Continuing Education Activity

Renal leiomyosarcoma (LMS) is a rare and aggressive mesenchymal tumor. The tumor usually arises from the smooth muscle cells of the intrarenal blood vessels or the renal pelvis. It has a high tendency for local recurrence and frequently metastasizes to distant organs. This activity reviews the evaluation and management of renal leiomyosarcoma and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Describe the clinical characteristics of renal leiomyosarcoma.
• Review the importance of image-guided percutaneous needle biopsy in establishing the diagnosis.
• Outline the entities that should be considered in the differential diagnosis of renal leiomyosarcoma.
• Identify interprofessional team strategies for improving care coordination and outcomes in patients with renal leiomyosarcoma.

Introduction

Renal leiomyosarcoma (LMS) is a rare and aggressive mesenchymal tumor that usually arises from the smooth muscle cells of the intrarenal blood vessels or the renal pelvis.[1] Primary leiomyosarcomas are rare in the kidney and represent 1%-2% of all malignant renal tumors. The mean age at presentation is 50–60 years with a female preponderance.There is a high tendency of local recurrence, hence complete surgical excision is recommended.[2][3][4] Renal LMS frequently metastasizes to distant body organs via hematogenous spread and carries an overall poor prognosis.[1][5] The diagnosis of primary renal leiomyosarcoma should be made with caution. Since the prognosis for a renal sarcoma is particularly poor, differentiation from sarcomatoid renal cell carcinoma is necessary.

Etiology

Few predisposing or etiologic factors have been recognized for leiomyosarcoma (LMS) in general,[6] and much less is known about risk factors for renal LMS. Renal LMS, like LMS in general, shows a strong predilection for the female gender (59-76%).[1][5][6] It is suggested that female predominance may be related to hormonal influences, but the evidence is inconclusive.[6]

Epidemiology

While leiomyosarcoma (LMS) is the most common sarcoma that occurs within the kidney, it remains an exceedingly rare tumor, accounting for only 0.1% of renal malignancies.[1][7] As mentioned above, renal LMS is more common in females. The typical presentation is between the 4th and 6th decades of life with a mean age at diagnosis of 58.5 (range 22-85).[1][8]

Histopathology

Like leiomyosarcoma (LMS) elsewhere in the body, renal LMS shows interlacing bundles of muscle fascicles with spindle cells that have blunt-ended (cigar-shaped) nuclei and eosinophilic cytoplasm. Cellular pleomorphism, foci of tumor necrosis, and increased mitoses are typical features. By immunohistochemistry, the tumor cells are positive for markers of muscle origin, such as smooth muscle actin and desmin, and are negative for cytokeratin, S-100, and HMB-45.[1][9] LMS is usually graded according to the French federation of cancer center sarcoma group, a three-tiered system with grades assigned based on tumor differentiation, mitotic count, and tumor necrosis.[10] The higher the grade of the tumor, the greater is the chance of local recurrence or distant metastasis.[10] The majority of reported cases of primary renal LMS tended to be high-grade (grade 2 or 3).[1][9]

History and Physical

In terms of its presenting symptoms, leiomyosarcoma (LMS) mimics other renal malignancies. There are no specific presenting symptoms that can differentiate renal LMS from other renal malignancies. As with renal cell carcinoma, symptoms occur relatively late in the course of the disease, and patients present with hematuria, abdominal pain, and an abdominal mass.[7] Moazzam et al. reported a case of renal leiomyosarcoma presenting with spontaneous retroperitoneal hemorrhage and hypotension.[11]

