NEUROENDOCRINE RENAL CARCINOMA – THERAPEUTIC AND DIAGNOSTIC ISSUES

Abstract

Introduction

Neuroendocrine renal carcinoma represents less than 1% of all primary neoplasia of the kidney. Most frequently poorly differentiated carcinoma is diagnosed in advanced stages and they have an aggressive evolution and limited survival rate. Neuroendocrine carcinomas that arise from the renal pelvis are frequently associated with squamous cell carcinoma or adenocarcinoma.

Material and method

We present the case of a female patient, known for 3 years before with an undefined retroperitoneal lymph node metastasis, being diagnosed at present with a left large cell neuroendocrine renal carcinoma, who initially had lymph node metastasis.

Results

Until now, 118 cases of primary neuroendocrine renal carcinomas have been reported. A limited number of poorly differentiated neuroendocrine carcinomas have been reported.

Discussion

Due to the clinical and biological findings, the aggressive evolution with early metastasis of lung and bone, the patient is included in the group of poorly differentiated carcinomas. In these cases, multimodal treatment is a gold standard. After surgical treatment and palliative chemotherapy with platinum salts, we obtained a partial remission of the disease and the control of symptoms.

Conclusions

Regarding large cell neuroendocrine carcinoma, the surgical treatment remains the treatment of choice. Chemotherapy can determine limited results, improve the quality of life and enhance the overall survival rate.

INTRODUCTION

Primary neuroendocrine tumors of the kidney are very rare tumors, 118 cases being described so far (1). The largest series, 21 patients with renal neuroendocrine carcinoma, was investigated over a period of 36 years by Hansel et al. (2). This kind of carcinoma can occur both in the renal parenchyma as well as in the renal pelvis, most frequently they were discovered in horseshoe kidney (3-5).

The WHO classification of neuroendocrine tumors takes into account the proliferation index (Ki-67, MIB-1), mitosis and angio-invasion, as follows: well differentiated (under 2 cm, Ki-67 under 2%), intermediate differentiation (above 2 cm, Ki-67 above 2% or angio-invasion) and poorly differentiated (Ki – 67 > 20%) (6).

It is claimed that neuroendocrine carcinoma of the renal pelvis is most frequently associated with adenocarcinoma, transitional cell carcinoma or squamous cell carcinoma, all arising in the renal parenchyma (7, 8).

Carcinoid tumors of the kidney tend to grow slow and can remain silent for a long period of time before manifesting any symptoms – such as flank or abdominal pain, hematuria, weight loss or abdominal mass. Due to the similarity with other renal neoplasm, a neuroendocrine tumor is rarely suspected prior to surgery (9, 10). Imagistic findings are not specific and cannot distinguish carcinoid renal tumors from renal cell carcinoma. The computer tomography (CT scan) findings in renal carcinoid are composed of a well circumscribed, none enhancing or slightly enhancing masses with a solid component (11).

The majority of neuroendocrine renal tumors are carcinomas with a slow evolution, good prognosis, and long overall survival (1, 11). Poorly differentiated neuroendocrine carcinoma has been reported in a limited case of series, having an aggressive evolution, with early metastasis, being diagnosed in advanced stages, and having bad prognosis (12).

MATERIAL AND METHOD

We report a case of a 65-year-old female patient with renal neuroendocrine carcinoma, admitted to the Oncology Department in March 2013 for worsening of the general health state for the past 2 months. She presented nausea, vomiting, asthenia, loss of appetite and left flank abdominal pain with an intensity of 5/6 on Visual Analogue Scale (VAS).

In 2010, the patient presented an episode of diffuse abdominal pain with headache and vertigo. At that time, the CT scan revealed enlarged celiac trunk, inferior and superior mesenteric, para aortic and interaortocaval lymph node. The patient was investigated in a Haematology Department for a possible diagnosis of lymphoma. In October 2010, she underwent a surgical intervention with a retroperitoneal lymph node biopsy. The immunohistochemistry result was serous papillary adenocarcinoma metastasis, most likely with genital formation, but not being able to exclude primary peritoneal origin of the primary tumor and without evidence of the primary tumor on clinical and imaging examinations.

