Review

Surgical management of appendicular carcinoids

¹Zuccon William, ¹Del Re Luca, ¹Iamele Angelo, ¹Paternollo Roberto, ¹Cordovana Andrea, ²Lunghi Claudio

• ¹Departments of General Surgery – Fatebenefratelli e Oftalmico Hospital, Milan
• ²Director of Departments of General Surgery - Fatebenefratelli e Oftalmico Hospital, Milan

• Submitted: November 13, 2012;
• Accepted January 6, 2013
• Published:17 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

The carcinoid of the appendix, or well differentiated neuroendocrine tumor, is often asymptomatic and the diagnosis is usually ‘accidental’ after a surgical procedure. Multidisciplinary approach is essential for accurate management included analysis primary tumor size, staging, treatment plan and follows up.

Case report

The authors reported 2 cases of appendicular carcinoid on 320 consecutive appendicectomy in the last two years and described clinical features and therapeutic approach for this art of tumors. Appendicectomy in little tumors (< 1 cm) is a gold standard for the treatment and the radical resection is often healing, if the tumor size is mean (between 1 and 2 cm) the resection (appendicectomy vs hemicolectomy) is subject to the valuation of individual case, while the right hemicolectomy is considered according to tumor size (> 2 cm), incomplete tumor resection and/or histological features (medium and high grade, mixed histological).

Conclusions

The size of the tumor is a standard that influences both surgical strategy, both prognosis.The carcinoid of the appendix presents favorable prognosis as regards carcinoid tumors of the gastro enteric tract.

Key words

Appendicular carcinoid well differentiated neuroendocrine tumor, appendicectomy.

Introduction

Generally, carcinoids of the gastrointestinal tract are neuroendocrine tumors which have - - low - malignant potential and grow slowly; they have a low tendency to contiguous spread or metastasize at both lymph nodal - at the systemic level (liver, bone, lung), but the neoplastic mechanism is irreversible and progressive [1]. The gastrointestinal localization constitutes the majority of these tumors (55 - 75%), with a more frequent involvement in the vermiform appendix (26%). The appendicular carcinoid (well-differentiated neuroendocrine tumor) is frequently located at the apex and is more prevalent in females with an average age reported of 42 – 49 years, with a frequency of one case in every 200-300 appendectomies [2]. This type of tumour is often asymptomatic and the diagnosis of certainty is mostly ‘accidental’ during a histological examination for an appendectomy, or during a laparoscopy or laparotomy for other surgical procedures [3]. If on the one hand the prognosis is excellent for the only appendicular localization (5-years survival of 85 - 100%), the other is very bad in the long term in hepatic secondaries (5-years survival of 18%) [4].

Referring to the data of the literature and on the basis of 2 particular cases of carcinoid of the vermiform appendix, occasional histopathologic findings during a consecutive series of exploratory laparoscopies / laparotomies over the past 2 years, where 320 appendectomies were performed (incidence rate equal to 0, 62%), the Authors wanted to report the clinical features and the surgical treatment of these tumours.

Case report

Case 1

A 36 years old female has come to our observation for acute abdominal pain, vomiting and diarrhea. The personal history is found to suit except for previous episodes of abdominal pain, no specific to spontaneous resolution was seen, symptoms were particularly localized to the lower quadrants; and the patient had never been subjected to any surgery or had any history of previous treatment. After necessary investigations, the patient was subjected to an exploratory laparoscopy -. The exploration of the peritoneal cavity revealed a pelvic peritonitis, the presence of a corpus luteum cystic of 3 cm in the right ovary, the latter displaced cranially in the right iliac lodge (with retroperitoneal atrophic tube and dead-end), of a corpus luteum cystic in the left micropolycystic ovary and of a consensual appendiceal; peritoneal cavity toilet, ovarian diathermy, to the right salpingectomy, the right ovarian biopsy and the appendectomy was carried out. The subsequent histopathological - immunohistochemical examination showed a scleroatrophy of the right fallopian tube and a not-pathological right ovarian stroma, and a sclerohypotrophical appendiceal with the appendicular bottom affected by one microfocus of classic carcinoid (surgical margins were free).