Evaluation

Advances in computerized tomography (CT), magnetic resonance imaging (MRI), and other specialized imaging techniques have created great improvements in the diagnosis of renal cell carcinoma (RCC), benign renal neoplasms, and in characterizing the level of aggressiveness of RCC subtypes, which informs management decisions in these tumors. However, renal leiomyosarcoma is rare and does not have known specific imaging characteristics. Unlike other retroperitoneal tumors, CT is limited in the evaluation of renal LMS. The most important differential of renal LMS is renal cell carcinoma, which cannot be reliably differentiated with any radiological technique.[12][13] Due to this limitation, CT-guided core needle biopsy is strongly recommended for histopathological diagnosis of the tumor, which is critical to planning appropriate therapy.[5][12] An image-guided percutaneous renal mass biopsy is a safe procedure with a high degree of diagnostic accuracy.[14]

Treatment / Management

Leiomyosarcoma (LMS) is the most common histological subtype and accounts for 50-60% of total renal sarcomas. However, renal leiomyosarcoma is still a remarkably rare tumor.[15] As mentioned above, a needle core biopsy of the tumor under image guidance is recommended to make a definitive diagnosis and to guide surgical treatment and neoadjuvant therapy. Clinically significant complications for preoperative core biopsy are rare,[14] and concerns regarding the risk of needle-track seeding, micro-metastasis, or acute intra-abdominal conditions appear unwarranted based on clinical data.[16]

There is no consensus on the role of neoadjuvant or adjuvant radio/chemotherapy in the management of renal LMS.[5] Due to the relatively low incidence of renal leiomyosarcoma, there are no randomized controlled trials to dictate treatment and are generally extrapolated from other retroperitoneal/intra-abdominal sarcomas and case reports. Prior to the initiation of therapy, all patients should be evaluated and managed by an interprofessional team with expertise and experience in sarcomas. For all patients, we should suggest participation in ongoing clinical trials, where available. Surgical resection has traditionally been the only potentially curative approach. The currently recommended treatment for resectable tumors is complete surgical excision of the tumor with negative margins. Due to the significant proportion of aggressive leiomyosarcomas that tend to recur locally, radical nephrectomy is a superior management option that provides better oncologic control.[17] Demir et al. described nephron-sparing surgery with no sign of recurrence, but the tumor was low grade with no change in size for 3 years.[17] If the surgeon anticipates a grossly incomplete resection, intraoperative radiation therapy (IORT) results in excellent local control and survival, with acceptable morbidity.

If protocol therapy is not available or the patient is not eligible, the treatment approach differs based upon grade and histology. For patients with intermediate and high-grade tumors, large tumors, and the risk of distant metastatic disease is high, then preoperative radiotherapy (RT) alone, preoperative chemotherapy (with postoperative RT), or preoperative chemoradiotherapy are all acceptable options. Responders to neoadjuvant treatments tend to do better than nonresponders, whether this reflects the impact of chemotherapy/RT or disease biology. In patients with large, high-grade leiomyosarcomas and dedifferentiated liposarcomas, the addition of neoadjuvant chemotherapy to surgery is being investigated in a randomized trial (STRASS-2) conducted by the European organization for research and treatment of cancer (EORTC).

Neoadjuvant radiotherapy is generally administered while it is not indicated postoperatively in R0 (tumor resection with negative macro and microscopic margins). Adjuvant chemotherapy is recommended in cases of R2 resections (tumors with positive macro and microscopic resection margins) as well as in unresectable and metastatic disease.[5] Anthracycline/ifosfamide-containing chemotherapy is usually the preferred regimen. A Single-institution phase II study by Mahmood et al. investigated the safety and efficacy of sunitinib malate in three common soft tissue sarcomas (STS) subtypes among patients with documented unresectable or metastatic disease. The median progression-free survival was 4.2 months, and the median overall survival was 10.1 months among patients with LMS. Further investigation with multicentric, phase 3 studies is warranted.

Differential Diagnosis

Although renal leiomyosarcoma (LMS) is the most common primary renal sarcoma (50 to 60%),[5] it is still a very rare entity, and other neoplasms must be ruled out before making the diagnosis of primary renal LMS.

