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Review Article | DOI: https://doi.org/10.31579/2640-1045/164
North manchester general hospital, department of urology, delaunays road, m85rb manchester United Kingdom.
*Corresponding Author: Anthony Kodzo-Grey Venyo, North manchester general hospital, department of urology, delaunays road, m85rb manchester United Kingdom
Citation: Anthony Kodzo-Grey Venyo, (2024), Terato-Neuroendocrine Tumour of Testis: Review and Update, J. Endocrinology and Disorders, 8(1): DOI:10.31579/2640-1045/164
Copyright: © 2024, Anthony Kodzo-Grey Venyo. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 22 November 2023 | Accepted: 11 December 2023 | Published: 18 January 2024
Keywords: neuro-endocrine tumour of testis; carcinoid tumour of testis; testicular carcinoid tumour; histopathology; immunohistochemistry; orchidectomy; recurrence; carcinoid syndrome
Neuro-endocrine tumours commonly emanate from intestinal and respiratory epithelium. Neuro-endocrine tumours could also on rare occasions afflict various organs of the human body. Neuro-endocrine tumour afflicting the testis is an uncommon tumour which does account for far less than one percent (<1%) of all tumours of testis. To the knowledge of the author, less than 100 cases of primary neuro-endocrine tumour of the testis had been reported so far in the global literature. The reported cases of neuro-endocrine tumour of testis have ranged between 10 years and 83 years of age and the reported incidence rate had been noted to be higher within the fifth and sixth decade of life. Majority of patients who are afflicted by neuro-endocrine tumour of testis do tend to manifest with unilateral painless testicular mass. Sixteen percent (16%) of patients who are afflicted by neuro-endocrine tumour of testis do manifest with symptoms of neuroendocrine tumour syndrome. Eleven percent (11%) of primary neuroendocrine tumours of testis tend to be diagnosed initially with a contemporaneously-associated metastasis. Neuro-endocrine tumours of the testis occur as a primary testicular neuroendocrine tumour, or they may be metastatic neuroendocrine tumour to the testis with the primary tumour originating from elsewhere in the body especially from the gastrointestinal or cardiorespiratory tract system. Primary neuro-endocrine tumour of testis, could be further sub-divided into: (a) primary pure neuroendocrine tumour of testis; and (b) neuro-endocrine tumour of testis contemporaneously associated with teratoma or dermoid/epidermoid cysts. Once a neuro-endocrine tumour of testis is diagnosed, it is pivotal that clinicians should exclude a metastatic neuroendocrine tumour to the testis with the primary tumour originating from elsewhere within the human body. It has been iterated that the presence of teratomas elements within the neuro-endocrine tumour of testis does sufficiently rule out the primary site outside the testis. In order to accurately diagnose the neuro-endocrine tumour of the testis, it has been advised that it is pertinent to submit the tumour mass entirely and to look for any additional lineage of differentiation. Twenty five percent of primary neuro-endocrine tumours of testis are associated with teratoma. Histogenesis of pure neuroendocrine tumour of the testis is yet to be clarified. Two postulates had been propounded in relation to the mode origin of neuroendocrine tumour of testis including: (1) Emanation from a teratoma which is the germ cell origin postulate; (2) Emanating from argentaffin cells that are located within crypts of Lieberkühn .A study related to three pure testicular neuroendocrine tumours of testis had indicated that pure neuroendocrine tumour of testis might have different genetic background other than germ cell tumour.[11] Histopathology examination of specimens of neuro-endocrine tumour of testis has tended to demonstrate tumour cells that tend to be typified by the presence of nests of small round cells with uniform nuclei forming small acini and rosettes or sheets. The cells tend to contain eosinophilic granules within the cytoplasm and granular chromatin within the nuclei. The tumour cells do exhibit positive staining for neuroendocrine markers like chromogranin and synaptophysin as illustrated in detail in the article. Radical orchidectomy is the most adopted option of treatment; nevertheless, necessitation for the undertaking of provision of adjuvant treatment depending upon histological grading has not been clarified. Because of the possibility of development of local recurrence and or distant metastases after a long time, it is pivotal for all clinicians to carefully follow-up their patients over a long-period of time with clinical, laboratory testing and radiology-imaging testing follow-ups in order to establish early diagnosis of any local recurrence or distant metastasis to be able provide further treatment of curative intent early. There is also the possibility that neuro-endocrine tumours of testis had so far been under-reported due to mis diagnosis of the tumour upon pathology examination of the testicular tumour or the correct set of monoclonal and polyclonal antibodies had not been utilized in the immunohistochemistry study assessment of the tumours. It would be advised that all clinicians and pathologists globally should have a high index of suspicion for a neuro-endocrine tumour of testis in order to establish prompt diagnosis of the tumour and to provide appropriate assessment, treatment and follow-up of all their patients.
