Primary large cell carcinoma of ureter ： a case report and review of the literature

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Primary large cell carcinoma of ureter ： a case report and review of the literature

https://doi.org/10.21203/rs.3.rs-2246068/v1

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Background： Neuroendocrine carcinoma mainly occurs in the lung and gastrointestinal tract, rarely in the urinary tract. The proportion of neuroendocrine carcinomas was less than 0.05 % [2] in urinary malignant tumors. The most common location of neuroendocrine carcinomas in the urinary system is the bladder. Fewer neuroendocrine carcinomas occur in the ureter than in the bladder.

Case presentation: A 62 years old woman presented with right ureteral obstruction due to ureteral mass. The patient began chemotherapy 2 weeks after surgery. During the 14-month follow-up, the patient received 6 courses of etoposide and Carbopol chemotherapy, and imaging examination showed no signs of recurrence. Postoperative pathological examination showed large cell neuroendocrine carcinoma of the right ureter.

Conclusions: Large cell carcinoma of ureter has a rapid course of disease and poor prognosis. Ureteral large cell carcinoma is a very rare tumor. At present, there is no specific treatment scheme. However, considering the good response of its lung counterpart to the standard chemotherapy scheme and the experience of the cure of related urinary large cell carcinoma by chemotherapy [28], we argue that platinum-based chemotherapy is effective for it and patients can benefit from it. The multimodal treatment scheme of surgery combined with platinum-based chemotherapy is the current standard scheme for the treatment of ureteral neuroendocrine carcinoma.

neuroendocrine carcinoma

ureteral carcinoma

large cell neuroendocrine carcinoma

diagnosis

treatment

According to the classification of neuroendocrine tumors in the urinary system by the World Health Organization, neuroendocrine tumors occurring in the ureter include small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, well-differentiated neuroendocrine tumor, and paraganglioma.[1] Neuroendocrine carcinoma mainly occurs in the lung and gastrointestinal tract, rarely in the urinary tract. The proportion of neuroendocrine carcinomas was less than 0.5 % [2] in urinary malignant tumors. The most common location of neuroendocrine carcinomas in the urinary system is the bladder. Fewer neuroendocrine carcinomas occur in the ureter than in the bladder. Since ureteral neuroendocrine carcinoma was first reported by Sénécal L et al. in 1986 [3], the industry has gradually begun to recognize this rare tumor entity. Here, we report a case of ureteral large cell neuroendocrine carcinoma and review the literature, hoping to have a deeper understanding of the clinical and pathological features of this rare entity.

A 62-year-old female presented with right low back pain that had been present for 20 days. The patient denied symptom of gross hematuria and urinary tract irritation. The patient underwent heart valve replacement for rheumatic heart disease 14 years ago and was treated with warfarin for a long time and there is no significant past family history of disease. The laboratory examination and physical examination were normal, except that urine routine showed 127 red blood cells per microliter. Urinary ultrasonography showed right renal effusion with right ureteral dilatation, and there was no abnormal echo in the visible segment of ureter. In order to further clarify the diagnosis, the patient underwent contrast- enhanced abdominal computed tomography scan. The results showed that there is soft tissue density shadow in the lumen of the right ureteropelvic segment, which was slightly to moderately enhanced after enhanced scanning, and it was considered as neoplastic lesions. At the same time, chest computed tomography scan was also reviewed and no primary or metastatic lung lesions were found. To be on the safe side, the patient also underwent retrograde ureterography of the right ureter and the results showed that the filling defect of the right ureteral pelvic segment. Fortunately, cystoscopy showed no obvious abnormalities. After excluding surgical contraindications, the patient underwent laparoscopic right lower ureterectomy + ureter bladder replantation and a mass was found within the wall of the right ureter. The surgeon did not find obvious infiltration of periureteral tissue with grossly negative surgical margins. Postoperative pathological examination showed large cell neuroendocrine carcinoma of the right ureter. In order to clarify the diagnosis, further immunohistochemical results showed as Figure1. The patient recovered well after the operation and began chemotherapy two weeks after operation. During the 14 months of follow-up, the patient underwent 6 courses chemotherapy by etoposide and Carbopol. There was no evidence of recurrence or metastasis in the imaging data.

Ureteral tissue specimens were fixed with 10% buffered formalin solution, dehydrated, embedded in paraffin, sectioned into 4 μm thickness and stained with HE. Representative paraffin sections were selected for immunohistochemical staining withUP-3, GATA-3, P53, CK20, Chromogranin A, Synaptophysin, CD56, Ki-67, Cytokeratin, Desmin, Mogemin, MoyD1.

