Clinicopathologic Features of Renal Neuroendocrine Neoplasms

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Clinicopathologic Features of Renal Neuroendocrine Neoplasms

https://doi.org/10.21203/rs.3.rs-4338214/v1

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Primary renal neuroendocrine tumors (NENs) are a unique and rare type of tumor, with relatively limited research. In our retrospective study, we aimed to comprehensively investigate the clinicopathological features, biological behavior, and prognosis of patients that diagnosed as renal neuroendocrine tumors and treated at our center. Histological evaluations were meticulously conducted on archived diagnostic slides obtained from pathological examinations. Notably, all six cases of primary renal neuroendocrine tumors presented as solitary lesions, with a predilection for the left kidney in the majority (4/6) of cases. In accordance with the latest WHO classification, one case was diagnosed as neuroendocrine carcinoma (NEC), while the remaining five cases were identified as well-differentiated neuroendocrine tumors (NETs). Microscopically, the tumor cells exhibited distinctive organ-like structures. One case demonstrated characteristics of a large cell type, with mitotic images and visible necrosis. All tumor synaptophysin were diffusely stained, although chromogranin and CD56 staining patterns varied. Further molecular investigation using next-generation sequencing (NGS) in one case unveiled copy number amplification of the MCL-1 gene; however, no common molecular changes observed in gastroentero-pancreatic neuroendocrine tumors (GEPNEN), such as VHL, ATRX, and DAXX mutations. The limited knowledge regarding the molecular profile and survival outcomes of primary renal neuroendocrine tumors underscores the necessity for enhanced understanding of their behavior. In the process of clinical diagnosis, an improved awareness and accurate diagnosis are imperative to facilitate optimal treatment strategies for patients.

Renal

Neuroendocrine tumors

Clinicopathologic Features

In 2022, the World Health Organization (WHO) consolidated the classification of Neuroendocrine Neoplasms (NENs) within the fifth edition of the Classification of Tumors of the Urinary System and Male Reproductive Organs. This unification is a departure from the preceding version, where NENs were categorized separately based on distinct anatomical sites ¹. The current edition integrates NENs into a singular chapter, encompassing well-differentiated neuroendocrine tumors (NET), large cell neuroendocrine carcinoma (LC-NEC), and small cell neuroendocrine carcinoma (SC-NEC). This amalgamation serves to eliminate redundancy, as many features of NENs, particularly their fundamental morphology and immunohistochemical results, exhibit similarity across different anatomical sites. The potential origin cells of NENs are diverse and vary to some extent by anatomical site. In the kidney, NENs may be derived from stem cells in the renal tubule lumen, natural neuroendocrine cells or stem cells associated with the calyceal urothelium ².

The renal neuroendocrine tumor originates within the renal parenchyma, presenting distinct morphological and immunohistochemical features of neuroendocrine tumors. Neuroendocrine tumors originating in the kidney are very rare (less than 1%) ³, with only about 166 cases reported since 1966 ⁴. This paper compiles and summarizes 6 cases of primary renal NENs, and informed consent has been obtained in all cases, adhering to ethical standards in research and publication practices.

In this study, the clinicopathological data of all patients with renal tumors diagnosed and treated in Zhongshan Hospital of Fudan University from January 2014 to December 2023 were collected and retrospectively analyzed. 6 cases were diagnosed as primary renal NENs ultimately. The tissue sections were reviewed separately by two senior pathologists. Laboratory data were recorded upon patient admission. Diagnostic imaging data was evaluated by at least 2 qualified radiologists. After discharge, patients were followed up every 6 months. This study was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University.