Neuro-endocrine tumours often tend to be sporadically encountered within the gastrointestinal tract system originating from embryonal gastrointestinal tract and at times within the respiratory tract. [1] However, on extremely rare occasions, neuroendocrine tumours could be found primarily origination from various organs of the human body. Primary or metastatic neuroendocrine tumour on exceedingly rare occasions could afflict the testis. The cell of origin of primary neuroendocrine tumour of the testis has not been clarified up to date.[1] Considering the rarity of both primary and metastatic neuroendocrine tumour of testis, it would be envisaged that majority of clinicians all over the world not have encountered a case of neuro-endocrine tumour of testis before and they would also tend not to be familiar with the manifestations, diagnostic features, management as well as outcome of patients who are afflicted by neuro-endocrine tumour of testis. The ensuing article on neuro-endocrine tumour of testis is divided into two parts: (A) Overview which has discussed miscellaneous general aspects of neuro-endocrine tumours, and (B) Miscellaneous narrations and discussions from some case reports, case series, and studies related to neuro-endocrine tumour of testis.
Aim
To review and update the literature on neuro-endocrine tumour of testis.
Methods
Internet data bases were searched including: Google; Google Scholar; Yahoo; and PUBMED. The search words that were used included: Neuroendocrine tumour of testis; Testicular neuroendocrine tumour; Testicular Carcinoid Tumour; Carcinoid tumour of testis. Thirty- eight (38) references were identified which were used to write the article which has been divided into two parts: A) Overview which has discussed miscellaneous general aspects of neuro-endocrine tumours, and (B) Miscellaneous narrations and discussions from some case reports, case series, and studies related to neuro-endocrine tumour of testis.
Results
[a] overview
Definition / general statement [2]
Essential features [2]
Terminology [2]
Epidemiology [2]
Sites
Pathophysiology [2]
Aetiology
Clinical features [2]
Laboratory tests
Routine urine tests
Haematology blood tests
Biochemistry tests including blood and urine tests
Radiology Imaging
Various types of radiology imaging could be utilized during the initial and follow up assessments and follow-up assessments of patients who have neuroendocrine tumour of testis and some of these include:
Diagnosis
Prognostic factors
Treatment [2]
Gross description [2]
Microscopic (histologic) description [2]
The ensuing summations had been made regarding microscopy histopathology examination findings on cases of teratoma-neuroendocrine tumour of testis:
Cytology description [2]
Immunohistochemistry staining studies
Positive stains [2]
It had been iterated that immunohistochemistry staining studies of specimens of teratoma-neuroendocrine tumour of testis does tend to demonstrate positive staining for the ensuing tumour markers which tend to be mostly positive:
It had also been iterated that immunohistochemistry staining examination of specimens of teratoma-neuroendocrine tumour of testis does tend to demonstrate positive staining for the ensuing tumour markers which tend to be less frequency expressed:
Negative stains [2]
It had also been iterated that immunohistochemistry staining examination of specimens of teratoma-neuroendocrine tumour of testis does tend to demonstrate negative staining for the ensuing tumour markers: [2]
Electron microscopy description
It had also been iterated that electron microscopy examination of specimens of teratoma-neuroendocrine tumour of testis does tend to demonstrate the ensuing [2]
Molecular / cytogenetics description
The molecular and cytogenetics features of teratoma-neuroendocrine tumours of the testes had been summated to include the ensuing: [2]
Differential diagnosis
The differential diagnoses of teratoma-neuroendocrine tumour of testis had been summated to include the ensuing: [2]
[B] Miscellaneous Narrations and Discussions from Some Case Reports, Case Series, and Studies Related to Neuroendocrine Tumours of Testis.
Widmeier et al. [11] stated the following:
Widmeier et al. [11] reported a 44-year-old patient who did not have any significant past medical history and who was diagnosed in September 2009 with primary testicular carcinoid tumour, which was surprisingly staining positively for Cdx-2, too. At the time of the initial diagnosis the tumour, the tumour was identified to have already shown histopathological infiltration of veins. DOTA-TATE-PET/CT radiology imaging and endoscopy studies did not demonstrate any signs of distant metastases and in particular no gastrointestinal manifestation following no further medical indication for systemic chemotherapy. Widmeier et al. [11] also reported that the continuous and close follow-up of the patient had reached a total of over 10 years at the time of publication and the patient had remained in complete remission.