All pathological sections were reviewed by 3 senior pathologists and made final diagnosis. The mitotic figures of 50 high power fields were counted in the active region of mitosis and divided by 5; We counted 1000 tumor cells in the region with the most nuclear marker positive to calculate Ki67 proliferation index and the results were expressed as percentage of tumor cells with positive nuclei.

We reviewed clinical and pathological features, type of treatment and clinical outcomes of LCNECs of the bladder, ureter and kidney by systematically searching the English- language literature (case reports and review articles) published up to April 2022 through databases; PubMed; Wanfang Database; CNKI; VIP; ScienceDirect; Search terms were: large cell neuroendocrine carcinoma, bladder, ureter, kidney, urinary tract. Articles were selected on the basis of their overall scientific quality and relevance to disease. A further check of the appropriateness of the articles based on full-text revision was performed after data extraction.

We reviewed all reports of large cell neuroendocrine carcinoma of the urinary system reported in the literature, as shown in Supplementary Table 2.

Microscopic findings showed tumor penetration into muscular layer. The tumor cells were large with highly atypical, that had moderately abundant coarse chromatin structure and large nuclei that had a high ratio of nucleus to cytoplasm. Mitoses were frequent with a mitotic index of 1mitotic count per 400 high-power fields (HPF). Tumor cells were mostly solidly arranged, and some are rosette with occasional necrotic foci.

The results of immunohistochemistry showed that neuroendocrine cell marker such as CD56 were diffusely positive, synaptophysin partially positive, chromogranin A was negative, epithelial markers such as CK was positive whereas CK20, GATA-3, UP-3 were negative, and the Ki67 proliferation index was more than 80%. The patient had a diffusely positive test for p53 and rest immunohistochemical staining for antibodies were negative. Based on the observation under microscope and immunohistochemistry results, the diagnosis of simple large cell neuroendocrine carcinoma was considered.

We reviewed all reports of large cell neuroendocrine carcinoma of the urinary system reported in the literature, as shown in Figure 1. In total, 60 cases were identified. The unreported case in our study was not included.

Neuroendocrine carcinomas refer to a group of heterogeneous malignant tumors that can develop in organs and tissues throughout the body, which are predominantly located in the gastrointestinal or respiratory tract[4]. Large cell neuroendocrine carcinomas (LCNECs) originating in the urinary tract is very rarely found, accounting for less than 0.05% of the cases, with high proliferative and invasive, that are frequently detected at an advanced stage at the time of detection in the most cases[5,6]. The most common type of urinary neuroendocrine carcinoma is small cell carcinoma, followed by large cell carcinoma, which often occurs together with other cancerous components [7]. In 1986, Aboza et al. first described large cell neuroendocrine carcinoma of the urinary system and considered it related to adenocarcinoma [8].

Grossly, the tumor is usually grayish-white and presents as a nodular or papillary mass within the ureter that invades the ureteral wall[9]. Diagnoses of primary urinary tract LCNECs are based on the criteria proposed for pulmonary LCNECs, which include the following: 1) Tumors have the morphological characteristics of neuroendocrine carcinoma (organoid nesting, palisading, rosettes, or trabeculae); 2) High mitosis activity; 3) Necrosis (usually over a large area). 4) Non-small cell carcinoma cytologic features, such as large cells, low ratio of nucleus to cytoplasm, vesicular or fine chromatin and/or frequent nucleolus. Some tumor cells with fine chromatin and lack nucleoli, but are rich in cytoplasm due to the large size of the cells still qualify as non-small cell carcinomas. 5) Positive immunohistochemical staining for one or more neuroendocrine markers, and / or neuroendocrine granules appear under electron microscopy[6]. The tumor histiocytic morphology of the patient in this case report is consistent with the appearance of large cell neuroendocrine carcinomas, and postoperative immunohistochemistry showed that the neuroendocrine cell marker CD56 was diffusely positive, synaptophysin was partially positive, and the Ki-67 proliferation index was more than 80%, which met the criteria above. After excluding metastatic tumor, the diagnosis of primary ureteral large cell neuroendocrine carcinoma was considered.

