Primary renal lymphoma: a comprehensive review of the pathophysiology, clinical presentation, imaging features, management and prognosis

Abstract

Primary renal lymphoma (PRL) is defined as a non-Hodgkin’s lymphoma restricted to kidneys with the absence of extensive nodal disease. It is an exceedingly rare clinicopathological entity, accounting for 0.7% of extranodal lymphomas. Published medical literature regarding the natural history and clinical outcomes of PRL remains limited. We describe a case of a young patient who presented with left shoulder pain, continuous fever, and unexplained weight loss as atypical initial manifestations of bilateral PRL, confirmed with the standard set of investigations. Furthermore, this article reviews the literature and discusses various aspects of PRL, including pathophysiology, presentation patterns, imaging and pathological characteristics, management, and prognosis. This paper serves to provide an update and aims to enhance the understanding of PRL. Timely diagnosis and treatment are imperative to achieve improved outcomes. Clinicians should maintain a high index of suspicion in order to prevent morbidity and mortality associated with this serious disease.

Background

Primary renal lymphoma (PRL) is a rare malignancy. It demonstrates the isolated involvement of the kidneys without affecting other organs. The true incidence of this disease remains controversial as most cases do not undergo autopsy confirmation of the presence of systemic disease. However, reported autopsy cases show non-Hodgkin’s lymphoma (NHL) involvement in 30%–60% and <1% of these cases are diagnosed with PRL.¹ The exact aetiology of this tumor remains to be determined. Several explanations are suggestive of the origin of PRL from the renal capsule with infiltration to parenchyma and/or infiltration of the kidney with lymphoid cells in response to chronic inflammatory conditions.² The criteria for diagnosis comprise the presence of unilateral or bilateral renal mass, with no extrarenal involvement of lymph nodes or other organs, absence of myelosuppression with blood tests negative for leukaemia.³ Definitive diagnosis is made on the basis of histopathological evidence from the renal biopsy. It is mostly observed in middle-aged and older patients.⁴ Although adults frequently have a unilateral presentation, bilateral involvement with PRL has been mostly found in paediatric patients.^{5 6} We report here the case of a young adult with bilateral PRL, which is a remarkably rare occurrence. Additionally, we performed a comprehensive review of the relevant medical literature in order to study this rare disease.

Case presentation

This study involves a 21-year-old man who presented with a 4-month history of left shoulder pain, continuous fever (100–101°F), and unexplained weight loss (6 kg). He developed dull, generalised abdominal pain 1 week prior to his current presentation. There was no history of diabetes mellitus, hypertension, cardiovascular, hepatic, pulmonary or kidney disorders. He received multiple courses of antipyretics, antibiotics, steroids, and non-steroidal anti-inflammatory drugs from local practitioners, with no improvement of his clinical symptoms. He was not under therapy with any medications or herbal products at the time of admission. His family history was negative for cancers. Physical examination was unremarkable for abnormalities, except for a temperature of 101°F.

Laboratory studies revealed haemoglobin 154 g/L, white cell count 16.6×10⁹/L, platelets 269×10⁹/L, and lactate dehydrogenase (LDH) 450 U/L. His serum calcium and uric acid levels were elevated at 11.2 mg/dL and 8.8 mg/dL, respectively. A biochemical evaluation indicated renal dysfunction with serum creatinine level increased to 2.1 mg/dL over the last 2 months from his baseline value of 1.3 mg/dL. No abnormality was noted in serum electrolyte levels and liver function tests. Urine complete examination and culture sensitivity were unremarkable, with trace proteinuria and no red blood cells. The workup for autoimmune diseases, including antinuclear, anti-double-stranded DNA, antimitochondrial and antismooth muscle antibodies, came back negative. Complement levels, thyroid function tests, and lipid and coagulation profiles were within normal limits. The tests for infectious aetiologies such as hepatitis panel, cytomegalovirus, Epstein-Barr virus, and HIV were negative. Chest and left shoulder radiographs were normal.

Abdominal ultrasonography revealed bilateral renal enlargement (13.7×6.7 cm and 14.1×6.1 cm), with grade I echogenicity. The size had increased compared with a prior scan. Subsequently, an uneventful percutaneous renal biopsy was performed. The histological examination of the biopsy specimen revealed a lymphocytic infiltrate composed of large B cells (figure 1). Immunohistochemical analysis revealed neoplastic cells positive for monoclonal antibody, CD20 (figure 2). Similarly, tumour cells came out positive for CD3 (figure 3). The cells had high-grade morphologies with a significantly high Ki-67 proliferative index (figure 4). The histological and immunophenotypic findings supported the diagnosis of a B-cell lymphoblastic NHL. Contrast-enhanced CT scans of the chest, abdomen and pelvis revealed bilateral diffuse enlargement of the kidneys with heterogeneous enhancement (figure 5). No mediastinal or abdominopelvic lymphadenopathy was noted (figure 6). Based on the findings of the diagnostic workup and exclusion of probable differentials, he was diagnosed with bilateral PRL.