The postoperative course war regular and the patient were discharged on the fifth postoperative day.

Case 2

A 26 year old female has come to our observation for acute abdominal pain. The personal history was found to suit, the patient had never been subjected to any surgery and not taking home therapy. After necessary investigations the patient was posted for an exploratory laparoscopy. The exploration of the peritoneal cavity revealed a sero-purulent peritonitis in the presence of a phlegmonous acute appendicitis; peritoneal toilet and appendicectomy was carried out. The subsequent histopathological - immunohistochemical examination showed an acute phlegmonous appendicitis with consensual acute peritonitis with the appendicular bottom affected by a classic carcinoid of 2 mm (surgical margins are found free).

The postoperative course was regular and the patient was discharged on the third postoperative day.

Discussion

Clinical considerations

The classic carcinoids of the appendix are rare well-differentiated neuroendocrine tumors, with a low proliferation index and are slow-growing, progressive and irreversible. They originate from the enterochromaffin cells present in the crypts of Lieberkuhn in the foil own of the mucous membrane (90% of the cases), called of Kulchitsky, ectodermal derivation of the neural crest; in fact, they have biochemical and ultrastructural features, typical of the APUD-system, deputy to the decarboxylation of aminical precursors [1].

This type of carcinoid occurs mainly in the apex - appendicular top (75%), and less frequently in the middle third – body (15%) or the proximal third – appendicular base (10%), as the subepithelial neuroendocrine cells, from which originates carcinoids, are most numerous in the distal third, increasing density in connection with the age until around 30 years and decreasing until low levels [2].

Appendicular carcinoid is mostly non secretory and due to their asymptomatic presentation and slow evolution it is difficult to diagnose preoperatively. It may have a non-specific symptom, varied and of ambiguous interpretation (vague abdominal pain or cramps, dyspepsia, vomiting, irregular habit, anorexia, weight loss, bloating, borborygmi); sometimes, chronic pain is felt in the right iliac fossa which, however, can be significant in appendicular carcinoid of partial and intermittent obstruction, clinically is not the symptom of distinction between a carcinoid and a ‘normal’ appendicopathy. Tumor can occur with a clinical picture of acute abdomen, and in this circumstance is possible to see the evolution in phlegmon or gangrene, perforation, mass - effect and, in more heavy forms, the obstruction by marked reduction in the caecum lumen (with superimposed inflammation - edematous process of a infiltrating lesion), the mesenteric fibrosis or the ischemia secondary to the mesenteric vascular involvement [3]. The multicentric variant, however infrequent, is now considered ‘intramural metastasis’, while the synchronous or metachronous co-existence of malignant tumors with different isotypes (second malignancy in gastrointestinal, pulmonary or utero-ovarian seat) reflects the potential of bioactive agents (growth factors) secreted of these lesions by cells which are ‘susceptible’ of neoplastic transformation [2, 4].

By contrast, the infrequent appendicular carcinoid functioning, expression of hepatic metastasis of tumour size greater than 2cm, can occur with sudden and episodical crises typical of carcinoid syndrome, which characterizes the triad cutaneous flushing (90%), with or without sweating (wet or dry flush), diarrhea (70%) and valvular heart disease (>30%) with steno-insufficiency by fibrosis (fibroblastic reaction); it may be associated to avitaminosis, wheezing (15%), paroxysmal hypotension or telangiectasis (25%), to the most advanced forms of cancer cachexia. Physiopathologically, this paraneoplastic syndrome is in relation to the significant secretion of serotonin (5-hydroxytryptamine or 5-HT for the intracellular conversion of tryptophan to 5-hydroxytryptophan or 5HTP), to the bradykinin or of other vasoactive substances by the carcinoid, which increases precisely the blood concentration of serotonin and as result the secretion of 5-hydroxyindolacetic (5-HIAA), its catabolite urinary. Theoretically, no general effect of serotonin appears if there are no localizations liver, while the effect becomes evident if the impaired function of the metastatic liver, as well as in advanced stage of necrosis of hepatic metastatic nodules, does not allow the metabolization and the inactivation. Sometimes, the symptomatology is favored by triggering factors for accumulation of amines in the body, as in the case of stress, the introduction of food based on tyramine, which stimulates the production of catecholamines (alcohol, red wine, fermented cheeses, pineapple, banana, chocolate, mushrooms, aubergine, nuts, fish, preserved meats, tomatoes, prunes, soy sauce) or the use of certain medicinal drugs (salicylates drug and psycho-drugs antidepressants) [1].