Widmejer et al. [11] made the ensuing conclusions:
Takada et al. [12] stated the following:
Takada et al. [12] reported a case of a primary pure TCT with an unusual manifestation in a 23- year-old man, who had an asymptomatic, enlarged scrotum on the right side for 7 years. On macroscopy examination, the tumour had measured 9.6 cm in diameter. The Ki-67 labelling index of the tumour was 19.8%. High inguinal orchidectomy was undertaken, and 30 months after his surgery the patient remained asymptomatic.
Darré et al. [7] stated that primary carcinoid tumours are rare and constitute 0.23% of all testicular tumours. Darré et al. [7] reported a case of primary carcinoid tumour of testicular localization, with a review of the literature. Darré et al. [7] reported a 29-year-old man, who did not have any specific ascendants, who had manifested to the urology department for progressive scrotal swelling of 6 months, that was associated with pain. After he had undergone orchidectomy surgery, histology examination of the testicular tumour demonstrated diffuse tumour proliferation which was composed of small round monotone cells with hyperchromatic nuclei evoking undifferentiated carcinoma. Immunohistochemistry staining studies of the tumour demonstrated that the tumour cells had exhibited positive staining for chromogranin A and negative staining for placental alkaline phosphatase and α-fetoprotein. Darré et al. [7] made the ensuing conclusions:
Chikkaraddi et al. [13] stated that primary carcinoid tumours of the testis are very rare, and they seldom manifest with carcinoid syndrome. Chikkaraddi et al. [13] reported a hereto unreported instance, where a patient who had a long-standing testicular mass had manifested with carcinoid heart disease, which is an uncommon form of carcinoid syndrome. He had manifested with symptoms of right heart-failure, episodic facial flushing and he was found to have severe right-sided valvular heart disease. His urinary 5-hydroxy indole acetic acid level was elevated. He underwent orchidectomy and histopathology of his testicular tumour confirmed a testicular carcinoid tumour.
Zavala-Pompa et al. [5] reported the cases of three patients who had primary carcinoid tumour of the testis. The reported patients were 41 years, 44 years, and 83 years of age. During his initial examination, all three patients had testicular masses with or without associated pain, and none had the carcinoid syndrome. The tumours had measured 4.3 cm, 3.0 cm, and 6.5 cm in dimension. All three tumours had manifested classic histopathology features of carcinoid tumours. The neoplastic cells had exhibited argyrophilia, and all were immunoreactive to chromogranin, serotonin, neuron-specific enolase, and cytokeratin. Two tumours also had positive test results for gastrin and one had positive test results for substance P and vasoactive intestinal polypeptide. None of the tumours had reacted with somatostatin, insulin, pancreatic polypeptide, or placental alkaline phosphatase. Intracytoplasmic, membrane-bound, round-to-elliptical pleomorphic granules were identified by ultrastructural analysis in all cases. DNA flow cytometric analysis demonstrated a low degree (near-diploid) DNA aneuploidy in all cases, with a DNA index of 1.15 in two tumours and 1.3 in the third tumour. The three patients were alive and well 11 years, 7 years, and 6 months, respectively, after the initial diagnosis of their tumours. A total of 57 cases of this entity, including the 3 reported here, have been reported. Of these, 43 were pure carcinoid, and 14 were associated with teratoma; 6 (11.6%) patients developed metastases. Tumour size and the presence of carcinoid syndrome have been found to correlate with metastatic potential. Neither tumour necrosis nor local tumour invasion (into vessels, tunica albuginea, etc.) correlated with adverse prognosis. Carcinoid tumour of the testis is a rare indolent neoplasm with potential for distant metastases.
