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Incidence of Gastrointestinal Neuroendocrine Tumor: Case Series, Armed Forces Hospital Southern Region, Hospital-Based Tumor Board Registry

Incidence of Gastrointestinal Neuroendocrine Tumor: Case Series, Armed Forces Hospital Southern... Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 8819392, 7 pages https://doi.org/10.1155/2020/8819392 Case Series Incidence of Gastrointestinal Neuroendocrine Tumor: Case Series, Armed Forces Hospital Southern Region, Hospital-Based Tumor Board Registry 1 2 3 Abdullah Mohammed Albishi , Ahmed Mostafa Mohamed Mostafa, Hatim Mahgoub Ali, 1 4 5 Yahia Atiah Alhagawi, Mohamed F. Bazeed, Mahmoud R. A. Hussein, 3 6 Elshfeia Elhag Mohmed Ali Aloba, and Ahmed Youssef Aboelyazid Gastroenterology and Endoscopy Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Clinical Oncology, Faculty of Medicine, Ain-Shams University, Egypt Oncology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Radiology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Pathology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Preventive Medicine Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Correspondence should be addressed to Abdullah Mohammed Albishi; dr.abdullah6975@gmail.com Received 9 April 2020; Revised 27 August 2020; Accepted 7 October 2020; Published 20 October 2020 Academic Editor: Peter F. Lenehan Copyright © 2020 Abdullah Mohammed Albishi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neuroendocrine tumors are aggressive and rare tumors which can occur almost everywhere in the body. The annual incidence of neuroendocrine tumors is 2.5-5 per 100000. We report seven cases of gastrointestinal neuroendocrine tumors which were diagnosed and treated at our hospital from the time period of 2016-2018 knowing that the total number of our hospital tumor board cases registry during the same period was 444 cases. 1. Introduction 2. Case Reports Generally, Neuroendocrine tumors (NETs) are rare This case series describes seven cases of gastrointestinal tumors comprising ~2% of all malignancies [1] with the NETs diagnosed and presented in the tumor board at our gastrointestinal tract and the lung as the most common hospital from the time period starting from 01/01/2016 till sites [2]. 31/12/2018 as shown in Table 1. Out of seven cases, four were Neuroendocrine tumors (NETs) are a heterogeneous male and three were females. Four patients out of seven group of epithelial neoplastic proliferations arising in many present beyond 60 years of age. Appendix is the most body organs. Irrespective of their primary site and of their common site of NETs in our hospital. grade of differentiation, neoplastic cells share features of neural and endocrine differentiation: the “neuro” property 2.1. 1st Case. A 60-year-old male presented with abdominal is based on the identification of dense core granules that are pain and vomiting with constipation for 4 days; CT of the similar to dense core granules (DCGs) present in serotoner- abdomen showed an enhancing mass at the ileocecal area gic neurons, which store monoamines, and the “endocrine” including the appendix; he was diagnosed as having complete property refers to the synthesis and secretion of these mono- intestinal obstruction and underwent right hemicolectomy; amines which is about two-thirds of NETs that arise in the histopathology report showed goblet cell carcinoid of the gastrointestinal tract and pancreas [1, 3]. 2 Case Reports in Oncological Medicine Table 1: Summary of the data of the patients diagnosed with GIT NET at AFHSR. Age, Initial Lymph Immunohistochemical Modality of Site Size Diagnostic workup Grade Outcome sex presentation node study treatment Alive and Acute CT of the abdomen shows an Positive Synaptophysin +, 60, Ileocecal 45 × 20 Moderately differentiated arising from Right following intestinal enhancing mass at the ileocecal for chromogranin +, CK- M mass mm goblet cell carcinoid Hemicolectomy with obstruction area including the appendix metastasis 20 + oncology Alive and Distal 1/3 Synaptophysin +, 4× 3 Follow-up CT was following up 20, F Appendicitis of the Grade 1, well differentiated No chromogranin +, Ki-67 Appendectomy mm unremarkable with an appendix less than 3% oncologist Alive and Distal 1/3 Synaptophysin +, 1× 2 Follow-up CT was following up 19, F Appendicitis of the Grade 1, well differentiated No chromogranin +, Ki-67 Appendectomy mm unremarkable with an appendix less than 2% oncologist CT of the abdomen showed an Alive and Acute enhancing mass at the ileocecal Synaptophysin NA, 52, Ileocecal Right following up intestinal 15 mm area including the appendix Grade1, well differentiated No chromogranin NA, Ki- M mass hemicolectomy with an obstruction Follow-up CT of the