Santos A, Sola I, de Alava E et al. Angiomyolipoma and PEComa are immunoreactive for MyoD1 in cell cytoplasmic stain­ing pattern. Appl Immunohistochem Mol Morphol 2003; 11(2): 156–160.

Štítky
Paediatric clinical oncology Surgery Clinical oncology

Článok vyšiel v časopise

Clinical Oncology

Číslo 6

2018 Číslo 6
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