Amin et al. [14] reported the cases of three patients who had primary carcinoid tumour of the testis. Amin et al. [14] reported that the patients were 41 years, 44 years, and 83 years of age. During their initial examinations, all three patients were noted to have testicular masses with or without associated pain, and none had carcinoid syndrome. The tumours had measured 4.3 cm, 3.0 cm, and 6.5 cm in dimension. All three tumours had manifested classic histopathology features of carcinoid tumours. The neoplastic cells had exhibited argyrophilia, and all tumours were immunoreactive to chromogranin, serotonin, neuron-specific enolase, and cytokeratin. Two tumours had positive test results for gastrin and one had positive test results for substance P and vasoactive intestinal polypeptide. None of the tumours had reacted with somatostatin, insulin, pancreatic polypeptide, or placental alkaline phosphatase. Intracytoplasmic, membrane-bound, round-to-elliptical pleomorphic granules were demonstrated by the undertaking of ultrastructural analysis in all cases. DNA flow cytometric analysis had demonstrated a low degree (near-diploid) DNA aneuploidy in all cases, with a DNA index of 1.15 in two tumours and 1.3 in the third tumour. The three patients were reported to be alive and well 11 years, 7 years, and 6 months, respectively, after diagnosis. Amin et al. [14] made the ensuing educative iterations:
Abbosh et al. [6] stated the ensuing:
Abbosh et al. [6] reported their analysis of protein and genetic markers of germ cell neoplasia, utilising immunohistochemistry and fluorescence in situ hybridization, in four testicular carcinoid tumours. Abbosh et al. [6] summarized their results as follows:
Abbosh et al. [6] concluded that their findings had indicated that testicular carcinoid tumour represents a phenotypic expression of testicular teratoma and is of germ cell origin.
Lu et al. [9] stated that primary pure carcinoid tumours of the testis (pPCTT) are rare, and there are only a limited number of studies available related to pPCTT. Lu et al. [9] described in their study, the clinicopathological and immune-phenotypical characteristics of 11 cases from their institution between 1978 and 2014, and they reported their experiences of the diagnosis and treatment of these patients. Lu et al. [9] summarized the results as follows:
Lu et al. [9] summated their findings as follows
Lubana et al. [15] made the ensuing iterations:
Lubana et al. [15] reported a 34-year-old man who did not have any past medical history who had manifested with right scrotal swelling for one year, with recent onset of pain. He did not have any history of testicular trauma, haematuria, undescended testis, systemic symptoms, or weight loss. He did not have any family history of testicular cancer. His clinical examination demonstrated an enlarged tender mobile right testicular mass. He had ultrasound scan which revealed an enlarged right testis, heterogeneous in echo texture (5×4.4×4.8 cm) with focal testicular parenchymal hypoechoic mass that measured 1.7 cm ×1 cm × 1.6 cm that was suspicious for neoplastic process (see figure 1).
Figure 1: Ultrasound showed enlarged right testis, heterogeneous in echotexture (5.0 x 4.4 x 4.8 cm) with a focal right testicular parenchymal hypoechoic mass-like area (1.7 x 1.0 x 1.6 cm). Reproduced from: [15] Under Creative Commons Attribution License which permits reproduction of figures and contents of the article provided the original source is cited and credited.
Beta human chorionic gonadotropin [β-HCG] and alfa-fetoprotein [AFP] were noted to be normal with elevated lactate dehydrogenase (LDH) 401 (90–225) U/L. He underwent staging computerized tomography (CT) which did not demonstrate any evidence of metastasis or lymph adenopathy. The patient underwent radical orchidectomy. Gross examination of the orchidectomy showed that the right testis and epididymis was covered by intensely fibrotic tunica vaginalis. The testis was found to be entirely occupied by the tumour which measured 4.5 cm × 4.5 cm × 4 cm, with 90% necrosis. The tumour was noted to be confined to the testis and epididymis without lympho-vascular invasion. Microscopy histopathology examination of the tumour demonstrated that the tumour was consistent with a well-differentiated neuroendocrine carcinoma. Histology examination demonstrated nests of monotonous tumour cells with relatively abundant eosinophilic cytoplasm, round to oval nuclei, distinct nuclear membrane with “salt and pepper”-like chromatin (see figure 2). Immunohistochemistry staining studies of the tumour showed that the tumour cells had exhibited positive staining with chromogranin, synaptophysin (see figure 3), cytokeratin AE1/AE3, and CAM5.2 and negative staining for placental alkaline phosphatase, CD30, β-HCG, AFP, and epithelial membrane antigen. Ki-67 labelling index was <1>
Figure 2: (A): Low-power view (40x); Showing nests of tumour cells with surrounding abundant blood vessels. (B): High-power view (400x); Monotonous tumour cells with relatively abundant cytoplasm, distinct nuclear membrane with ‘’salt and pepper’’-like chromatin. Reproduced from: [15] Under Creative Commons Attribution License which permits reproduction of figures and contents of the article provided the original source is cited and credited.
Figure 2: Low-power view (40x); Showing nests of tumour cells with surrounding abundant blood vessels. (B): High-power view (400x); Monotonous tumour cells with relatively abundant cytoplasm, distinct nuclear membrane with ‘’salt and pepper’’-like chromatin. Reproduced from: [15] Under Creative Commons Attribution License which permits reproduction of figures and contents of the article provided the original source is cited credited.
