Acute haemorrhage from a large renal epithelioid angiomyolipoma: diagnostic and management considerations in a teenage patient with a rare cancer

Abstract

Acute renal haemorrhage is a life-threatening condition that is complicated in the context of renal malignancy. Here, we present the case of a teenage male presenting acutely with a large, bleeding renal epithelioid angiomyolipoma (EAML) of the kidney—a rare cancer, which is part of the perivascular epithelioid cell tumour family. The patient was managed acutely with prompt resuscitation, transfer to a centre of expertise and haemorrhagic control using radiologically guided endovascular techniques; this subsequently permitted an oncologically sound procedure (radical nephrectomy, inferior vena cava thrombectomy and lymphadenectomy) to be performed within 24 hours. The description and discussion around this unique case summarises the patient’s clinical journey, while exploring the current literature surrounding diagnosis and outcomes of patients with renal EAMLs.

Background

Twenty-four per cent of kidney cancers diagnosed in the UK present as an emergency,¹ which is higher than the average for all cancers 19% (15%–37% across different regions).² Patients presenting as an emergency have poorer oncological outcomes,³ and by default, require more urgent management; this can lead to higher levels of stress and anxiety for patients that ultimately lead to poorer patient experiences of their care.⁴ In this case, we present the complex management considerations of controlling renal haemorrhage from a malignant renal mass in a teenage malef: first, in the strategies used to secure haemodynamic stability that allowed for an oncologically sound procedure to be performed; and second, in the subsequent identification and management of a rare renal epithelioid angiomyolipoma (EAML) tumour on histopathology.

Renal angiomyolipomas (AMLs) are typically benign renal tumours of the perivascular epithelioid cell tumour (PEComa) family with a triphasic composition of adipose, spindle and epithelioid smooth muscle, and thick-walled blood vessels. AMLs constitute 1% of all surgically excised renal lesions.⁵ Epithelioid AMLs (EAMLs) are a rare histological variant, which predominantly arise from the urinary and gastrointestinal tracts, retroperitoneum and female reproductive organs. EAMLs have been reclassified as a distinct entity from AMLs due to their malignant potential.⁵ Compared with renal AMLs, EAMLs are typically found in younger, male patients^6–9 and have a higher association with tuberous sclerosis (TS) (8% in AML vs 25% of EAML patients)^{6 7}; however, there are very few renal EAMLs reported in the literature and no clear consensus on histological diagnostic criteria, treatment protocols or follow-up.

Case presentation

A teenage boy presented to a district general emergency department with a 4-day history of left-sided flank pain and visible haematuria. He had no significant medical, social or family history. Abdominal examination revealed a palpable, tender mass in the left flank.

Investigations

On admission, his haemoglobin was 101 g/L, creatinine 74 µmol/L and an estimated glomerular filtration rate (eGFR) of >90 mL/min. After resuscitation and stabilisation with intravenous fluids, a contrast-enhanced abdominal CT scan identified a source of the bleeding: a left-sided 14.5×12.0×8.5 cm renal mass, suspicious for a large renal cell carcinoma (RCC) (figure 1).

Figure 1.

Contrast-enhanced CT images of the left renal EAML with an associated large retroperitoneal haematoma. From left to right: axial, coronal and sagittal CT images. EAML, epithelioid angiomyolipoma.

Treatment

After local resuscitation, he was immediately transferred to a tertiary urology centre with interventional radiology (IR) and renal oncology services. To gain haemorrhagic control, IR performed emergency endovascular nester coiling of the lower pole arterial branch (figure 2); they then sited a 14 mm Amplatzer plug in the main left renal artery. As the bleeding was adequately controlled, it allowed for an oncologically sound procedure to be performed—open radical nephrectomy and para-aortic lymphadenectomy with inferior vena cava (IVC) thrombectomy (rather than emergency nephrectomy), just 12 hours after presentation. Intraoperative blood loss reached four litres and the operative duration was 6 hours. On postoperative day 3, he developed sharp pleuritic chest pain and shortness of breath. CT pulmonary angiogram demonstrated bilateral lower lobe pulmonary emboli. As haemorrhagic control had been achieved using IR expertise and a more controlled nephrectomy, the clinical team had more confidence that he could withstand therapeutic anticoagulation just a few days after his surgery. Hence, he received anticoagulation without delay and made a good recovery thereafter.