Surgical considerations

Generally, the criteria that orient towards a lesser or a greater surgical approach are represented by the size of the tumor and from the seat, by the infiltration of the serosa and/or the appendicular mesentery, by the loco-regional lymph node involvement and the presence of metastases; in particular, the tumor size affects both the surgical strategy, both on prognosis [5,6].

Based on the evidence, is enough the simply appendectomy if the tumor has a dimension less than 1 cm (70 – 90%), since there is no tendency of the little tumor to metastasize, where the calculated risk of metastatic spread equals virtual zero [7]. If the tumor has a size between 1 and 2 cm (4 – 25%) the indication for resection (simple appendectomy vs. right ileo-colic resection) is subject to the valuation of each single case by a significant increase of the risk of metastases (< 20%) especially lymphonodal, it means more greater resections with oncological criteria of radicality (lymphadenectomy of the right colic artery and of the middle colic) in case of transmural parietal invasion or infiltration of the mesenteric fat [3]. If the tumor’s size is greater than 2 cm (< 4%), or with an extension at the appendicular base or to the lymphovascular or mesoappendicular district, becomes necessary the right ileo-colic resection with oncological criteria of radicality for an increased loco-regional metastatic spread or distant (20 - 85%) (4); the same criterion is applied in the process of positive resection margins and in tumors with specific histological features (medium and high grade, pleomorphism and mixed histology goblet type and adenocarcinoids) [8,9].

A separate variant is represented by a very rare carcinoid with goblet cells, which is different for a natural, aggressive and unpredictable history. The recommendations are inclined to a more extensive surgery both of the biological unpredictability of the tumor, both for the late local recurrences, liver and lung metastases; compared to the classic carcinoid, the tumor with globet cells is associated with a worst prognosis (5-years survival equal to 73 – 83%) [2-4]. In this regard, the immunohistochemical markers, with the aim of predicting the metastatic potential, show that a high index of tumoral proliferation correlates with an aggressive biological behavior, it means carcinoids with high mitotic index (> 20) and high positivity Ki67 (> 20%) must be considered potentially aggressive.

As regards the treatment of hepatic metastases, while the cytoreductive surgery of the liver (as lobectomy, metastasectomy, ablation with radiofrequency or microwave) becomes rarely curative, it may also have positive effect both on the survival in the short term, both on the temporary improvement of symptoms; with the same effects, plus the option of resection, if allowed, in the tumors increased in size it is possible to adopt the embolization of the hepatic artery [5]. The mesenteric dissection, with positive influence on symptoms and survival, is performed in selected patients and after careful preoperative evaluation, including the timing and the extension of the resection. The possibility of a liver transplant for those selected patients (low grading and low mitotic index) requires the absence of evidence of the extrahepatic disease [3]. Preoperatively the electrolyte and nutritional deficits need to be corrected, and a premedication with subcutaneous octreotide (250-500 mcg) or continuous infusion during more procedures (50-500 mcg/h) is given.

A special mention for medical therapy which uses mostly symptomatic medicines for manifestations of the vasoactive syndrome if present. The most widely used in the octreotide (or lanreotide in Europe), somatostatin analogues, and potent inhibitors of the hormonal secretion (serotonin) of the carcinoidal cells; this medicine can also be applied in the advanced stages of disease or in rare cases of recurrence or of metastases. The octreotide has proven effective in improving symptoms in 85% of patients and stable disease in 50% of cases, with effective ability to delay the progression. In the same way, the interferon allows the remission of the symptoms and the disease stabilization, as somatostatin analogues, but with a delayed response. If indicated, symptomatic medical therapy uses more drug combinations such as antihistamines, pancreatic enzymes or niacin [5].