Between November 2010 and April 2011, the patient underwent 5 series of cyclophosphamide and carboplatin chemotherapy, which were interrupted at the patient’s request.

The patient was admitted in the Oncology Department of “St. Luke” Chronic Disease Hospital, in March 2013, with left flank abdominal pain, fatigability, and weight loss. She underwent an abdominal CT scan (Figs 1, 2) which showed an 11/12/13 cm inhomogeneous tumor in the left kidney, with peripheral iodophilic lumps, central necrosis, which invaded the spleen and was adjacent to the splenic vein, left psoas muscle, left lateral wall of the abdominal aorta, posterior caudal region of the pancreas, but did not invade the left suprarenal gland and lymph nodes enlargement. The case presented as follows: 22/ 11 mm bilateral axillary node, multiple nodes situated on the left side of the lumbar area, near the aorta, measuring approximately 11 mm, external iliac and bilateral obturator of 18mm. As a result of the primary biological and clinical evaluation, a tumoral mass was found in the left abdominal flank, together with secondary anaemia (Hb = 7.6 g/ dL), thrombocytosis and chronic kidney disease.

Figure 1.

Preoperative abdomen CT scan large tumor arising from the left superior kidney pole, measuring 11/ 12 cm in diameter, with inhomogeneous contrast filling, iodophilic peripheral lumps and central necrosis.

Figure 2.

Preoperative abdominal CT scan tumour in the left kidney invading the spleen at its posterior half and the lineal vein on a distance of approximately 22 mm.

RESULTS

After a gross control of the symptomatology, the patient was transferred to the General Surgery Department of “Bagdasar-Arseni” Clinical Emergency Hospital.

Concerning the advanced stage of the tumor, which surpassed the renal capsule and invaded the proximity organs, the multiple enlarged lymph node discovered on CT scan, the severe anaemia and the presence of microscopic hematuria, a surgical palliative treatment, with haemostatic target was performed.

At that time, a mixed team of general surgeons and urologists performed a left thoraco-phreno-laparotomy, and found a large left kidney tumor of 18/ 12 cm, which invaded the left diaphragmatic column, had a close contact and a minimum separation space with the abdominal aorta which was pushed medially, and had contact with the visceral surface of the spleen and the left psoas muscle (Figs 3, 4). We also discovered multiple enlarged para aortic and renal hilum lymph nodes. We performed a left nephrectomy with a gross excision of the enlarged lymph nodes, para aortic lymph nodes were left in place; a partial resection of the left diaphragmatic column and splenectomy was performed, leaving the left suprarenal gland in place. Intraoperatively, no other tumoral masses or pathological findings were discovered.

Figure 3.

Gross postoperatory aspect of the left tumoral kidney.

Figure 4.

Intraoperative aspect of the left tumoral kidney.

The patient never presented to the regular assessment. In June 2013, she presented to the Emergency Department of “Bagdasar-Arseni” Clinical Emergency Hospital with a worsening of the general state (ECOG Performance Status 3 from 5) and intense abdominal and lumbar pain. X-ray examination in the ER department showed multiple secondary determinations of the lungs and bones and the patient was transferred to the Oncology Department for palliative care.

Macroscopic examination of the tumoral left kidney showed a grey tumor of 8/6/4.4 cm, situated intrabasinal, spreading into the cortex and the perirenal fat and in the hilar structure, suggesting a poorly differentiated adenocarcinoma (Figs 5, 6). Ureteral resection limit was tumor free. Microscopic examination showed carcinoma, high anaplastic with monstrous nuclear proliferation. The aggressivity was confirmed by the number of typical and atypical mitosis: 74 mitoses/ 10HPF. Immunohistochemistry set the diagnosis of poorly differentiated carcinoma, with a major neuroendocrine component partially positive for CK7, CD10 and diffuse for CD 56 (Fig. 7) and Chromogranin, Syn positive (Fig. 8), VIM positive (Fig. 9), CK34BetaE12 negative, EMA and CD10 partially positive, not being able to identify a positive receptor for ER and PR.