Figure 3: Positive synaptophysin staining of right testis in primary carcinoid tumour. Reproduced from: [15] Under Creative Commons Attribution License which permits reproduction of figures and contents of the article provided the original source is cited and credited.
The possibility of an extra-testicular carcinoid tumour was excluded with negative esophagogastroduodenoscopy and colonoscopy. A nuclear octreotide scan had demonstrated focal radiotracer activity projecting over the scrotum (benign physiologic variant); nevertheless, an octreotide avid tumour could not be excluded. The rest of the body demonstrated no evidence of octreotide avid tumour. Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A were within normal range.
Lubana et al. [15] made the ensuing summative iterations:
Lubana et al. [15] made the ensuing educative concluding iterations:
Amine et al. [36] studied the main epidemiological, clinical, para clinical, pathological, therapeutic, and evolutionary features of patients who had testicular neuroendocrine tumours (TNET). Amine et al. [36] identified nine case series and sixteen case reports by searching PubMed database and qualified for inclusion in this study. Amine et al. [36] added the data of one case treated in the department of urology in Habib Bourguiba Hospital in Sfax, to the published cases. Amine et al. [36] summarized the results as follows:
Amine et al. [36] made the ensuing conclusions:
Reyes et al. [8] studied 10 cases of primary pure testicular neuroendocrine carcinoma. Reyes et al. [8] reported that the patients were between 16 years and 48 years old and they had testicular swelling with pain or a painless testicular mass and no history of neuroendocrine carcinoma or other malignant neoplasm. All 10 patients underwent orchidectomy. The tumours were low (n = 9) and intermediate (n = 1) grades with a variegated histopathology appearance that was characterized by a nesting pattern, cords of neoplastic cells with rosettes, or sheets of neoplastic cells. Mitotic activity was noted to be lacking in 9 cases. In 1 case, mitotic-figures were noted to have ranged from 7 to 8 per 10 high-power fields, and cellular atypia and comedo-like necrosis were observed. Immunohistochemistry staining studies utilising a keratin cocktail, chromogranin, synaptophysin, epidermal growth factor, p53, placental-like alkaline phosphatase, and CD117 (c-kit) were undertaken in all cases. Keratin, chromogranin, and synaptophysin were positive in all tumours. Clinical follow-up information was obtained for 6 patients and the follow-up had ranged between 12 months and 60 months; 5 of the patients who had low-grade tumours were alive 24 to 60 months after the initial diagnosis; 1 patient who had an intermediate-grade tumour died of his tumour 12 months after the initial diagnosis. Han et al. [8] stated the following:
Han et al. [37] explored the clinicopathological characteristics and differential diagnosis of primary neuroendocrine tumour (G1) of the testis. Han et al. [37] analysed the clinical, histomorphology and immunohistochemistry staining study findings, treatment and prognosis of a patient who had primary neuroendocrine tumour of the testis, and discussed the relevant literature. Han et al. [36] reported a-52-year-old man who had manifested with a painless testicular swelling over a period of 6 months. Histopathology examination of the testicular tumour mass demonstrated that the tumour cells were arranged in island and beam patterns. The tumour cells were noted to be uniform, polygonal and had moderately eosinophilic cytoplasm and fine granular nuclear chromatin. Immunohistochemistry staining studies of tumour demonstrated that the tumour cells had exhibited positive staining for cytokeratin, CD56, synaptophysin and chromogranin A, and negative for inhibin, placental alkaline phosphatase and alpha-fetoprotein. Han et al. [37] stated the following:
Albalawi et al. [48] stated that testicular neuroendocrine tumours (TNETs) are extremely uncommon. rare. Albalawi et al. [48] reported a 47-year-old man who manifested with a painless right testicular mass. The results of all his tumour markers levels were within normal ranges. The patient underwent a high inguinal radical orchidectomy. Histopathology examination of the orchidectomy specimen demonstrated a well-differentiated neuroendocrine tumour. He underwent radiology imaging investigations which demonstrated multiple prominent axillary, supraclavicular, mediastinal, and hilar lymph nodes and no bowel or mesenteric lesions suggesting carcinoid. Albalawi et al. [] stated the following:
Conflict of Interest – nil
Acknowledgements
Acknowledgements to: American Journal of Case reports for granting permission for reproduction of contents and figures from their article under copy right: Copyright © Am J Case Rep, 2015. This work is licensed under a Creative Commons Attribution-Non-Commercial-No Derivs 3.0 Unported License which permits reproduction of contents and figures from the Journal article provided the original source is cited.
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Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