abdomen 67 less than 3% oncologist showed a free anastomosis site CT of the abdomen shows Abdominal Positive Synaptophysin +, multiple liver lesions with an 80, F pain and Appendix — Grade 1 for chromogranin +, Ki-67 — Died enlarged appendix weight loss metastasis 1-2% Liver biopsy Grade 1, well differentiated; tumor Alive and Synaptophysin +, Appendectomy 22, Follow-up CT was invades the muscle to periappendiceal following up Appendicitis Appendix 7 mm No chromogranin +, Ki-67 followed by right M unremarkable fatty tissue, and there is perineural with an 1% hemicolectomy invasion oncologist Synaptophysin NA, Follow-up in 86, UGI Gastroscopy showed ugly- Stomach — Grade 1 — chromogranin NA, Ki- — another M bleeding looking gastric ulcer 67 NA center Case Reports in Oncological Medicine 3 Figure 1: Case 4. Coronal postcontrast CT scan study showed a collapsed cecum with dilated ileum and enhanced lesion at the ileocecal valve. appendix. The patient is doing well with follow-up with an oncologist. 2.2. 2nd Case. A 20-year-old female presented with right iliac fossa abdominal pain for 2 days, was diagnosed as having acute appendicitis, and underwent appendectomy; histopa- Figure 2: Case 5. Axial postcontrast CT scan showed patchy thology report showed a well-differentiated neuroendocrine heterogeneous enhancement of liver metastasis. tumor of the appendix. Patient is doing well with follow-up with an oncologist. 2.7. 7th Case. An 86-year-old male presented with vomiting of blood for 2 days, underwent gastroscopy, and showed 2.3. 3rd Case. A19-year-old female presented with right iliac ugly-looking gastric ulcer; histopathology report showed a fossa abdominal pain for 1 day, was diagnosed as having low-grade neuroendocrine tumor. Patient is following up acute appendicitis, and underwent appendectomy; histopa- with an oncologist. thology report showed a well-differentiated neuroendocrine tumor of the appendix grade 1. Patient is doing well with follow-up with an oncologist. 3. Results and Discussion 2.4. 4th Case. A 52-year-old male presented with abdominal As neuroendocrine cells are distributed among the whole pain and vomiting with constipation for 3 days; CT of the body, so NETs have been described in multiple organs such abdomen showed an enhancing mass at the ileocecal area as the central nervous system, respiratory tract, the larynx, including the appendix as shown in Figure 1; she was diag- gastrointestinal (GI) tract, thyroid, skin, breast, and urogenital nosed as having complete intestinal obstruction and under- system. The GIT and lung are the most common primary sites went right hemicolectomy; histopathology report showed a for NET [1, 2]. This type of neoplasia has substantial varia- well-differentiated neuroendocrine tumor of the small bowel. tions in both tumor biology and clinical presentation; the biol- Patient is doing well with follow-up with an oncologist. ogy of each NET depends on its primary tumor localization, Follow-up CT of the abdomen showed a free anastomosis cellular morphology, and mitotic activity, and clinically, NET site, with follow-up with an oncologist. may manifest by the expression of autonomous hormone secretion of either a peptide hormone or biogenic amine [4]. 2.5. 5th Case. An 80-year-old female presented with abdom- The pathologic classifications of neuroendocrine tumors inal pain and weight loss for 4 months; ultrasound of the across different organ systems use a range of site-specificter- abdomen showed multiple liver lesions. CT of the abdomen minologies and criteria, creating significant confusion among showed multiple liver lesions with an enlarged appendix as pathologists and treating clinicians [5]. The most widely used shown in Figure 2; she underwent liver biopsy, and histopa- is the WHO system for classification of NET which is fre- thology report showed a metastasis of the neuroendocrine quently updated, and at the time of starting our case series, tumor. The patient died. we were using the WHO version 4 for classification of neuro- endocrine tumors [6] and according to this classification, 2.6. 