Figure 5.

Renal tumor – histological aspect at interface with remaining tissue. Van Gieson stain.

Figure 6.

Renal tumor – Hematoxylin – Eosin stain, detail X40.

Figure 7.

Renal tumor - CD 56 expression (X20).

Figure 8.

Renal tumor – Synaptophysin positivity (X20).

Figure 9.

Renal tumor – Vimentin (X20).

The lymph node obtained in 2010 (Fig. 12) was reviewed and the immunohistochemistry showed a diffuse positivity for ER, p53 (Fig. 13) and CK7 (Fig. 14). Partially, markers for CA-125 were identified. In 40% of the tumor nuclei, Ki67 (Fig. 15) was quantifiable. The testing for WT1 showed contradictory values – the examination was done in two different laboratories. The diagnosis of lymph node metastases of papillary serous adenocarcinoma with genital formation was confirmed.

Figure 12.

Tumoral lymph node – histopathology aspect – Hematoxylin – Eosin stain (X20).

Figure 13.

Tumoral lymph node – nuclear p53 expression (X40).

Figure 14.

Tumoral lymph node–CK 7positivity (X20).

Figure 15.

Tumoral lymph node Ki 67 immunostaining.

The patient started palliative chemotherapy (Etoposid plus Carboplatin), osteoclast inhibitors, and pain and anaemia treatment. The patient’s clinical, biological, and imaging assessment was done at every 21 days. We mention that patient had normal Chromogranin A, Serotonin and 5-hydroxyindoleacetic acid levels. We could not perform an Octreoscan and, because the patient had normal neuroendocrine biomarker levels we did not consider the opportunity of somatostatin analogues therapy. In November 2013, the CT scan evaluation revealed a partial remission of the disease, with enlarged lymph node: bilateral axillary, 1.5 cm, cephalic pancreatic 33/ 19mm, lumbar and aortic app 14 mm; lack of pulmonary metastasis or local recurrence (left renal lounge) (Figs 10, 11). During the entire follow-up period, even after the first series of chemotherapy, the clinical evolution was favorable by converting the patient’s performance status to 1, maintaining the serum hemoglobin values between 8.3 and 10 g/ dL and total control of symptomatology.

Figure 10.

7 months lung control CT scan. Absence of secondary metastatic lesion in the lung or tumoral relapse after surgical and oncologic treatment.

Figure 11.

Seven months abdomen control CT scan.

The particularity of the case was the diagnosis of a left kidney neoplasia T2N2M1LYM stage (neuroendocrine large cell carcinoma) – with pulmonary and bone metastasis in the evolution, metachronous lymph node metastasis of poorly differentiated adenocarcinoma of unknown origin, treated surgically and with chemotherapy. The medical literature was reviewed by analyzing cases of neuroendocrine renal tumors and possible synchronous or metachronous neoplasia, possible therapeutic methods, the evolution, and the overall survival.

DISCUSSION

The first case of renal neuroendocrine tumor was described by Resnick et al. in 1966 (13, 14). In 2006, Murali et al. referred to 51 cases described in literature, and in 2007, Romero et al. referred to 56 cases. In 2010, Jain et al. analyzed 90 cases of renal neuroendocrine tumors and, in 2013, Korkmaz reported 24 new cases from 2010 to February 2013. To the total of 116 cases, 2 other cases, reported in the Anglo-Saxon literature and presented in 2013 (1, 8, 13, 15-20), were added. The majority of renal neuroendocrine tumors were represented by carcinoids or atypical neuroendocrine carcinomas. Until 2007, 16 cases of small cell renal neuroendocrine carcinomas were reported, and other 4 cases from 2009 until 2013, representing 16.95% from the total neuroendocrine renal tumors. Only 8 cases (6.78%) of large cell neuroendocrine renal carcinomas were reported – category in which our patient was included (15, 16, 18).

