Robotic-assisted laparoscopic resection of a primary renal neuroendocrine carcinoma

Abstract

Primary renal neuroendocrine carcinomas (RNC) are extremely rare urological neoplasms, with fewer than 100 cases reported in the literature. There are no established protocols concerning diagnosis and treatment, and there is no definitive data on prognosis. Here, we report the findings of a 54-year-old woman who presented with intermittent back pain due to a large mass, which was initially suspected to be a renal cell or upper tract urothelial carcinoma. The patient underwent robotic-assisted laparoscopic nephrectomy and lymph node dissection without complications. Pathology revealed an RNC with local metastases to para-aortic lymph nodes without evidence of another primary origin. Subsequent surveillance showed no evidence of disease until 48-month follow-up imaging revealed a liver lesion suspicious for possible metastatic cancer. This report represents the second documented usage of robot-assisted laparoscopic nephrectomy for RNC and the longest follow-up in the literature. We review the diagnosis, treatment and follow-up of patients with RNC.

Background

Neuroendocrine carcinomas (NECs) are uncommon tumours that arise from the enterochromaffin cells within the gastrointestinal tract and respiratory system. Neoplasms originating from either of these regions account for approximately 98.8% of neuroendocrine tumours (NETs).¹ NECs originating from the genitourinary system are particularly rare but have been reported to arise from the kidney, urinary bladder, urethra and prostate.² Although there are reports of non-parenchymal NECs arising from the kidneys, urologic NECs seldom arise from renal parenchyma.²

Primary renal neuroendocrine carcinomas (RNC) are extremely rare, with fewer than 100 cases reported in the literature.³ No established guidelines exist for the diagnosis and management of primary RNCs owing to the rarity of the disease. Additionally, no radiological features exist to differentiate RNC from other primary renal tumours.^{4 5} Although 20% of RNCs are discovered incidentally, the clinical presentation can include abdominal pain, flank pain, weight loss and haematuria.² In fact, the presentation does not feature any clear distinction from other renal tumours as characteristic NET symptoms are rarely seen in primary RNCs.⁶

Primary RNCs are associated with other renal pathologies. Horseshoe kidney is the most common association (18%–25% of cases), but other teratomas and polycystic kidney disease have been reported.^{3 7} There are limited data on the pathogenesis and long-term prognosis of patients with primary RNC. Understanding long-term behaviours and recurrence rates of RNC will assist in providing more concrete treatment and follow-up guidelines for patients with the condition. Herein, we report the diagnosis, surgical management and follow-up protocol used to treat this rare renal neuroenNET in a 54-year-old woman with back pain.

Case presentation

A 54-year-old woman with a medical history significant for hypertension presented with an incidental left renal mass during evaluation for a thyroid nodule. The patient’s only symptom was mild, intermittent back pain.

The patient was initially evaluated by an endocrinologist for osteoporosis and was found to have a thyroid nodule (biopsy negative for malignancy) and an abdominal mass. No lymphadenopathy was noted and the patient denied weight loss, fever, chills and abdominal pain. She had no known family history of malignancies.

Investigations

Initial CT imaging demonstrated an enhancing, partially necrotic 12×12.7×7.8 cm left lower pole medial renal mass. The mass was positioned near the hilum, causing obstruction and resultant severe hydronephrosis with cortical thinning (figure 1). A staging chest CT and liver function tests were negative for metastases. Further investigation of the mass was done after bivalving the resected kidney.

Figure 1.

CT scan with contrast showing severe hydronephrosis and cortical thinning of the left kidney with a 12 cm necrotic left medial lower pole renal mass (A: axial plane; B: coronal plane; C: coronal plane).

The gross specimen consisted of a 15.0×9.0×8.5 cm intact kidney weighing a total of 556 g. The cut surface showed an almost completely necrotic tumour with a variable rim of kidney measuring up to 0.7 cm in thickness. The tumour was 14 cm in its largest diameter. Microscopic examination of the mass demonstrated tumour cells of renal origin exhibiting typical neuroendocrine growth patterns including nesting, cording and rosettes. Higher magnification demonstrated the classic ‘salt and pepper’ chromatin pattern. Staining was positive for synaptophysin and chromogranin, and patchy positive for CD57, CK7 and CD10 (figures 2 and 3). Neoplastic cells were negative for PAX-8, TTF-1, WT-1, renal cell carcinoma (RCC) antigen and AMACR. Ki-67 index by quantitative image analysis demonstrated an average proliferative index of 1.6%.⁸ A diagnosis of intermediate grade neuroendocrine carcinoma was warranted due to the presence of extensive necrosis.⁹ One of eight para-aortic lymph nodes was positive for metastatic carcinoma.