6th Case. A 22-year-old male presented with right iliac NETs are classified into three grading subgroups based on fossa abdominal pain for 2 days, was diagnosed as having the mitotic activity and Ki67 immunostaining: G1 acute appendicitis, and underwent appendectomy; histopa- (mitotic count < 2/10 HPF and/or Ki − 67 index < 3%), G2 thology report showed a low-grade neuroendocrine tumor (mitotic count 2-20/10 HPF and/or Ki-67 index 3-20%), and of the appendix. Patient is doing well with follow-up with G3 (mitotic count > 20/10 HPF and/or Ki − 67 index > 20%). an oncologist and planned for right hemicolectomy. G1 and G2 NETs have well-differentiated morphology and 4 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (l) Figure 3: Histopathology features of one of the cases, well-differentiated neuroendocrine tumor of the small intestine (ileum), classic type: (a– c) the histological sections show tumor cells with minimal pleomorphism arranged in cording and nesting growth patterns, extensively involving the mucosa, submucosa, and muscle layer. The main bulk of the tumor is seen in the submucosa and the muscle layer. The tumor cells have stippled chromatin, inconspicuous nucleoli, and slightly granular eosinophilic cytoplasm. There is no significant mitotic activity, and the tumor cells show little pleomorphism. There is no cell necrosis (H&E stains: (a) ×4, (b) ×10, (c) ×20, and (d) ×40). The tumor cells were positive for the epithelial markers CDX-2 ((e) ×10) and pancytokeratin ((f) ×10) and negative for CK7 ((g) ×10) and CK20 ((h) ×10). The tumor cells were diffusely and strongly reactive for the markers of neuroendocrine differentiation including both synaptophysin ((i) ×40) and chromogranin ((j) ×4 and (k) ×10). Ki67 labelling index was very low (less than 1%, (l) ×10). Case Reports in Oncological Medicine 5 Medical NET patient diagnosed oncology team Primary Surgery diagnosing team team Tumor board Pathology Radiology team team Treatment plan Figure 4: The NET tumor board and treatment plan construction. are referred to as G1 or G2 neuroendocrine tumors (NET), surgery is still the cornerstone modality of treatment of non- while G3 NETs are considered poorly differentiated and metastatic NET [11]. Several imaging methods are available referred to as neuroendocrine carcinomas (NEC) [4]; one of including CT, magnetic resonance imaging, ultrasonography, the main advantages of this system is the higher ability to scintigraphy, and positron emission tomography [1]; follow- determine prognosis [7]. The total number of NETs diagnosed ing imaging and localization, biopsy should be obtained for and presented in the tumor board at our hospital from the histopathological diagnosis as shown in Figure 3 and this time period starting from 01/01/2016 till 31/12/2018 was 11 may include performing upper endoscopy and colonoscopy out of 444 total cases representing almost 0.03%, and this is with ileoscopy for gastrointestinal NET [7]. Commonly measured tumor markers in NETs include of low incidence if compared to the usual global incidence [8], whereas the total number of GIT NETs was 7 cases, repre- serum CgA and 5-HIAA, the final secreted product of seroto- senting almost 65% of the all NET cases diagnosed at our hos- nin, levels in a 24-hour urine sample [12], and actually, serum pital. Most of our cases were appendicular NETs (6 out of the CgA is more sensitive and broadly applicable marker than uri- 7 cases), and all these cases were of low grade (grade 1). There nary 5-HIAA because it does not depend on serotonin secre- tion so it is preferred over 5-HIAA for bronchial and rectal was slight male predominance representing 4 out of 7 cases, and 3 out of 7 patients were beyond 60 years of age. tumors, because they do not generally secrete serotonin [13]; We have to mention that the term carcinoid has been crit- also, plasma CgA levels correlate with tumor bulk, differentia- icized because it was used to describe different tumors distinct tion, and secretory activity, which, in turn, may predict treat- in their etiology, prognosis, and management, leading to termi- ment response [14]; after completion of the workup, patients should be staged based on the American Joint Committee on nological confusion and diagnostic unreliability [1], and also, th this term is considered to be a straight misnomer as the malig- Cancer (AJCC) staging system 8 edition [15]. nancy of this tumor group can be confirmed on the basis of At our hospital, every case with a histopathological diag- local invasion prior to metastases [9] and not benignly as nosis of NET should be presented within the weekly tumor Oberndorfer mistakenly assumed [1], and so the term carcinoid board (in attendance of the primary diagnosing team, based should be used whenever there are the symptoms of this syn- usually on the tumor location, medical oncology, surgery dromewhich arewaterydiarrhea, flushing, bronchospasm, team, radiology, and pathology) after completion of the hypotension, and right-sided heart disease that correlates with workup—radiological and laboratory—and treatment plans serotonin hypersecretion since properties of serotonin include are constructed for each case specifically, based on multiple vasodilation, bronchoconstriction, and smooth muscle contrac- parameters including the stage, performance status, and the tion [10]. In our case series, no single case presented with secre- clinical picture as shown in Figure 4. tory