The patients were aged between 21 and 90 years, with a median age of 52 years (16, 20) and no signification concerning the gender. Our patient was diagnosed at the age of 65 years.

The literature case analysis showed that the majority of patients in the diagnostic period had a localized disease, which permitted radical or partial nephrectomy, rare cases having T3, T4 or metastatic tumors (17.79%). In the cases with a metastatic disease at the time of diagnosis, most frequently, the metastasis encountered was para aortic lymph nodes (6.78%) or hepatic (5.08%) (16, 17). At presentation, approximately 45% of renal neuroendocrine tumors had over 4 cm, the largest being of 30 cm (13, 16). At presentation, our patient had a renal tumor with a lymph node metastasis (axillary, iliac and aortic-lumbar). There were few cases in which they were associated with other carcinomas, such as breast carcinoma (6 months prior the diagnosis of renal neuroendocrine carcinoma) or mixed carcinomas (13, 20-24). Until 2007, only 3 cases that had a mitotic activity above 2/ 10 HPF were described, this being characteristic for high aggressivity and metastasis pattern. In the next period, other 5 cases with mitotic index above 5/ 10 HPH were described, of which only one was over 32/ 10HPF (2, 16, 17, 25, 26). Romero et al. established three prognosis factors: age above 40 years, tumor size over 4 cm, extrarenal extension, and mitotic index above 10/ 10 HPF (16, 17, 20). Those prognosis factors were present in our patient: age 65 years, tumor size of 11/12/13 cm with extrarenal extension, and mitotic index 74/ 10HPF. Histopathological characteristics do not describe the future evolution of neuroendocrine tumors, even though poorly differentiated carcinoma tend to early metastasis and have a small survival rate (between 2 and 8 months); a case of renal neoplasia with hepatic metastasis, that had a survival of over 2 years, was described (14, 17).

The elective treatment in patients with neuroendocrine carcinoma remains the surgical treatment, sometimes palliative resection of metastases, especially of hepatic ones, brings benefits to the survival rate (9, 12, 16). Chemotherapy remains a controversial treatment, some authors claim that poorly differentiated tumors are responsive to platinum salts, but the results obtained until now in literature were minimal with a rapid evolution of the disease under treatment, on average, after 2 months (15, 16, 18). Sandostatine analogues are presented to have a good rate of response to the treatment – 36-70%, even in metastatic disease (9, 15).

After surgical treatment our patient underwent treatment with 6 series of etoposid 100 mg/m² and carboplatin (AUC =6) at every 21 days and acidum zoledronicum 4 mg at every 28 days, obtaining a partial remission of the secondary lymph node lesions and a complete remission of the pulmonary metastasis. The benefit of chemotherapy was shown by the improvement of the patients’ performance state and pain control after the first series, this benefit being maintained during the entire follow-up period.

Due to normal values of Chromogranin A, serotonin and 5-hydroxyindoleacetic acid and the lack of carcinoid syndrome, we did not consider necessary the treatment with somatostatin analogues, although their antitumor effect is known. Isolated cases underwent palliative radiotherapy, but the benefit could not be established (18).

In conclusion, poorly differentiated neuroendocrine renal tumors are rare, aggressive tumors, diagnosed in advanced stages, sometimes metastatic, and have limited survival rates.

Surgical treatment remains elective, because neuroendocrine carcinomas cannot be differentiated preoperatively from other renal malignancies.

Although chemotherapy is still controversial, it can raise the quality of life in patients with metastatic neuroendocrine renal carcinoma by easing the symptomatology and the performance status, with a possible benefit in survival rates.

Conflict of interest

The authors of this article have no conflict of interest.