Figure 2.

Tumour cells exhibiting typical neuroendocrine growth pattern including nesting, cording and rosettes (A, B). Higher magnification showing the classic ‘salt and pepper’ chromatin pattern (C). (D) Tumour necrosis (H&E, 10×). (E) Lymphovascular invasion (H&E, 20×). (F) Lymph node metastasis.

Figure 3.

Immunohistochemical stains for tumour cells positive for neuroendocrine markers including (A) chromogranin and (B) synaptophysin.

Differential diagnosis

Differential diagnoses for the mass included upper tract urothelial carcinoma (UTUC) and RCC. Primary RNC was not initially considered due to its rarity. Gross examination of the mass was inconclusive; only after a frozen section of the resected mass was examined was a pathological diagnosis of RNC considered. This diagnosis was later confirmed by final pathology.

Treatment

Preoperatively, the primary treatment options discussed with the patient were neoadjuvant chemotherapy given the possibility of UTUC and surgical resection given the high clinical suspicion for RCC. The surgical options, including open, laparoscopic and robotic nephrectomy as well as lymph node dissection were discussed with the patient, along with their risks and benefits. She elected to undergo robotic-assisted laparoscopic radical nephrectomy with lymph node dissection.

The patient was placed in the left modified flank position. After creating the pneumoperitoneum to 15 mm Hg, three 8 mm robotic ports as well as a 12 mm assistant port were placed under direct vision. The da Vinci XI surgical system was used. The procedure started by incising the white line of Toldt, and the colon and spleen were reflected medially, exposing the mass in the retroperitoneum. The renal vein and adrenal vein were identified. The adrenal gland appeared to be benign both on imaging and grossly so it was spared. A plane was established between the upper medial pole of the kidney and the adrenal gland. Next, the ureter and gonadal vessels were elevated off the psoas muscle and placed on traction to help expose the renal hilum. The renal artery, renal vein and ureter were secured, and the kidney was freed from the retroperitoneum. We then proceeded with a lymph node dissection, removing the nodal tissue from the renal hilum to below the inferior mesenteric artery. The lymph nodes and kidney were extracted with a 15 mm endocatch bag through a lower midline incision, extended from the assistant port. The case proceeded smoothly with minimal blood loss.

Outcome and follow-up

The patient tolerated the procedure well with no complications and did well postoperatively. She was followed closely postoperatively with imaging every 4 months due to the limited data on the management and recommended follow-up of RNC. At 25 months follow-up, MRI revealed scattered subcentimetre hypervascular nodules in the liver that were too small to characterise. Subsequent follow-up remained unremarkable until 48 months, at which point one lesion located in segment VIII of the liver was noted to have increased in size from 3 to 7 mm, suspicious for metastatic neuroendocrine carcinoma. A subsequent workup is being undertaken at the time of this publication. Even still, she remains symptom free at 48 months follow-up following resection alone.

Discussion

NECs are characterised by the presence of epithelial neoplasia with neuroendocrine differentiation.¹⁰ When active, NECs secrete vasoactive peptides such as serotonin that can result in symptoms including diarrhoea, flushing, bronchoconstriction or palpitations.¹¹ RNCs, however, rarely present with the hallmark symptoms associated with conventional NECs, making them difficult to distinguish from other renal tumours.⁶ Primary RNCs have previously been reported less than 100 times in the literature. Therefore, limited information exists regarding their prognosis and long-term management.³ The focus of this report was to characterise the presentation, treatment and follow-up of a patient with primary RNC.

RNCs are incidentally discovered by abdominal imaging in 20% of cases.² Symptoms warranting further workup for RNC include abdominal pain, flank pain, weight loss and haematuria.³ CT of the abdomen and pelvis is often the first-line diagnostic tool, and can be used to assess for urological malignancies that may explain these symptoms. However, imaging alone cannot distinguish RNCs from other renal tumours. Consequently, histopathological examination is required to confirm the diagnosis.