symptoms and all of them presented with either a clinical There are different treatment modalities that can be used picture of acute appendicitis or right hypochondrial pain. in the management of NET as shown in Figure 5 [1]. Actually, the optimal therapeutic sequence should be 3.1. Diagnosis. The improvement of the current diagnostic based on the evaluation of at least three major issues [16]: techniques has led to an increased number of patients diag- nosed with GIT NET, and, in contrast with the past, most of (i) Tumor characterization (primary site, histological the tumors belong to the so called “nonfunctioning” category diagnosis, and staging) and not associated with symptoms and signs of hormone (ii) Patient’s clinical status (performance status, clinical hypersecretion [3]. The diagnosis of NET includes different picture, prior treatments, and comorbidities) modalities, but proper tumor localization is essential because 6 Case Reports in Oncological Medicine Suspected NEN 24 h urinary 5-HIAA Imaging, including SSRS Plasma CgA: fasting gut hormones Metastatic Consider surgery Histology Curative G3 NEN or G3 NEC G1 NEN G2 NEN Biotherapy Chemotherapy Chemotherapy (i) Somatostatin analog Cisplatin/etoposide Cisplatin/etoposide (i) (sms) Combinations of STZ, Toopotecan (ii) (ii) IFN-alpha 5-FU, capecitabine TMZ-based combinations Sunitinib (iii) TMZ, and doxorubicin SMS for symptom control (iv) Everolimus (v) Bevacizumab (iii) SMS for symptom control Progression with hepatic predominant disease Consider: Selective internal radiation therapy Liver surgery Ablation therapy (chemo)-embolization SMS: somatostatin analog 5FU : fluorouracil NEN: neuroendocrine neoplasm Consider radionuclide therapy IFN: interferon e.g., l-131 MIBG: TMZ: temozolomide Y-90 DOTA octreotide SSRS: somatostatin receptor scintigraphy STZ: streptozocin CgA: chromogranin A Experimental agents, e.g., RRx-001 Figure 5: Different treatment modalities that can be used in the management of NETs [1]. (iii) Defining the objectives of care a higher incidence of suspicion is required. Also, there are still some controversies regarding the sequence of systemic Fortunately, 5 of our patients were diagnosed in early treatments used in the management of GIT NET that needs stages and thus, these 5 patients were treated radically aiming more clarification. for cure and they underwent radical surgeries; 2 cases under- went upfront right hemicolectomy, and 2 cases underwent Conflicts of Interest appendectomy, whereas the last case underwent appendec- tomy, but based on the histopathological findings and the The authors declare that they have no conflict of interest. discussion of the case within the tumor board completion, right hemicolectomy was done. Based on the clinical picture and staging of these 5 cases, no adjuvant treatment was References required. One case presented with a metastatic disease to [1] B. Oronsky, P. C. Ma, D. Morgensztern, and C. A. Carter, the liver, and she presented in poor general condition, and “Nothing but NET: a review of neuroendocrine tumors and unfortunately, she died without starting any treatment. All carcinomas,” Neoplasia, vol. 19, no. 12, pp. 991–1002, 2017. patients who did radical surgery were following in surgery [2] A. Anaizi, A. Rizvi-Toner, J. Valestin, and R. Schey, “Large cell and oncology clinics; follow-up consists of clinical examina- neuroendocrine carcinoma of the lung presenting as pseudoa- tion and abdominal imaging (6 months after imaging and chalasia: a case report,” Journal of Medical Case Reports, vol. 9, then as clinically indicated). no. 1, p. 56, 2015. [3] S. Uccella, F. Sessa, and S. L. Rosa, “Diagnostic approach to neuroendocrine neoplasms of the gastrointestinal tract and 4. Conclusion pancreas,” Turkish Journal of Pathology, vol. 31, pp. 113–127, Despite the increasing number of patients diagnosed with 2015. GIT NET and also the increasing knowledge within this field, [4] I. Kruljac and U.-F. Pape, “The classification of neuroendo- still, most of the cases are diagnosed in advanced stages; thus, crine neoplasms: ‘neuroendocrine carcinomas’ revisited-a Case Reports in Oncological Medicine 7 2017 update and future perspectives,” Endocrine Oncology and Metabolism, vol. 3, no. 2, pp. 37–42, 2017. [5] G. Rindi, D. S. Klimstra, B. Abedi-Ardekani et al., “A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus pro- posal,” Modern Pathology, vol. 31, no. 12, pp. 1770–1786, 2018. [6] N. D. Bosman, F. T. Carneiro, F. Hruban, and R. H. Theise, WHO Classification of Tumours of the Digestive System, Inter- national Agency for Research on Cancer, 4th edition, 2010. [7] W. J. Salyers, K. J. Vega, J. C. Munoz, B. W. Trotman, and S. S. Tanev, “Neuroendocrine tumors of the gastrointestinal tract: case reports