Patient 1:

A 53-year-old man presented to our hospital due to palpitations and dizziness. CT scan of the abdomen revealed a solid mass measuring 2.4 x 2.3 cm in the middle of the left kidney with necrosis in the central region (Fig. 1A). Two weeks after admission, the patient underwent laparoscopic radical surgery for kidney cancer. Macroscopic examination of the surgical specimen revealed a solid mass of 2cm diameter in the mesial pole of the left kidney (Fig. 1B). Microscopically, the tumor cells exhibited an arrangement in beamlike cords, thrull-shaped clusters, and small nests, with inconspicuous cell atypia. The cells were single, round or oval, displaying abundant cytoplasm, vacuolar nuclei, fine nucleoli, and chromatin; mitoses were scarcely visible (approximately 1 per 10 HPF). The tumor stroma was accompanied by collagen, and no discernible neoplastic necrosis was observed (Fig. 1C). Immunohistochemical results revealed a slight positive for CKpan, diffuse positive for CD56 and SYN, with a Ki-67 proliferation index of about 3% (Fig. 1D-I). The tumor tissue invaded the adipose tissue surrounding the renal capsule without evidence of vascular and nerve tract invasion. The final pathological diagnosis indicated a well-differentiated neuroendocrine tumor (NET G2). This patient underwent regular annual MRI examinations and was followed up for 48 months after surgery, demonstrating no signs of recurrence or metastasis.

(C)The tumor cells were arranged organoid. (D)CD56 was positive. (E)Which are negative for CgA immunostain. (F) Synaptophysin was diffusely strongly positive in tumor cells. (G)Ki-67 immunostaining intensity. (H)CK was expressed in a few tumor cells. (I)PAX-8 was negative.

Patient 2:

A 42-year-old woman was diagnosed with a tumor in the upper pole of her right kidney over a year ago. Subsequent MRI examination disclosed a nodule (1.6cm) exhibiting equivalent signal intensity on T1 and low signal intensity on T2-HASTE (Fig. 2A). The coronal view of the nodule revealed a splitting sign. Following this diagnosis, the patient underwent a partial nephrectomy at our hospital, and a mass about 1.7cm in diameter was observed (Fig. 2B). Microscopic examination indicated that the tumor cells were slightly epithelioid, arranged in nests and ribbons, featuring abundant cytoplasm, vacuolar nuclei, visible nucleoli, mild-moderate cell atypia, delicate chromatin resembling pepper salt, and scanty mitoses (less than 1 per 50 HPF). No neoplastic necrosis was observed, some tumor stroma was accompanied by collagen, and certain vascular walls displaying thickening (Fig. 2C). Immunohistochemical results demonstrated positive expression for CKpan in some cells, along with diffuse positive for CD56, CgA, and SYN, accompanied by a Ki-67 proliferation index of 1% (Fig. 2D-I). The pathological diagnosis was well-differentiated neuroendocrine tumor (NET G1). Regular annual reviews and a 46-month follow-up period revealed no signs of recurrence or metastasis in this patient.

Patient 3:

A 51-year-old woman complained of abdominal or flank pain, diarrhea, bloody stools, and mucous stools occurring approximately 3 times per day. CT plain scan + enhanced scan showed a protrusion in the local contour of the middle and lower poles of the left kidney, displaying a visible mass with abnormal density measuring 4.5cm in diameter. The density was non-uniform, featuring a necrotic area in the center (Fig. 3A). Subsequently, the patient underwent laparoscopic left nephrectomy and retroperitoneal lymphadenectomy in our hospital. Intraoperatively, a 4.5cm diameter mass was observed, demonstrating partial cystic characteristics (Fig. 3B). Microscopic examination showed tumor cells arranged in organoid structures: thrusoid, island-shaped, and sieve-shaped patterns. The cell atypia was not obvious, with uniform cell size, round or oval shape, fine chromatin, indistinct nucleoli, occasional mitoses, and no observed neoplastic necrosis (Fig. 3C). Immunohistochemical examination showed positive expression for CKpan, CD56 and SYN, and negative expression for CgA. The Ki-67 proliferation index was about 5%, and pathological diagnosis of well-differentiated neuroendocrine tumor (NET G2) was confirmed (Fig. 3D-I). Ga-DOTA TATE imaging, conducted one month post-surgery, revealed signs of paracolic sulci metastasis (1.2cm). Subsequently, the patient received 20 mg of Sandostatin LAR for 36 months, accompanied by annual PET-68Ga-DOTA TATE scans. Results showed that the expression level of somatostatin receptor (SSTR) gradually decreased, and the patient has maintained a good condition so far.