Figure 2.

Endovascular image intensifier images showing: (A) extravasation and contrast blush from the left lower pole artery; (B) nester coiling of the lower pole renal artery with resolution of contrast extravasation.

Outcome and follow-up

Histological evaluation of the renal tumour revealed a 14.5×12.0×8.0 cm EAML with 70% epithelioid component, tumour necrosis, invasion of the renal vein, low mitotic activity and no evidence of nuclear atypia (figure 3 A–C). Six hilar lymph nodes were retrieved intraoperatively, none of which showed evidence of metastasis. Due to the emergency presentation, formal CT staging was performed postoperatively, revealing no locoregional or distant metastases. The uro-oncology multidisciplinary team meeting (MDT) outcome was for close surveillance due to the malignant clinicopathological features identified. His case was also discussed at an international centre of expertise for EAMLs in Toronto. Genetic counselling, and subsequent genetic testing, was performed to determine whether the patient had underlying TS, although he had no family history nor clinical features of the disease at presentation. Next-generation sequencing was performed and confirmed that he did not harbour mutations in either of the TS genes (TSC1, TSC2).

Figure 3.

Histopathology of EAML. (A) Macroscopic appearance of the necrotic tumour (T) with background kidney (K) and perirenal haemorrhage (H). (B) Adipose tissue and epithelioid smooth muscle cells surrounding a thick-walled vessel. (C) High power view of smooth cell cells showing epithelioid morphology, a mitotic figure (asterisk) and an intranuclear inclusion (black arrowhead). EAML, epithelioid angiomyolipoma.

Regular clinical and radiological reviews were paramount in this man’s follow-up. Unfortunately, a suspicious lesion in the intrahepatic portion of the IVC was identified on surveillance CT at 15 months, and was thought to be recurrent tumour. MRI suggested that the lesion was located in the caudate lobe of the liver, abutting rather than invading the IVC (figure 4). His case was once again discussed at a supraregional MDT meeting (The Christie National Health Service (NHS) Foundation Trust, Manchester, USA), who recommended segmental liver resection as the best chance of cure. Twenty-four months after his initial presentation, he underwent en bloc resection of the caudate lobe of the liver and resection of the left lateral wall of the IVC, which contained infiltrating tumour. Histopathology again confirmed EAML tumour in the surgical specimens (figure 5 A, B) with clear margins, suggesting complete excision. At 37 months after his initial presentation, and 13 months postliver resection, his surveillance CT has shown that he is free from disease.

Figure 4.

Axial MRI images of hepatic recurrence of EAML in the caudate lobe of the liver close to the intrahepatic IVC. (A) Precontrast T1 image; (B) arterial phase T1 image; (C) portal-venous phase T1 image; (D) T2-weighted contrast-enhanced image. EAML, epithelioid angiomyolipoma; IVC, inferior vena cava.

Figure 5.

(A) Macroscopic appearance of liver (L) and tumour (T) within IVC (blue outline). (B) Histology showing tumour with similar morphology to the initial presentation and adjacent liver. IVC, inferior vena cava.

Discussion

EAML: emergency management of a bleeding malignant renal tumour

Acute renal haemorrhage is a potentially life-threatening urological emergency, and requires prompt resuscitation, accurate diagnosis and decisive management. The gold standard for diagnosing renal haemorrhage is contrast-enhanced CT imaging, with precontrast, arterial, venous and delayed phases.¹⁰ Acquiring haemorrhagic control and haemodynamic stability is the first critical step, which traditionally would have been delivered through emergency nephrectomy.¹¹ However, with more recent advances in IR technology, selected angiography and embolisation in the acute setting, for example, in renal trauma,¹² has emerged as a feasible alternative in centres where IR expertise is available. Thus, selective arterial embolisation (SAE) has become more commonplace in the management of renal haemorrhage.