and literature review,” World Journal of Gastroin- testinal Oncology, vol. 6, no. 8, pp. 301–310, 2014. [8] B. G. Taal and O. Visser, “Epidemiology of neuroendocrine tumours,” Neuroendocrinology, vol. 80, no. 1, pp. 3–7, 2004. [9] J. Soga, “The term "carcinoid" is a misnomer: the evidence based on local invasion,” Journal of Experimental & Clinical Cancer Research, vol. 28, no. 1, p. 15, 2009. [10] J. I. S. Robertson, “Carcinoid syndrome and serotonin: thera- peutic effects of ketanserin,” Cardiovascular Drugs and Ther- apy, vol. 4, no. 1, pp. 53–58, 1990. [11] G. Akerström, C. Makridis, and H. Johansson, “Abdominal surgery in patients with midgut carcinoid tumors,” Acta Onco- logica, vol. 30, no. 4, pp. 547–553, 1991. [12] R. Kapoor, T. Bhattacharyya, R. Gupta, B. Mittal, and N. Kalra, “A systematic review of management of neuroendocrine tumors: an experience from a tertiary care centre from India,” Clinical Cancer Investigation Journal, vol. 3, no. 5, pp. 363– 372, 2014. [13] M. H. Kulke, “Clinical presentation and management of carci- noid tumors,” Hematology/Oncology Clinics of North America, vol. 21, no. 3, pp. 433–455, 2007. [14] W. C. Chou, J. S. Chen, Y. S. Hung et al., “Plasma chromogra- nin a levels predict survival and tumor response in patients with advanced gastroenteropancreatic neuroendocrine tumors,” Anticancer Research, vol. 34, no. 10, pp. 5661–5669, [15] AJCC, American Joint Committee on Cáncer, AJCC Cancer Staging Manual, 8th edition, 2018. [16] M. Rinzivillo, F. Panzuto, and G. D. Fave, “Controversies in the treatment of digestive neuroendocrine tumors,,” Journal of Cancer Metastasis and Treatment, vol. 2, no. 8, p. 304, 2016. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Incidence of Gastrointestinal Neuroendocrine Tumor: Case Series, Armed Forces Hospital Southern Region, Hospital-Based Tumor Board Registry

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Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 8819392, 7 pages https://doi.org/10.1155/2020/8819392 Case Series Incidence of Gastrointestinal Neuroendocrine Tumor: Case Series, Armed Forces Hospital Southern Region, Hospital-Based Tumor Board Registry 1 2 3 Abdullah Mohammed Albishi , Ahmed Mostafa Mohamed Mostafa, Hatim Mahgoub Ali, 1 4 5 Yahia Atiah Alhagawi, Mohamed F. Bazeed, Mahmoud R. A. Hussein, 3 6 Elshfeia Elhag Mohmed Ali Aloba, and Ahmed Youssef Aboelyazid Gastroenterology and Endoscopy Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Clinical Oncology, Faculty of Medicine, Ain-Shams University, Egypt Oncology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Radiology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Pathology Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Preventive Medicine Department, Armed Forces Hospital Southern Region, Khamis Mushayt, Saudi Arabia Correspondence should be addressed to Abdullah Mohammed Albishi; dr.abdullah6975@gmail.com Received 9 April 2020; Revised 27 August 2020; Accepted 7 October 2020; Published 20 October 2020 Academic Editor: Peter F. Lenehan Copyright © 2020 Abdullah Mohammed Albishi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neuroendocrine tumors are aggressive and rare tumors which can occur almost everywhere in the body. The annual incidence of neuroendocrine tumors is 2.5-5 per 100000. We report seven cases of gastrointestinal neuroendocrine tumors which were diagnosed and treated at our hospital from the time period of 2016-2018 knowing that the total number of our hospital tumor board cases registry during the same period was 444 cases. 1. Introduction 2. Case Reports Generally, Neuroendocrine tumors (NETs) are rare This case series describes seven cases of gastrointestinal tumors comprising ~2% of all malignancies [1] with the NETs diagnosed and presented in the tumor board at our gastrointestinal tract and the lung as the most common hospital from the time period starting from 01/01/2016 till sites [2]. 31/12/2018 as shown in Table 1. Out of seven cases, four were Neuroendocrine tumors (NETs) are a heterogeneous male and three were females. Four patients out of seven group of epithelial neoplastic proliferations arising in many present beyond 60 years of age. Appendix is the most body organs. Irrespective of their primary site and of their common site of NETs in our hospital. grade of differentiation, neoplastic cells share features of neural and endocrine differentiation: the “neuro” property 2.1. 