The classic histopathological finding of NETs is positive staining for chromogranin A and synaptophysin.¹⁰ NET growth is also notable for nesting patterns, palisading and rosettes with a low rate of proliferation.⁵ If the origin of the tumour is unknown, markers of primary origin can be used to assess the initial site of the tumour. Examples include thyroid transcription factor-1 (TTF1), CDX2 and PDX1, which are markers of pulmonary, gastrointestinal and pancreatic NETs, respectively.¹⁰

In our case, the tumour cells stained positive for chromogranin and synaptophysin, which supported the diagnosis of a NET. CD57 was also positive, and markers indicative of renal cell carcinoma, including, PAX8, TTF-1, CDX2 and PDX1, were negative. This combination suggested that the primary origin was neither gastrointestinal or bronchopulmonary. Although the literature does not note a specific biomarker for primary RNC, the tumour was large, confined to the kidney and not found to be of any other primary origin. The presence of necrosis and CK7, CD10 and alpha-methylacyl-CoA racemase (AMACR) immunophenotype markers further supported an RNC diagnosis.⁵ This extensive workup to confirm tumour identity underscores the rarity of RNCs and reinforces why imaging alone is insufficient to make a definitive diagnosis of this class of tumours.

Treatment for primary RNCs conventionally entails radical nephrectomy with lymph node dissection for local metastases. In a prior review of the literature, 47% of patients who underwent nephrectomy for RNC and local metastases were disease free over the course of a 3-year follow-up period.⁷ In general, robotic-assisted laparoscopic and conventional laparoscopic nephrectomy have been shown to be equally efficacious as open nephrectomy and are associated with lower rates of mortality for other renal cancers.¹² These surgical modalities have the added benefit of minimising a patient’s postoperative hospital course. Our case represents only the second documented usage of robot-assisted laparoscopic nephrectomy as treatment for RNC.¹³

Despite the paucity of literature on primary RNC, survival rates for NETs of the kidney have thus far been excellent. Omiyale et al reviewed 29 patients with RNC, 27 of whom underwent surgical treatment.³ They described a disease-free rate of 73.1% at 20 months of follow-up. However, little information is available on survival rates of patients with metastatic or recurrent RNC.

The first documented robotic nephrectomy for primary RNC reported the patient was disease free at 1 month after surgery. Our patient also appeared to remain disease free for 25 months; however, follow-up imaging revealed hypervascular hepatic nodules, one of which increased in size over the next 2 years and is suspicious for metastatic neuroendocrine carcinoma.

Little is known about the prognosis and outcomes for patients presenting with distant metastatic disease from a primary RNC, and thus no treatment protocols are in place for extrarenal metastatic disease.¹⁴ Because NETs of other primary origins have been reported to overexpress Vascular endothelial growth factor (VEGF), there has been interest in using antiangiogenic therapy such as sunitinib in the setting of metastasis.¹⁵ Initially, we elected not to proceed with this form of adjuvant treatment in our case given the lack of evidence of in this particular clinical scenario. Given that our patient seems to have developed a lesion suspicious for metastasis several years after treatment, one could begin to examine the potential role of adjuvant antiangiogenic therapy in cases of primary RNC.

The lack of literature concerning primary RNC makes it clinically challenging to establish guidelines for follow-up of patients with RNC. Current long-term surveillance and management of primary RNCs is based on the behaviour of other neuroendocrine carcinomas, primarily of gastrointestinal origin. After resection of gastrointestinal NETs, it is recommend to perform CT or MRI studies every 6 months for the first year after surgery, with eventual transition to annual scans if initial imaging remains negative.¹⁶ This follow-up interval can be modified and shortened if the patient’s tumour was high grade or if they are receiving adjuvant therapy after resection. Our case demonstrates that radical nephrectomy and lymph node dissection alone may be insufficient to treat node positive RNC. While regular imaging can be used as effective surveillance to monitor if patients remain disease free, adjuvant chemotherapy may be indicated to reduce the incidence of metastatic disease.^{3 5}

Patient’s perspective.

I was shocked and very disappointed that other doctors did not find this mass sooner—especially because it was so large. I had some very heavy menstrual bleeding a year or so before so I knew something was wrong, but they did not find anything. On viewing the CT scan, the initial urologist joked: ‘This kidney's a dud, it has to go.’ I was not thrilled about the surgery, but since it was not functioning anyway, figured it was a done deal. Also, it didn't seem wise to keep a tumour growing like that in my body. Post-surgery I felt great! Plus, compared with recovering from my orthopaedic surgery, I had less pain and complications. I remember being a bit tired and nauseous, but on the pain scale probably a 3 or 4.

Learning points.

• Primary renal neuroendocrine carcinomas (RNC) are rare and limited data exists on the diagnosis and management of these patients.

• Radical nephrectomy (including minimally invasive techniques like standard laparoscopic and robotic-assisted laparoscopic) and lymph node dissection may be insufficient for a durable cure in cases of primary RNC with lymph node positive disease.

• Follow-up imaging and surveillance are recommended to continue to understand the natural history of patients who present with RNC.