This case of acute renal haemorrhage was confounded by the presence of a suspected renal malignancy. Emergency presentations of cancer often have poorer oncological outcomes,³ hence, when managing such a young patient with a suspected bleeding renal tumour, a more measured approach was adopted with the aim of delivering both a safe and oncologically sound procedure. In this case a combination of an endovascular coil and plug were employed to achieve maximum haemorrhagic control. It is worth noting that the location of the vascular plug is essential—as there must be enough residual length of the proximal renal artery to allow for surgical clamping and ligation.¹³ SEA facilitated the delivery of radical nephrectomy, tumour thrombectomy and lymphadenectomy for this patient, which would otherwise have not been feasible; and had SAE been unavailable, or failed, his longer-term oncological outcomes may have been compromised.

EAML: diagnosis

The diagnosis of renal EAMLs is challenging radiologically and histologically. Renal EAMLs have hugely variable imaging characteristics, and are often misdiagnosed as more common renal malignancies, such as RCC, sarcoma, lymphoma or transitional cell carcinoma, due to their relative lack of adipose.^{7 14–18} Because of this, accurate diagnosis relies heavily on the histological identification of perivascular epithelioid cells and immunopositivity to smooth muscle (eg, smooth-muscle actin) and melanocytic (eg, Melan-A and HMB45) markers. Melanocytic markers are often positive across all three cell types.¹⁹ Histologically, there is no current consensus on the percentage of epithelioid tumour component required to differentiate between benign renal AMLs and malignant EAMLs, where histopathological inclusion criteria for EAML in case series range from 5% to 100% (table 1).6–9 14 20–27 Therefore, renal masses suspicious for EAML should be taken in context with the clinical presentation, identifiable risk factors, radiological features, meticulous histopathological examination and judicious use of immunohistochemistry.

Table 1.

Summary of EAMLs studies in the literature, their baseline characteristics, epithelioid component, follow-up duration and outcome data

First author (year)	Cases (n)	Proportion male (%)	Median age (years)	Mean epithelioid component (%)	Mean follow-up (months)	Progression/mortality risk
Hwang23 (2008)	3	100	43.6	ND	34	Progression ND; mortality 33%
Faraji7 (2009)	69	25.0	44.0	Not as %*	22.5	Progression 38%; mortality 21%
Aydin6 (2009)	15	13.3	38.6	51.0	62	Progression 0%; mortality 0%
Brimo20 (2010)	40	38.4	50.5	68.0	52	Progression 26%; mortality 12%
Nese21 (2011)	41	50.0	37.0	100†	44.5	Progression 49%; mortality 33%
He8 (2013)	20	45.0	49.7	94.0	85	Progression 5%; mortality 0%
Hassan24 (2014)	12	33.0	49.0	48.0	12	Progression 10%; mortality 0%
Tirumani14 (2014)	8	ND	ND	ND	11.5	Progression 72%; mortality ND
Benson25 (2014)	3	ND	ND	ND	22.8	ND
Lei22 (2015)	43	58.1	38.4	43.8	44	Progression <10%; mortality 0%
Park26 (2016)	5	60.0	41.4	77.0	60	Progression 20%; Mortality 0%
Lee9 (2018)	27	55.6	41.2	ND	46.3	Progression 18%; mortality 11%
Guo27 (2021)	7	42.8%	35.0	ND	13.8	Progression 100%; mortality 14%.

*Defined as greater than 5.5 mm focus of EAML within the tumour.

†Defined as a maximum of 1%–2% of typical AML within the tumour high power field.

AML, angiomyolipoma; EAML, epithelioid angiomyolipoma; ND, not documented.