1st Case. A 60-year-old male presented with abdominal is based on the identification of dense core granules that are pain and vomiting with constipation for 4 days; CT of the similar to dense core granules (DCGs) present in serotoner- abdomen showed an enhancing mass at the ileocecal area gic neurons, which store monoamines, and the “endocrine” including the appendix; he was diagnosed as having complete property refers to the synthesis and secretion of these mono- intestinal obstruction and underwent right hemicolectomy; amines which is about two-thirds of NETs that arise in the histopathology report showed goblet cell carcinoid of the gastrointestinal tract and pancreas [1, 3]. 2 Case Reports in Oncological Medicine Table 1: Summary of the data of the patients diagnosed with GIT NET at AFHSR. Age, Initial Lymph Immunohistochemical Modality of Site Size Diagnostic workup Grade Outcome sex presentation node study treatment Alive and Acute CT of the abdomen shows an Positive Synaptophysin +, 60, Ileocecal 45 × 20 Moderately differentiated arising from Right following intestinal enhancing mass at the ileocecal for chromogranin +, CK- M mass mm goblet cell carcinoid Hemicolectomy with obstruction area including the appendix metastasis 20 + oncology Alive and Distal 1/3 Synaptophysin +, 4× 3 Follow-up CT was following up 20, F Appendicitis of the Grade 1, well differentiated No chromogranin +, Ki-67 Appendectomy mm unremarkable with an appendix less than 3% oncologist Alive and Distal 1/3 Synaptophysin +, 1× 2 Follow-up CT was following up 19, F Appendicitis of the Grade 1, well differentiated No chromogranin +, Ki-67 Appendectomy mm unremarkable with an appendix less than 2% oncologist CT of the abdomen showed an Alive and Acute enhancing mass at the ileocecal Synaptophysin NA, 52, Ileocecal Right following up intestinal 15 mm area including the appendix Grade1, well differentiated No chromogranin NA, Ki- M mass hemicolectomy with an obstruction Follow-up CT of the abdomen 67 less than 3% oncologist showed a free anastomosis site CT of the abdomen shows Abdominal Positive Synaptophysin +, multiple liver lesions with an 80, F pain and Appendix — Grade 1 for chromogranin +, Ki-67 — Died enlarged appendix weight loss metastasis 1-2% Liver biopsy Grade 1, well differentiated; tumor Alive and Synaptophysin +, Appendectomy 22, Follow-up CT was invades the muscle to periappendiceal following up Appendicitis Appendix 7 mm No chromogranin +, Ki-67 followed by right M unremarkable fatty tissue, and there is perineural with an 1% hemicolectomy invasion oncologist Synaptophysin NA, Follow-up in 86, UGI Gastroscopy showed ugly- Stomach — Grade 1 — chromogranin NA, Ki- — another M bleeding looking gastric ulcer 67 NA center Case Reports in Oncological Medicine 3 Figure 1: Case 4. Coronal postcontrast CT scan study showed a collapsed cecum with dilated ileum and enhanced lesion at the ileocecal valve. appendix. The patient is doing well with follow-up with an oncologist. 2.2. 2nd Case. A 20-year-old female presented with right iliac fossa abdominal pain for 2 days, was diagnosed as having acute appendicitis, and underwent appendectomy; histopa- Figure 2: Case 5. Axial postcontrast CT scan showed patchy thology report showed a well-differentiated neuroendocrine heterogeneous enhancement of liver metastasis. tumor of the appendix. Patient is doing well with follow-up with an oncologist. 2.7. 7th Case. An 86-year-old male presented with vomiting of blood for 2 days, underwent gastroscopy, and showed 2.3. 3rd Case. A19-year-old female presented with right iliac ugly-looking gastric ulcer; histopathology report showed a fossa abdominal pain for 1 day, was diagnosed as having low-grade neuroendocrine tumor. Patient is following up acute appendicitis, and underwent appendectomy; histopa- with an oncologist. thology report showed a well-differentiated neuroendocrine tumor of the appendix grade 1. Patient is doing well with follow-up with an oncologist. 3. Results and Discussion 2.4. 4th Case. A 52-year-old male presented with abdominal As neuroendocrine cells are distributed among the whole pain and vomiting with constipation for 3 days; CT of the body, so NETs have been described in multiple organs such abdomen showed an enhancing mass at the ileocecal area as the central nervous system, respiratory tract, the larynx, including the appendix as shown in Figure 1; she was diag- gastrointestinal (GI) tract, thyroid, skin, breast, and urogenital nosed as having complete intestinal obstruction and under- system. The GIT and lung are the most common primary sites went right hemicolectomy; histopathology report showed a for NET [1, 2]. This type of neoplasia has substantial varia- well-differentiated neuroendocrine tumor of the small bowel. tions in both tumor biology and clinical presentation; the biol- Patient is doing well with follow-up with an oncologist. ogy of each NET depends on its primary tumor localization, Follow-up CT of the abdomen showed a free anastomosis cellular morphology, and mitotic activity, and clinically, NET site, with follow-up with an oncologist. may manifest by the expression of autonomous hormone secretion of either a peptide hormone or biogenic amine [4]. 