Patient 4

A 48-year-old male patient was presented with lateral abdominal pain and impaired urination. CTU examination revealed a round cystic solid mass in the middle and upper regions of the left kidney, measuring approximately 9.4 cm in diameter with uneven density. Scattered nodular calcification was observed within the mass (Fig. 4A). Enhancement CT scan showed uneven reinforcement of solid components, convex growth toward the renal hilus, pressure-induced flattening of the left renal pelvis, renal arteriovenous involvement, left renal hilus involvement, and alterations in renal pelvis compression. The patient underwent laparoscopic radical nephrectomy (> 7cm) coupled with perirenal adhesion lysis. Intraoperatively, a substantial mass, measuring approximately 11 cm in length (Fig. 4B), was identified on the left kidney, primarily cystic and containing dark red fluid. Microscopic examination showed tumor cells arranged in an "organ-like" pattern, with abundant interstitial vessels. The cells exhibited mild to moderate atypia, fine granular nuclei, delicate pepper-salt-like chromatin, inconspicuous nucleoli (Fig. 4C), and rare mitoses (< 1/50HPF), no neoplastic necrosis was observed (Fig. 4C), and tumor tissue invaded the renal capsule while infiltrating the surrounding adipose tissue. Immunohistochemical examination showed positive expression for CKpan, CD56 and SYN, along with weakly positive expression for CgA. The Ki-67 proliferation index was 3%, and pathological diagnosis of well-differentiated neuroendocrine tumor (NET G2) was confirmed (Fig. 4D-I). Subsequent follow-up assessments conducted for 15 months revealed no signs of recurrence or metastasis in this patient.

Patient 5:

A 59-year-old male patient presented for treatment due to changes in urination habits. CTU examination revealed a slightly high-density mass of 4.4 cm in the middle of the right kidney, featuring a low-density shadow. The enhancement degree of enhanced scan was comparatively weaker than that of the renal parenchyma, showing uneven enhancement, pressure-induced narrowing of the adjacent renal pelvis, slightly widening of the right renal pelvis calyx, and mild hydrops of the right kidney (Fig. 5A). Subsequently, the patient underwent laparoscopic radical nephrectomy with perirenal adhesion release. Postoperatively, a 4.5 cm diameter mass was identified in the middle of the right kidney (Fig. 5B-D), which was partially cystic. Microscopic examination showed that the tumor cells were arranged in Daisy clusters and nests, exhibiting inconspicuous cell atypia. The cells were round or oval, with rich cytoplasm, delicate chromatin, and no visible mitosis (< 1/50 HPF) (Fig. 5E-F). Immunohistochemical examination showed positive expression for CKpan, CD56, SYN and CgA. The Ki-67 proliferation index was 3%, and pathological diagnosis was well-differentiated neuroendocrine tumor (NET G2) (Fig. 5G-L). There was no recurrence or metastasis during a 4-month follow-up.

Patient 6:

A 70-year-old man with a history of hydronephrosis was presented due to hematuria. CTU examination revealed an irregular mixed solid density mass in the left kidney with an irregular shape, protruding renal envelope, invading the left renal pelvis calyces, accompanied by left upper ureter hydrops, left renal hilus and retroperitoneal lymph node enlargement (Fig. 6A). The patient underwent laparoscopic radical nephrectomy (> 7cm) along with perirenal adhesion lysis. A single mass with a diameter of 4.1 cm was observed at the extreme of the left kidney during the operation (Fig. 6B). Microscopic examination demonstrated tumor cells arranged in nests and islands (Fig. 6C), characterized by conspicuous cell atypia, an increased nucleo-plasma ratio, abundant cytoplasm, thickened chromatin, visible nucleolus, visible mitoses (about 42 /10HPF, Fig. 6D), visible neoplastic necrosis (about 40%, Fig. 6E). Tumor cells invaded lymphatic vessels and peripheral nerves, extending into the renal pelvis and the extra-capsular fibrous adipose tissue (Fig. 6F). Immunohistochemistry showed positive expression for CKpan, CD56, and SYN, while negative expression for CgA, and a high Ki-67 proliferation index (about 90%) (Fig. 6G-L). Considering the morphological and immunohistochemical results, the pathological diagnosis was determined as large cell neuroendocrine carcinoma (LCNEC). Nine months post-surgery, there was no recurrence or metastasis.