• Retroperitoneal leiomyosarcoma, involving the kidney should be ruled out before making the diagnosis of primary renal LMS for which radiological techniques can play an important role in defining the boundaries of the lesion.
• Sarcomatoid carcinoma of the kidney, arising from renal cell carcinoma or less commonly from urothelial carcinoma, is perhaps the most important histopathologic differential diagnosis when dealing with a spindle cell renal tumor. Histological evaluation of sarcomatoid carcinoma often shows a malignant epithelial component, in contrast to the uniform fascicular architecture of leiomyosarcoma. In limited samples, where only spindle cell component is encountered, immunohistochemistry can help as the spindle cell component of sarcomatoid carcinoma is typically positive for keratin and negative for actin, while the reverse is true for leiomyosarcoma.[1]
• Angiomyolipoma, a tumor of perivascular epithelioid cells, can mimic renal LMS histologically. The histological finding of mature adipose tissue with thick hyalinized blood vessels favors angiomyolipoma. But, if only the spindle cell component predominates with significant atypia, immunohistochemical reactivity for HMB-45 (a melanocytic marker) is seen in angiomyolipoma but is negative in LMS, which is helpful in this differential.[1]
• Renal leiomyomas are the benign counterparts of leiomyosarcoma, and they are exceedingly rare neoplasms. Radiological techniques are not sufficient to distinguish them from leiomyosarcoma, and histological evaluation of the tumor is necessary to make the definitive diagnosis, which shows the fascicular arrangement of benign smooth muscles with no atypia, or necrosis and very rare or absent mitosis. It is important to note that many leiomyosarcomas have focal areas that resemble leiomyoma, and adequate sampling of the tumor is crucial for an accurate diagnosis.

Prognosis

Renal leiomyosarcoma (LMS) carries a poor prognosis with a median overall survival of 25 months. Among soft-tissue sarcomas, the stage is the most important prognostic factor. Other factors include histological subtype, grade, age of the patient, and gender. The rate of local recurrence and the risk of metastasis is determined by the grade of tumor and inferior vena cava extension.[5]

Complications

Rare cases presenting with spontaneous retroperitoneal hemorrhage and hypotension have been reported in the literature. In a case series of 67 patients with renal vein leiomyosarcoma (LMS), 50% of the patients experienced disease progression despite treatment. Metastasis to distant body sites (liver, lungs, bones, soft tissue) occurred in 30% of patients. The rate of local recurrence was 4.5%, while 15% of the patients experienced combined local recurrence and distant metastasis.[5] Intra-renal LMS appears to behave in the same manner.[1]

Consultations

The management of renal leiomyosarcoma requires a multidisciplinary team consisting of:

• Urologist
• Nephrologist
• Medical oncologist
• Radiation oncologist
• Interventional radiologist
• Pathologist

Deterrence and Patient Education

Renal leiomyosarcoma (LMS) is a rare, but aggressive malignancy that carries an overall poor prognosis. There are no established risk factors, so prevention is not an option. Many studies suggest patients succumb to the disease, this observation was common in the patients with intermediate to high-grade tumors. Patient education is important as the rate of local recurrence of this tumor in the first two years is high, good compliance with regular follow-up can help to identify the recurrence at an early stage and improve the outcome.

Enhancing Healthcare Team Outcomes

Renal leiomyosarcoma is a rare, aggressive malignancy that carries an overall poor prognosis. Its clinical presentation is not different from that of the far more common renal cell carcinoma with hematuria, flank pain, and an abdominal mass. Radiologists play a crucial role in the diagnosis, not simply by identifying the renal mass, but by performing an image-guided percutaneous biopsy to obtain adequate and representative tissue for biopsy. Radiologists also select the imaging modalities appropriate for staging the disease. Histopathologists examine the biopsy tissue using routine microscopic and immunohistochemical techniques to make a specific diagnosis and assign a grade to the tumor. The grade is another important prognostic indicator. Surgeons perform radical nephrectomy, which is the recommended definitive treatment. Medical oncologists and radiation oncologists may offer additional therapy depending on the margin status as confirmed by the pathologist postoperatively and taking into account the clinical staging.[Level 5]