Figure 1.

H&E stain showing tumour cells with large vesicular nuclei and moderate cytoplasm.

Figure 2.

Immunohistochemistry showing tumour cells positive for CD20.

Figure 3.

Immunohistochemical examination of neoplastic cells positively stained with CD3.

Figure 4.

Tumour cells showing a high Ki-67 proliferative index.

Figure 5.

Axial view of contrast-enhanced CT scan of the abdomen showing bilateral diffuse enlargement of the kidneys with heterogeneous enhancement.

Figure 6.

Coronal reconstructed contrast-enhanced CT scan of the abdomen showing bilateral diffuse enlargement of kidneys with heterogeneous enhancement. No mediastinal or abdominopelvic lymphadenopathy was noted.

Treatment

The patient was educated about his disease. He was referred to an oncologist for the appropriate chemotherapeutic treatment of PRL. He was then initiated on standard treatment of diffuse large B-cell lymphoma, consisting of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen.

Outcome and follow-up

The response to the R-CHOP regimen was excellent with the diminution of his clinical symptoms. His kidney function returned to baseline within 2 months of treatment. He has been on a regular follow-up after chemotherapy. The patient has been symptom-free and continues to do well to date, with the most recent serum creatinine level of 1.2 mg/dL.

Discussion

PRL is a rare form of NHL restricted to the kidneys without the extensive nodal disease. In 1948, Gibson first described this primary renal tumour.⁷ However, the first confirmed case was reported by Coggins in 1980.⁸ PRL still remains an extremely rare disease representing <0.7% of NHL in North America.^{1 9} The published medical literature regarding PRL remains scarce. In a recent study from the Surveillance, Epidemiology and End Results (SEER) database, the age-adjusted incidence was 0.035 per 100 000 population.¹⁰ This disease commonly involves the white population, with a male-to-female ratio of 1.7:1.¹⁰

Pathophysiology

Renal lymphoma commonly occurs secondary to lymphomatous infiltration of advanced systemic disseminated disease.¹¹ Renal involvement is more common in NHL. In most cases, the histological subtype is intermediate or high-grade B-cell lymphoma.¹¹ The major risk factors include Epstein-Barr virus proliferation, HIV infection, organ transplantation, ataxia-telangiectasia and chemotherapy.^12–15 PRL is of non-Hodgkin’s type and is rare as the kidneys lack lymphatic tissue.¹⁶ The proposed pathogenesis implicates its likely origin in the lymphatics of renal capsule or subcapsular tissue. It then involves the renal parenchyma or it can be as a result of any chronic inflammatory process.³ Tumour proliferation begins within the interstitium. The underlying nephrons, collecting ducts and vascular beds act as a scaffold for its growth.⁴ The parenchymal structures and renal contour remain preserved due to the infiltrative growth pattern of this lesion.¹⁰ The increase in the size of the lymphomatous tumour causes compression of the surrounding renal parenchyma. The tumour gradually displaces normal tissue, forming solitary or multiple expansile masses.^{4 10} Non-uniform growth may also invade into the perinephric space, the feature most primary renal neoplasms manifest.¹⁰ The aforementioned factors contribute to the difficulty in diagnosing patients with this tumour.

Clinical presentation

Renal lymphoma may show coexistence with unusual initial clinical manifestations.¹⁷ In regard to PRL, approximately 50% of the patients remain asymptomatic until incidental detection.¹⁰ The most common initial clinical features in symptomatic patients include flank pain due to a palpable abdominal mass and haematuria along with laboratory evidence of deranged renal function.¹⁸ Fever, weight loss, and elevated LDH are typical characteristics of lymphoma. On incidental radiological detection, these tumours may have variable diameters, mostly ranging from 1 cm to 4.5 cm.¹⁸ This presentation is seen in 50%–60% of cases.¹⁹ Similarly, contiguous renal or perinephric space involvement resulting from the invasion of giant nodular lesions from retroperitoneal planes is another common presentation (25%–30% of cases).¹⁹ In a recent study of PRL, unilateral involvement was demonstrated in 95%, whereas bilateral disease was encountered in only 2.5% of the cases.¹⁰ Thus, the present patient was unique in this regard as his initial clinical presentation was dominated by atypical left shoulder pain along with fever and weight loss. Therefore, a combination of atypical symptoms with renal function abnormalities may lead to a diagnosis of PRL

