Typical Kidney Tumor With Atypical Presentation

A White woman in her late 50s with a medical history of osteoporosis, hyperlipidemia, and migraines presented with hematuria. Results of computed tomography (CT)imaging showed an 8×6×5-cm right kidney lesion (Figure 1,A).The patient underwent surgical resection with a right nephrectomy and an apparent diagnosis of angiomyolipoma (AML). One year later, the patient underwent excision of a right iliac wing lesion, and pathologic findings demonstrated xanthoma of bone with sclerosis. Three years after this second surgery, she presented with new abdominal pain. Results of CT imaging revealed a 4.3-cm retrocaval mass at the level of the renal right vein. She underwent surgical resection, and results of pathologic evaluation were consistent with the original tumor. Follow-up CT imaging revealed a 1.2-cm left upper lobe lung nodule and a 0.8-cm right upper lobe lung nodule, as well as a pulmonary embolism and a left 6th rib fracture. These lesions were fluorodeoxyglucose-positron emission tomography avid. The patient denied constitutional symptoms such as fatigue, fever, chills, and night sweats. She underwent bilateral video-assisted thoracoscopic surgery wedge resections of the lung lesions, which were also consistent with the primary tumor. Five years later, the patient (now in her late 60s) presented with multiple left pleural-based lung lesions (Figure 1, B). Results of all laboratory testing were within reference ranges. These pleural-based lesions were resected with left video-assisted thoracoscopic surgery partial pleurectomy, and results of pathologic evaluation were positive for HMB45 and Melan-A.

Figure 1.

Computed tomography images of the kidneys (A) and lungs (B) demonstrating a right kidney lesion (yellow arrowhead) and a left pleural-based lung lesion (yellow arrowhead).

Diagnosis

WHAT IS YOUR DIAGNOSIS?

1. Epithelioid angiomyolipoma
2. Lymphoma
3. Renal cell carcinoma
4. Renal oncocytoma

A. Epithelioid angiomyolipoma

Discussion

This patient has metastatic epithelioid angiomyolipoma (EAML), an unusual variant of AML, which is among the most commonly encountered types of kidney masses. The resected masses were consistent with an epithelioid mesenchymal neoplasm with clear cell morphology having low to intermediate grade features (low mitotic rate with focal tumor necrosis; Figure 2). The diagnosis of EAML was confirmed with HMB45 and Melan-A staining.

Figure 2.

Hematoxylin-eosin of kidney tumor showing epithelioid cells with abundant clear to pale eosinophilic granular cytoplasm admixed with thin-walled capillary vessels and a layer of mesothelial cells overlying the advanced malignant perivascular epithelioid cell tumors (black arrowhead).

Perivascular epithelioid cell neoplasms (PEComas) is a family of related mesenchymal tumors, including AML, lymphangiomyomatosis, clear cell tumors of the lung, and rare morphologically and immunophenotypically similar tumors.¹ These tumors are defined by perivascular epithelioid cells or spindle cells with clear eosinophilic cytoplasm and are typically arranged around blood vessels with immunoreactivity to smooth muscle and melanocytic (HMB5 and Melan-A) markers.² Typically, PEComa tumors occur at visceral, retroperitoneal, and abdominopelvic sites (the uterus being the most common site)³ and are rarely malignant (only 6% to 7% demonstrate distant metastasis).¹

A subset of PEComa tumors includes AMLs, which are the most frequent benign kidney tumor, have a prevalence of 0.2% to 0.6%, have a strong female predilection, and occur as sporadic isolated entities in 80% of cases.⁴ A distinct subset are EAMLs, distinguished by the presence of smooth muscle markers (caldesmon and smooth muscle actin)as well as melanocytic markers.⁴ These tumors are described as a malignant neoplasm with distant metastasis in one-third of patients and with metastasis more common for patients with marked nuclear atypia or necrosis.¹ These tumors are associated with tuberous sclerosis complex (TSC) variations leading to mTOR pathway activation.⁵ Approximately 80% of patients with kidney EAML have autosomal dominant germline variations in TSC1 or TSC2 gene; however, only 5% to 10% of patients have tuberous sclerosis disease. Imaging and differentiation of EAML from renal cell carcinoma can be challenging, but new magnetic resonance imaging modalities help to differentiate these tumor types.⁶

Treatment strategies for this disease process include active surveillance for small asymptomatic masses. Symptomatic masses and masses greater than 4 cm should be treated with radical or partial nephrectomy or ablative therapy.⁷ For patients with metastatic disease, treatment with mTOR inhibitors such as everolimus is often beneficial. A phase 2 registration trial⁸ studied response to nabsirolimus and found that median progression-free survival was 8.9 months, with response depending on TSC gene variation—100% of patients with TSC2 variation had a partial response vs 20% of those with TSC1 variation and 9% of those without a TSC gene variation. Another study estimated that distant metastasis occurs 1.5 years to 9years postoperatively, with death within 1 year of metastasis.⁹ Limited data exist on the benefit of surgical management for distant metastasis in EAML.

This patient underwent initial therapy with radical nephrectomy followed by therapy with mTOR inhibition at the time of metastatic diagnosis. She subsequently underwent multiple surgeries to remove oligometastases. This case illustrates the use of oligometastatic resection for minimization of tumor burden as an overall strategy to preemptively palliate expected symptom(s) and translate to longer overall survival. Additionally, a surgical strategy secondarily provides tumor tissue that can be genotyped for further research efforts.