Clinical features and follow up times of cases are shown in Table 1. Pathological features of cases are shown in Table 2. Immunohistochemical features of cases are shown in Table 3. In this study, a cohort of six patients (four males and two females) participated, with a mean age of 54 years (ranging from 42 to 70 years). One patient exhibited abnormal physical examination findings, while the remaining patients presented diverse clinical symptoms, including lateral abdominal pain (2 cases), changes in urination habits (2 cases), and palpitation (1 case). No patient developed carcinoid syndrome or other NE symptoms. Tumor distribution was observed in four cases in the left kidney, two cases in the right kidney. Three of them were in the upper pole (UP), two were in the lower pole (LP), and one was in the middle pole (MP). Suspicion of a kidney mass can be tracked by imaging tests such as color ultrasound or CT scans, but it is difficult to distinguish the specific type of lesion, so a biopsy must be performed. None of the patients had a history of neuroendocrine tumors in other organs.

One patient underwent partial nephrectomy and five underwent laparoscopic radical nephrectomy. The average tumor size was 4.7cm (ranging from 1.7 to 11cm), and cystic changes were observed in four patients. Microscopically, tumor morphology exhibited typical characteristics of neuroendocrine neoplasms (NENs) found in other systems, with cells arranged in organoid shapes such as cords, nests, trabeculae, or acini. Five tumors displayed mild and single tumor cells, characterized by slight nuclear pleomorphism and typical speckled chromatin. The mitosis was not visible, and the Ki67 proliferation index ranged from 1–10%. In contrast, one case exhibited obvious atypia, high-grade and pleomorphic nuclei, visible nucleoli, significant necrosis (approximately 40%), and a high Ki67 proliferation index. Immunohistochemical results revealed consistent CKpan expression in all six tumors, with at least two markers (CgA, SYN, and CD56) staining positively. Finally, according to the latest WHO classification, 5 of them were diagnosed as well-differentiated neuroendocrine tumors (subdivided into 4 G2 and 1 G1 based on Ki67 proliferation index and mitoses). One patient was diagnosed as large cell neuroendocrine carcinoma (LCNEC).

We conducted clinical follow-up on 6 patients, ranging from 4 months to 48 months after surgery (median time was 26 months). All patients recovered well after surgery and were alive and well. Regular annual reviews were conducted for all six patients. Notably, Patient 3 presented with a 1.2 cm mass in the left paracolic sulci at the lumbar and vertebral body level on the 30th day post-surgery, as identified through PET-68Ga-DOTA TATE imaging. She was the only individual experiencing definite recurrence and metastasis, currently undergoing treatment with Gentle Lung (octreotide microspheres) in the Department of Oncology. The remaining five patients showed no signs of recurrence or metastasis.

Additionally, NGS assay was performed on Patient5 and copy number amplification of MCL-1 gene was found.

Neuroendocrine tumors (NETs), which are arised from cells (APUD cells) capable of amine precursor uptake (such as dopamine and 5-hydroxytryptophan) and decarboxylation, represent a rare and highly heterogeneous tumor in comparison to other tumor types. In recent decades, its incidence and prevalence have been increasing due to increased detection of early-stage disease and improved survival rates ⁵. Although NETs can originate from various organs, the majority occur in gastroenteropancreatic (GEP) regions.

Primary renal NENs constitute a minute proportion of all neuroendocrine tumors. Existing studies are predominantly case reports or small-scale cases, with reported primary renal carcinoid not exceeding 100 cases, and only a few reported cases of atypical carcinoid. Primary large-cell and small-cell renal neuroendocrine carcinoma are exceptionally rare, with fewer than 20 reported cases. It has been suggested the origin of renal NENs may arise from neuroendocrine cells within renal metaplasia or malformed epithelial foci ⁶. The pathogenesis of renal NENs remains contentious. Some studies have found that chromosome abnormalities, especially chromosome 3 abnormalities, are related to the pathogenesis of renal carcinoid cancer. Heterozygosity loss at chromosome 3p21 locus, a common aberration in renal cell carcinoma (RCC), has been proposed as a potential precursor to all renal tumors, including carcinoid tumors ⁷.