Imaging

The radiological manifestation of a solitary mass is observed in 10%–25% of patients with renal lymphoma.^{1 20 21} On contrast-enhanced CT, PRL shows minimal enhancement. Notably, isolated perinephric lymphoma is unusual with <10% of cases.^{22 23} Contrast-enhanced CT scans are invaluable to identify a ring of homogeneous perinephric tissue encasing the normal parenchyma, without significant renal dysfunction. Nephromegaly, without a distinct tumour formation, is noted in 6%–19% of cases. It results from diffuse infiltration of the renal interstitium by malignant lymphocytes, sparing the glomeruli and tubules.^24–27 This patient also had a similar presentation. Plain CT shows global renal enlargement. However, intravenous contrast helps to detect the heterogeneous renal enhancement, absence of parenchymal differential enhancement, and renal sinus fat invasion.^{28 29} Abdominal ultrasound shows globular renal enlargement, heterogeneous texture, and effacement of renal sinuses.²⁹ Given the overlapping features, the demarcation of PRL from other kidney tumours is imperative. The most common variant of PRL is multinodular renal parenchymal involvement, seen in around 50%–60% of cases. Differentials for multinodular renal masses include multifocal renal cell carcinoma (RCC), transitional cell carcinoma, and renal metastasis. RCC is usually an avidly enhancing lesion with a propensity for vascular invasion and rarely presents with notable lymphadenopathy.³⁰ Therefore, in lesions lacking typical radiological features of RCC or with multinodular renal involvement along with lymphadenopathy, a biopsy can play a key diagnostic role.

Management

PRL can be initially treated with systemic chemotherapy with or without radiation. This patient showed bilateral renal involvement with no signs of nodal or extranodal localisation. Systemic chemotherapy using an R-CHOP regimen is the treatment of choice in patients with bilateral disease.¹¹ Therefore, despite its rare occurrence, it is of immense therapeutic significance to distinguish PRL from RCC. In our patient, the rapid deterioration of the residual renal function was likely due to parenchymal infiltration and the hypercalcaemia, probably induced by vitamin D overproduction from the lymphoid cell mass. After the restoration of normal calcium levels and involution of the renal mass, the renal function returned to the patient’s baseline values. It is notable that the combination of surgery and chemotherapy shows longer overall survival in patients with PRL.³¹ Due to the low incidence of this disease, randomised studies comparing different treatment approaches are not available.

Prognosis

The prognosis of patients affected by PRL is poor, despite no disseminated disease. Chemotherapy usually improves or normalises renal function. However, the rapid recurrence of PRL or serious infectious aetiologies during or after chemotherapy may result in poor outcomes. Long-term disease-free interval with overall survival rate is relatively better with combined surgery–chemotherapy treatment.¹⁸ The R-CHOP regimen is preferred with promising clinical response in bilateral PRL.¹¹ This preserves the organ function, but the subsequent prognosis is poor. However, surgical intervention using bilateral nephrectomy makes patients dependent on dialysis. The earlier reports suggested a poor prognosis for patients with PRL, with a median survival of <1 year.^{3 18} However, recent case reports depict better overall survival probably due to the addition of rituximab to the combination CHOP chemotherapy.^{32 33} The present patient also received R-CHOP and is alive in remission. The tumour mass was markedly reduced and the patient has been on regular follow-up with oncologist and nephrologist, without further worsening of renal profile. Therefore, the present study further adds to the clinical evidence that chemotherapy can be beneficial in the treatment of bilateral PRL.

Learning points.

• Primary renal lymphoma (PRL) remains an extremely rare form of extranodal non-Hodgkin’s lymphoma that may present with atypical clinical features like shoulder pain, in addition to typical features of lymphoma such as continuous fever, weight loss, and high lactate dehydrogenase levels.

• A high index of clinical suspicion for PRL should be maintained, especially if the lesion shows multinodular renal involvement along with lymphadenopathy.

• Preoperative diagnosis is important as earlier recognition and prompt treatment of PRL with systemic chemotherapy may lead to disease remission unlike other renal tumours, which invariably require nephrectomy.

• Although it will be difficult due to the rarity of PRL, a prospective study providing a context in the evaluation and treatment of patients with PRL is warranted.