2.5. 5th Case. An 80-year-old female presented with abdom- The pathologic classifications of neuroendocrine tumors inal pain and weight loss for 4 months; ultrasound of the across different organ systems use a range of site-specificter- abdomen showed multiple liver lesions. CT of the abdomen minologies and criteria, creating significant confusion among showed multiple liver lesions with an enlarged appendix as pathologists and treating clinicians [5]. The most widely used shown in Figure 2; she underwent liver biopsy, and histopa- is the WHO system for classification of NET which is fre- thology report showed a metastasis of the neuroendocrine quently updated, and at the time of starting our case series, tumor. The patient died. we were using the WHO version 4 for classification of neuro- endocrine tumors [6] and according to this classification, 2.6. 6th Case. A 22-year-old male presented with right iliac NETs are classified into three grading subgroups based on fossa abdominal pain for 2 days, was diagnosed as having the mitotic activity and Ki67 immunostaining: G1 acute appendicitis, and underwent appendectomy; histopa- (mitotic count < 2/10 HPF and/or Ki − 67 index < 3%), G2 thology report showed a low-grade neuroendocrine tumor (mitotic count 2-20/10 HPF and/or Ki-67 index 3-20%), and of the appendix. Patient is doing well with follow-up with G3 (mitotic count > 20/10 HPF and/or Ki − 67 index > 20%). an oncologist and planned for right hemicolectomy. G1 and G2 NETs have well-differentiated morphology and 4 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (l) Figure 3: Histopathology features of one of the cases, well-differentiated neuroendocrine tumor of the small intestine (ileum), classic type: (a– c) the histological sections show tumor cells with minimal pleomorphism arranged in cording and nesting growth patterns, extensively involving the mucosa, submucosa, and muscle layer. The main bulk of the tumor is seen in the submucosa and the muscle layer. The tumor cells have stippled chromatin, inconspicuous nucleoli, and slightly granular eosinophilic cytoplasm. There is no significant mitotic activity, and the tumor cells show little pleomorphism. There is no cell necrosis (H&E stains: (a) ×4, (b) ×10, (c) ×20, and (d) ×40). The tumor cells were positive for the epithelial markers CDX-2 ((e) ×10) and pancytokeratin ((f) ×10) and negative for CK7 ((g) ×10) and CK20 ((h) ×10). The tumor cells were diffusely and strongly reactive for the markers of neuroendocrine differentiation including both synaptophysin ((i) ×40) and chromogranin ((j) ×4 and (k) ×10). Ki67 labelling index was very low (less than 1%, (l) ×10). Case Reports in Oncological Medicine 5 Medical NET patient diagnosed oncology team Primary Surgery diagnosing team team Tumor board Pathology Radiology team team Treatment plan Figure 4: The NET tumor board and treatment plan construction. are referred to as G1 or G2 neuroendocrine tumors (NET), surgery is still the cornerstone modality of treatment of non- while G3 NETs are considered poorly differentiated and metastatic NET [11]. Several imaging methods are available referred to as neuroendocrine carcinomas (NEC) [4]; one of including CT, magnetic resonance imaging, ultrasonography, the main advantages of this system is the higher ability to scintigraphy, and positron emission tomography [1]; follow- determine prognosis [7]. The total number of NETs diagnosed ing imaging and localization, biopsy should be obtained for and presented in the tumor board at our hospital from the histopathological diagnosis as shown in Figure 3 and this time period starting from 01/01/2016 till 31/12/2018 was 11 may include performing upper endoscopy and colonoscopy out of 444 total cases representing almost 0.03%, and this is with ileoscopy for gastrointestinal NET [7]. Commonly measured tumor markers in NETs include of low incidence if compared to the usual global incidence [8], whereas the total number of GIT NETs was 7 cases, repre- serum CgA and 5-HIAA, the final secreted product of seroto- senting almost 65% of the all NET cases diagnosed at our hos- nin, levels in a 24-hour urine sample [12], and actually, serum pital. Most of our cases were appendicular NETs (6 out of the CgA is more sensitive and broadly applicable marker than uri- 7 cases), and all these cases were of low grade (grade 1). There nary 5-HIAA because it does not depend on serotonin secre- tion so it is preferred over 5-HIAA for bronchial and rectal was slight male predominance representing 4 out of 7 cases, and 3 out of 7 patients were beyond 60 years of age. tumors, because they do not generally secrete serotonin [13]; We have