The mean age of onset for primary renal NENs was 49 years, NETs occurred in a wide age range of adults (median: approximately 53 years), and the mean age of onset for NECs was under 60 years, with no gender differences or side predilections. Reports indicate a significantly increased risk of kidney NENs in patients with horseshoe kidney, approximately 62 times higher than that of normal individuals ⁸, and it was reported that about 17.8–19% of patients had horseshoe kidney according to related kidney NENs researches. However, in our study, none of the patients had horseshoe kidney. Due to the slow growth of renal NENs and the emptiness of retroperitoneal space, the tumor is challenging to detect even with prolonged growth, and around 25% of patients have no symptoms at the time of diagnosis ⁴. Most cases were incidentally discovered (48.3%) during routine physical examinations. Other cases were discovered due to symptoms including abdominal pain (17.2%), lateral abdominal pain (20.7%), hematuria (6.9%), or metastasis as the first symptom (3.4%) ⁶. Carcinoid syndrome is observed in about 12.7% of patients ⁸.

Imaging plays a pivotal role in renal carcinoma diagnosis. Techniques such as abdominal ultrasound, CT scan, and MRI aid in determining the nature, location, aggressiveness, and staging of the kidney mass. While imaging assists in formulating treatment plans and evaluating efficacy, it cannot reliably distinguish between renal cell carcinoma and renal neuroendocrine tumors. Given the rarity of renal neuroendocrine tumors, imaging findings alone cannot substitute for the accuracy and confirmability of pathological examinations. Hence, a combination of various imaging modalities with pathological examinations is essential for a precise diagnosis in clinical settings.

Since renal neuroendocrine tumors are rare, the possibility of metastasis should be ruled out before confirming a primary renal disease. A thorough clinical history and comprehensive examination are essential components of the diagnostic process. Secondly, differentiation from other tumors is crucial, considering that approximately 14% of renal NET cases were initially misdiagnosed as type I papillary renal cell carcinoma, urothelial tumor, renal stromal tumor, and nephroblastoma by histopathological examination ³. The differential diagnoses are as follows: ①metanephric adenoma: the section exhibits predominantly gray and grayish-yellow-brown coloration, characterized by a uniform and soft texture. Calcifications are observable, and in the majority of cases, there is an absence of conspicuous necrosis and bleeding. A few cases have reported the presence of large tumor bodies exhibiting hemorrhage, necrosis, and cystic changes. Microscopically, the tumor displays a consistent arrangement of uniformly sized cells forming a distinctive dense tubular adenoid structure. In some cases, papillary structures and a small amount of glomeruloid structures were observed. The tumor stromal tissue appears weakly eosinophilic and translucent, with scant stromal cells scattered in individual lymphocytes, and sand body structures or calcium salt deposits were identified between tumor tissues. Immunohistochemically, the tumors expressed WT1, CD57 and BRAF V600E, while lacking expression of SYN and CgA. ②Papillary renal cell carcinoma: The section appears granular, often accompanied by necrotic bleeding. Some papillary renal cell carcinomas characterized by less interstitial, less obvious interstitial axis, and dense arrangement need to be distinguished from neuroendocrine tumors. The differential diagnosis should particularly focus on the atypia of papillary renal cell carcinoma and the obvious nucleolus, often accompanied by obvious hemorrhage and necrosis, and the accumulation of foam cells in the interstitium and the axis of the papilla. Immunohistochemistry showed positive staining for CK7 and P504S, but negative staining for SYN and CgA. Moreover, it is characterized by 7 and 17 chromosome presence and Y chromosome deletion. ③Poorly differentiated renal cell carcinoma/urothelial carcinoma: These tumors are not accompanied by SYN and CgA expression, which can help differentiate from poorly differentiated neuroendocrine tumors. ④Nephroblastoma: In epithelial nephroblastoma, it is imperative to identify a subset of cases presenting as a solitary form, characterized by immunohistochemical expression of WT1 and CD56, while lacking expression of SYN and CgA. In addition, it also needs to be differentiated from some small round cell malignant tumors, including neuroblastoma, primitive neuroectodermal tumor (PNET), lymphoma, malignant melanoma, small round cell malignant tumor of fibroconnective tissue hyperplasia, rhabdomyosarcoma and other poorly differentiated tumors, which can be primarily differentiated by immunohistochemical and related molecular detection. Therefore, in the diagnosis of renal NENs, the integration of HE morphology and immunohistochemical markers is recommended, with molecular detection if necessary. A clinicopathological study involving 21 renal NENs cases conducted by Hansel et al. revealed frequent positivity of immunomarkers, including SYN (18/20), CgA (13/20), Cam5.2 (14/16), and vimentin (12/15) ⁹. In this study, 6 cases exhibited positive staining for SYN, CgA and broad-spectrum CK, and 3 cases showed negative staining for CD56 (3/6).