Given normal neuroendocrine cells have not been found in the urinary tract, the histogenesis of large cell neuroendocrine cell carcinoma in the urinary tract is not well understood [10]. At present, there are four most widely accepted hypotheses about the origin of this tumor. They believe that the tumor originates from (1) pluripotent urothelial stem cells, (2) neuroendocrine cells originally existing in submucosa or normal urothelium, (3) urothelial metaplasia, and (4) transformation of urothelial cancer cells [11-14]. More than 50% of urinary neuroendocrine cancers are found to be associated with other cell forms, such as urothelial carcinoma and adenocarcinoma. The immunohistochemical heterogeneity of neuroendocrine carcinoma revealed by epithelial and neuroendocrine determinant staining to some extent supports the pluripotent stem cell theory [15]. However, the evidence provided by Chang MT et al. shows that the genomic changes in bladder neuroendocrine carcinoma are more like urothelial carcinoma than small cell lung cancer, which indicates that the carcinogenesis mechanism of neuroendocrine carcinoma is organ specific, which supports that urothelial neuroendocrine carcinoma originates from normal or metaplastic neuroendocrine cells of urothelial mucosa in a certain way [16]. It is important to differentiate bladder LCNEC from metastatic LCNEC originating from other organs, poorly differentiated prostate adenocarcinoma or lymphoma showing local extension, and primary bladder tumors such as high grade urothelial carcinoma and squamous cell carcinoma. 1) Metastatic tumors: it is necessary to refer to clinical history or chest computed tomography to exclude primary tumors in the lungs and other places. 2) High-grade urinary tract cell carcinoma: the tumor with poor differentiation and accompanied by small cell morphology needs to be distinguished. The immunohistochemical staining of high-grade urinary tract cell carcinoma does not express neuroendocrine markers, but expresses urothelial-specific markers. 3) Poorly differentiated prostate cancer or Locally invaded lymphoma, which can be distinguished by combining cell morphology and immunohistochemistry[17].

From our review of the literature, we found that up to 36% of cases had large cell neuroendocrine carcinoma accompanied by other cancerous components. It is not difficult to see that the concomitant occurrence of neuroendocrine cancer and other cancerous components is not an accident. Therefore, we support the introduction of the concept of mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) because it describes this phenomenon from a special perspective.[18]

The clinical manifestations of ureteral neuroendocrine carcinoma are diverse, among which the most common are low back pain and hematuria [19]. Ultrasonography can detect hydroureter caused by obstruction, but it is not sensitive to the detection of primary focus. Intravenous urography and retrograde urography can confirm the existence of lumen mass by showing the filling defect of urinary tract. However, in order to accurately judge the primary focus, spiral CT or magnetic resonance imaging is a better choice. Urinary tract neuroendocrine carcinomas rarely develop in the ureter. Due to the lack of specific imaging manifestations of large cell neuroendocrine carcinomas of the urinary tract and the low positive rate of urine exfoliated cells, final diagnosis still depends on postoperative histopathology and immunohistochemistry[20].

According to the research of Ouzzane et al., they argue that the long-term prognosis of patients with the upper urinary tract neuroendocrine carcinomas in stage pT1-2 is better than that of patients in stage pT3-4, and adjuvant chemotherapy is beneficial to the prognosis of patients [21]. Studies from N.W. Choong et al., M. Mukesh et al., D.N. Church et al. and N.S. Majhail et al. also confirmed that patients with urinary system neuroendocrine cancer benefit from platinum-based chemotherapy [22-25]. In a recent study of 70 patients with neuroendocrine carcinoma of the upper urinary tract, Nakasato T et al. believe that chemotherapy and radiotherapy combined with surgical therapy are likely to improve prognosis of patients with stage T1–2 [26]. Similarly, in the report of Dowd et al., a case of bladder neuroendocrine carcinoma did not recur within one year after treatment with surgical resection, adjuvant chemotherapy and radiotherapy [27]. Coincidentally, according to data from the National Cancer Database, radical cystectomy plus chemotherapy and chemoradiotherapy were associated with better OS in the treatment of bladder endocrine cancer compared with monotherapy [28].

Like small cell carcinoma, large cell carcinoma of ureter has a rapid course of disease and poor prognosis. Ureteral large cell carcinoma is a very rare tumor. At present, there is no specific treatment scheme. However, considering the good response of its lung counterpart to the standard chemotherapy scheme and the experience of the cure of related urinary large cell carcinoma by chemotherapy [29], we argue that platinum-based chemotherapy is effective for it and patients can benefit from it. The multimodal treatment scheme of surgery combined with platinum-based chemotherapy is the current standard scheme for the treatment of ureteral neuroendocrine carcinoma.

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethics approval and consent to participate: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images.

Consent for publication: All the authors agreed to publish the article.

Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: none.

Funding: none.

Authors' contributions: GY and HBT, manuscript conception. YG, manuscript drafting. YBT and PTD, data acquisition and literature search. XHW, manuscript revisions.

Acknowledgements: none.

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No competing interests reported.

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Primary large cell carcinoma of ureter ： a case report and review of the literature

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