to mention that the term carcinoid has been crit- also, plasma CgA levels correlate with tumor bulk, differentia- icized because it was used to describe different tumors distinct tion, and secretory activity, which, in turn, may predict treat- in their etiology, prognosis, and management, leading to termi- ment response [14]; after completion of the workup, patients should be staged based on the American Joint Committee on nological confusion and diagnostic unreliability [1], and also, th this term is considered to be a straight misnomer as the malig- Cancer (AJCC) staging system 8 edition [15]. nancy of this tumor group can be confirmed on the basis of At our hospital, every case with a histopathological diag- local invasion prior to metastases [9] and not benignly as nosis of NET should be presented within the weekly tumor Oberndorfer mistakenly assumed [1], and so the term carcinoid board (in attendance of the primary diagnosing team, based should be used whenever there are the symptoms of this syn- usually on the tumor location, medical oncology, surgery dromewhich arewaterydiarrhea, flushing, bronchospasm, team, radiology, and pathology) after completion of the hypotension, and right-sided heart disease that correlates with workup—radiological and laboratory—and treatment plans serotonin hypersecretion since properties of serotonin include are constructed for each case specifically, based on multiple vasodilation, bronchoconstriction, and smooth muscle contrac- parameters including the stage, performance status, and the tion [10]. In our case series, no single case presented with secre- clinical picture as shown in Figure 4. tory symptoms and all of them presented with either a clinical There are different treatment modalities that can be used picture of acute appendicitis or right hypochondrial pain. in the management of NET as shown in Figure 5 [1]. Actually, the optimal therapeutic sequence should be 3.1. Diagnosis. The improvement of the current diagnostic based on the evaluation of at least three major issues [16]: techniques has led to an increased number of patients diag- nosed with GIT NET, and, in contrast with the past, most of (i) Tumor characterization (primary site, histological the tumors belong to the so called “nonfunctioning” category diagnosis, and staging) and not associated with symptoms and signs of hormone (ii) Patient’s clinical status (performance status, clinical hypersecretion [3]. The diagnosis of NET includes different picture, prior treatments, and comorbidities) modalities, but proper tumor localization is essential because 6 Case Reports in Oncological Medicine Suspected NEN 24 h urinary 5-HIAA Imaging, including SSRS Plasma CgA: fasting gut hormones Metastatic Consider surgery Histology Curative G3 NEN or G3 NEC G1 NEN G2 NEN Biotherapy Chemotherapy Chemotherapy (i) Somatostatin analog Cisplatin/etoposide Cisplatin/etoposide (i) (sms) Combinations of STZ, Toopotecan (ii) (ii) IFN-alpha 5-FU, capecitabine TMZ-based combinations Sunitinib (iii) TMZ, and doxorubicin SMS for symptom control (iv) Everolimus (v) Bevacizumab (iii) SMS for symptom control Progression with hepatic predominant disease Consider: Selective internal radiation therapy Liver surgery Ablation therapy (chemo)-embolization SMS: somatostatin analog 5FU : fluorouracil NEN: neuroendocrine neoplasm Consider radionuclide therapy IFN: interferon e.g., l-131 MIBG: TMZ: temozolomide Y-90 DOTA octreotide SSRS: somatostatin receptor scintigraphy STZ: streptozocin CgA: chromogranin A Experimental agents, e.g., RRx-001 Figure 5: Different treatment modalities that can be used in the management of NETs [1]. (iii) Defining the objectives of care a higher incidence of suspicion is required. Also, there are still some controversies regarding the sequence of systemic Fortunately, 5 of our patients were diagnosed in early treatments used in the management of GIT NET that needs stages and thus, these 5 patients were treated radically aiming more clarification. for cure and they underwent radical surgeries; 2 cases under- went upfront right hemicolectomy, and 2 cases underwent Conflicts of Interest appendectomy, whereas the last case underwent appendec- tomy, but based on the histopathological findings and the The authors declare that they have no conflict of interest. discussion of the case within the tumor board completion, right hemicolectomy was done. Based on the clinical picture and staging of these 5 cases, no adjuvant treatment was References required. One case presented with a metastatic disease to [1] B. Oronsky, P. C. Ma, D. Morgensztern, and C. A. 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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Oct 20, 2020

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