PAX8, a prominent transcriptional regulator pivotal for embryonic development in the thyroid, kidney, male and female reproductive tract, assumes a pro-tumor role in malignancies arising within PAX8-expressing organs. PAX8 is expressed in several tumors of the genitourinary system, such as the majority of pediatric nephroblastomas, about 80% of renal cell carcinomas (RCC) and nephrogenic adenomas. Notably, PAX8 expression exhibits difference in tumors associated with the collecting system. Given the derivation of the upper half of the collecting system from the PAX8-positive metanephridium, approximately 23% of tumors in this region, particularly those affecting the renal pelvis, exhibit PAX8 positivity. However, the origin of primary renal neuroendocrine tumors was not clear. In this study, different expression levels of PAX-8 were identified in 3 cases (1 NET G1, 1 NET G2, 1 LCNEC).

Most renal NENs manifest as low-grade malignant NETs; however, their clinical course may be invasive. Post-nephrectomy pathological examination often finds well-differentiated neuroendocrine tumors accompanied by local lymph node metastasis, which may lead to distant organ metastasis. However, these patients have a good prognosis and a long survival time. As Patient 3 in this study, diagnosed with a well-differentiated neuroendocrine tumor (NET G2), the development of paracolic sulci metastasis one month post-surgery did not impede an excellent prognosis. NEC has a poor prognosis, and like other anatomical tumors, these patients often present with locally advanced disease prone to distant metastasis and associated symptoms, resulting in rapid disease-related mortality post-diagnosis. However, SCNEC and LCNEC exhibit potential responsiveness to chemotherapy, thereby enhancing patient survival. Hence, accurate identification and diagnosis of these tumors by pathologists are pivotal.Patient 6 in this study was histopathologically diagnosed as large cell neuroendocrine carcinoma, with no evidence of tumor recurrence or residual disease observed to date. Metastatic disease is often present in patients with primary renal NENs (about 45.6% of reported cases). Liver metastasis predominates (34%), while metastases to bone, lung, and spleen are less frequent, and the risk of metastasis is directly related to the size of the primary tumor ¹⁰. 75% of primary renal NENs are larger than 4 cm in diameter, and 45% of tumors can invade perirenal fat, or invade renal veins. One study reported that 47% of patients had lymph node metastases ¹¹, the most common of which were hilar and paraaortic lymph nodes. If the scan reveals any enlarged lymph nodes, a regional lymph node dissection should be performed.