EAML: prognostic features

Although the renal EAML is limited to retrospective case reports and case series, adverse clinical prognostic factors for recurrence, progression or metastases have been identified in four of the larger studies on EAMLs (table 2),^{7 20–22} including male sex,⁷ large tumour diameter,^{7 21 22} extrarenal extension and/or renal vein involvement²¹ and concurrent TS.²¹ Adverse histological features have also been described: higher percentage epithelioid component,^{20 22} higher percentage of atypia,^{20 22} higher mitotic count,²⁰ higher percentage atypical mitoses,²⁰ evidence of tumour necrosis,^{20 21} higher percentage of lymphovascular invasion²⁰ and carcinoma-like growth pattern.²¹ The large variation in recurrence, progression, metastases and survival in contemporary case series likely reflects variable inclusion criteria (percentage epithelioid component, range 5%–100%), case numbers (n=3–69), follow-up duration (range 11.5–85 months) and the retrospective nature of these studies.

Table 2.

Adverse clinical and histopathological features of renal EAMLs

Adverse prognostic features for EAML
Clinical	Pathological
Male sex	% epithelioid or % atypia
Larger tumour	mitotic count or % atypical mitoses
Renal vein/inferior vena cava invasion	Tumour necrosis
Extrarenal extension	Lymphovascular invasion
Concurrent tuberous sclerosis	Carcinoma-like growth

EAML: elective management of a rare cancer

Rare cancers make up 24% of all cancers in Europe and have poorer 5-year survival rates.²⁸ Patients often have limited evidence-based treatments due to lack of, and access to, clinical trials, which provide the foundation of evidence for defined therapeutic strategies. To improve outcomes for patients with rare cancers, it is recommended that patients with these cancers—where possible—are treated in recognised centres of expertise (with higher volume caseload), with collaborative multidisciplinary networks and approaches.²⁸ This case reflects these principles, where the patient was transferred safely to a centre of expertise, allowing for prompt diagnosis, supraregional multidisciplinary discussion and cross-disciplinary surgical management.

Another challenge after diagnosing a rare cancer is establishing an appropriate management and surveillance strategy. Currently, guidance on the management and surveillance of renal EAML patients is lacking, where review of the literature revealed only a small number of retrospective studies with variable follow-up durations (11.5–85 months) (table 1). The limited data likely reflect that EAMLs have only recently been defined as a malignant entity in 2016, and the rare natural history of the disease. With a paucity of high-level evidence, nor consensus guidance recommendations, it seems that these patients may be best managed as high risk, as progression and mortality rates in small retrospective studies range from 0% to 100% and 0% to 33%, respectively. There is some suggestion that these patients may also need to be followed up for more extended periods, as late recurrence, for example, in gynaecological PEComas (25% of all PEComas), is not uncommon.²⁹

Finally, there is a need to better understand the biology of rare cancers. For example, PEComas are thought to have frequent inactivation of the TSC1/TSC2 gene, and subsequent activation of the mammalian target of rapamycinm (mTOR) pathway²⁹; hence, may be susceptible to mTOR inhibition. Several case reports have shown efficacy of mTOR inhibitors, such as rapamycin, sirolimus and everolimus, in patients with renal EAMLs,^{27 30–32} some of whom had tumour sequencing confirming TSC1/TSC2 mutations.^{27 32} With more recent advances in, and access to, genomic data, improved biobanking technology, and greater access to clinical trials for patients with rare cancers, there is optimism about developing improved diagnostic, treatment and surveillance strategies for patients with these rare cancers.

Learning points.

• Renal haemorrhage is a life-threatening emergency that requires prompt resuscitation, accurate diagnosis and definitive management; this may be more complex in the context of a new renal malignancy.

• If possible, urgent transfer to a centre with uro-oncology and interventional radiology services may be beneficial, especially where embolisation techniques may provide haemorrhagic control to facilitate an oncologically sound surgical procedure.

• Epithelioid angiomyolipoma (EAML) of the kidney is a rare cancer with few documented cases in the literature; given the variable progression/mortality rates, it should be considered to have high-malignant potential.

• EAMLs and perivascular epithelioid cell tumour have a high association with TS, thus, patients should be referred for genetic counselling and/or testing; mutations in the TSC1/TSC2 genes in these patients may confer susceptibility to mTOR inhibitors.

• Rare cancers, such as EAMLs, have poorer oncological outcomes; hence, should be managed in a multidisciplinary approach, ideally in a specialist centre of expertise.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).