Treatments for renal NENs are contingent upon factors such as location, diameter, and tumor type. Standard approaches involve either partial nephrectomy or radical nephrectomy ¹². For poorly differentiated neuroendocrine tumors, postoperative cisplatin chemotherapy is commonly administered. Renal preservation surgery is advantageous when dealing with small kidney masses or masses located in proximity to the ureter or other adjacent structures, as it preserves renal function ¹³. In cases where the tumor's size precludes complete removal via partial nephrectomy, radical nephrectomy becomes a viable option. It is the main treatment for primary renal NENs. However, small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas often present as extrarenal dilatation and may not be suitable for complete resection. Radio-labeled octreotide scintillation scanning is often used to monitor NENs metastasis and recurrence after treatment ⁴. Patients with elevated levels of metabolites and protohormones in plasma and urine should undergo octreotide screening ¹². Octreotide, a long-acting secretin analogue, serves a dual purpose for detection and as a primary anti-tumor systemic therapy ¹⁴. It has been proven to shrink tumors and clinically improve the condition of advanced renal NENs patients ⁸, and the response rate of this therapy in advanced diseases is 36–70% ¹². Cytotoxic chemotherapy has limited efficacy and low response rate in the treatment of metastatic carcinoid. Systemic chemotherapy is more beneficial for aggressive carcinoid patients ¹². Radiation therapy has not been extensively studied, available evidence suggests its tolerability, offering symptomatic palliative care for metastatic NEC and symptoms relief associated with carcinoid syndrome ³.

The 5-year, 10-year and 20-year disease-specific survival rates of primary gastrointestinal carcinoid were 91.3%, 86.1% and 77.1%, respectively ¹⁵. The 5-year survival rates of patients for stage I-IV lung carcinoid cancer stand at 93%, 85%, 75%, and 57%, respectively ⁸. The prognosis of renal NEN is difficult to predict due to its rarity and heterogeneity ⁶. Some studies have shown that poor prognosis in patients is associated with increased mitotic activity, necrosis, and cytological atypia. However, the stage at onset is the most robust predictor of survival. Poorly differentiated NEC (small cell and large cell types) are highly aggressive, and most patients die from tumor metastasis. Patients with primary renal NEN with bone, liver and contralateral renal metastases have poor prognosis ¹⁶.

Neuroendocrine tumors, a highly heterogeneous and relatively rare tumor type, manifest throughout the body, and research is relatively limited due to the lack of disease models. Nevertheless, their molecular changes have been intensively studied in recent years, especially in pancreatic neuroendocrine tumors (PanNET). The advent of multiomics has propelled two large-scale genomics studies, enhancing our comprehension of the genetic level of PanNET. As early as 2011, Jiao et al. conducted WES on 10 cases of non-functional pNET and targeted sequencing on 58 cases of pNET, revealed MEN1 as the most frequently mutated gene in pNET (44%), followed by DAXX or ATRX mutation (43%). In addition, mutations of genes involved in the mTOR pathway were found in 14% of pNET ¹⁷. Scarpa et al. conducted high-throughput next generation sequencing (NGS) on 102 pNET cases in 2017, uncovering a relatively high frequency of gene germline mutation (17%) including MEN1, VHL, MUTYH, CHEK2 and BRCA2. Somatic mutations, encompassing point mutations and gene fusions, commonly implicate four pathways: chromatin remodeling, DNA damage repair, telomere maintenance, and mTOR signaling pathway activation ¹⁸. In contrast, renal neuroendocrine tumors, being rarer and less studied, pose challenges in the characteristics of their molecular changes. In this study, high-throughput sequencing of tissues from patient 5 unveiled the presence of MCL1 gene copy number amplification. MCL1 is a pivotal anti-apoptotic member of the BCL-2 family, has gained attention in recent studies for its association with chemotherapy resistance and adverse prognosis in cancer patients ¹⁹. The first direct and selective Mcl-1 inhibitors are currently undergoing clinical evaluation, exploring their potential as monotherapies or in combination with other anticancer agents.

In our role as pathologists, a keen awareness of rare renal neuroendocrine tumors is imperative, and appropriate tests can assist in diagnosis. Given that neuroendocrine tumors are mostly low-grade malignancies, accurate histological diagnosis serves as a compass, guiding appropriate clinical treatment, thereby avoiding unnecessary overtreatment.

Funding Statement

The study was supported by the National Clinical Key Specialty Project—Next-generation Integrated Pathological Diagnosis of Oncologic Diseases under the Department of Pathology (YWP2023-001); Shanghai Municipal Clinical Specialty (shslczdzk01302).

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by the Fudan University, Zhongshan Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Clinicopathologic Features of Renal Neuroendocrine Neoplasms

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