Follow up

The small appendicular carcinoid presents usually no risk of recurrence after resection. Moreover, the follow up should provide a first revaluation with seriated examinations 3-6 months after complete resection and, subsequently, every 6-12 months for at least 7 years, in relation to the capacity of these tumors to metastasize at a distance of years. Initially, the investigations include chest x-ray (if in absence of evidence of thoracic disease), the blood exams (dose 5-HIAA and chromogranin A) and abdominal sonography; the study of CT and abdominal-pelvic MRI (such as targeted biopsy or selective hepatic arteriography), or scintigraphy with octreotide are performed when clinically indicated [3].

The laboratory tests include the dosage in whole blood of 5-HT (plasma and platelet level) and of 5-HIAA (specificity equal to 88%), the latter significant if > 100 mmol of 24-hours urine in absence of substances that may alter the utility of the test (feed and pharmacological restriction). If in the early phase of the disease specific determinations may have little diagnostic value, even in those forms with minimal neuroendocrine activity, during the disease’s progression their dosage becomes a useful parameter for monitoring; in this regard, after surgical resection, the urinary values of 5-HIAA, if high, tend to normalize in a longer or shorter time, or the level of urinary catabolite may remain high, even without that there is a correlation with a set of symptoms [1, 5]. More specific markers are the neuron-specific enolase, the chromogranin A, B and C, the pancreostatin, the substance P, the neurotensin, the neurokinin A and the pancreatic polipeptide. Among these, the chromogranin A, a glycoprotein secreted by neuroendocrine tumors, is an additional factor, also expressed in the clinically silent forms, or useful in the follow up and early diagnosis of recurrences (sensitivity and specificity between 70 – 100%), where his plasma level is mostly related to the extension of the disease; the marker may be common to other non-carcinoid tumors (microcytoma), or in patients receiving proton pump inhibitors, or in those suffering from hepato-renal diseases [4].

Generally, the sonography, the CT multiphase scan, the MRI (in patients with allergy to iodinated contrast method or with renal failure) and the PET are mainly used in the initial valuation of the disease’s extension, in the surveillance after complete resection, during the stability periods of the disease, in patients with advanced disease or in assessing of the treatment’s response. In particular they are indicated for the detection of enlarged lymph nodes, fibrosis of the mesentery and in the valuation of the retroperitoneum (CT), and for small metastatic liver imaging (MRI); the PET often does not produce additional information on the extension of the disease, as the carcinoid has almost a low proliferative activity. Many Authors argue that the first-line investigation is represented by the diagnostic of nuclear medicine (Octreoscan), scintigraphy with a synthetic analogue of somatostatin (octreotide labeled with indium 111), in order to obtain a correct staging prognosis, even with an identification of residual extra-abdominal and extra-hepatic lesions, obtaining key information about location, but not details on size. Its accuracy (sensitivity up to 90%) is ‘exploited’ also preoperatively, it means suggested in the course of increased levels of 5-HIAA, as selectively capable to identify the receptors for the somatostatin present in the carcinoid, even in the initial phase [3].

Conclusions

Classics appendicular carcinoids fall into a class of tumors characterized by the direct effects of the tumor on the section involved, manifesting itself mostly with subtle symptoms; rarely do they have characteristics more or less typical of the vasoactive syndrome, expression of advanced metastatic tumor.

The excellent survival rate at 5 years, and therefore the early diagnosis, is to refer to the involved anatomical site and to the frequency of procedures performed on that seat; the prevalence of these cancers in young patient is to be sought in the fact that precisely these patients are more ‘easily’ subjected to appendectomy for an appendiceal pathology, as well as for the increase of exploratory laparoscopy procedures (and appendectomy) for a pelvic pathology in women, which increases the incidence, allowing an increase in ‘accidental’ diagnosis and therefore also of the carcinoid.

The multidisciplinary approach is the basis of a correct management which includes the valuation of the primary tumor, the staging, the treatment plan and the follow up.

The surgical therapy is often the only potentially curative approach for this kind of tumors. In those patients with non-functioning and small tumors, in absence of lympho-vascular and mesoappendicular infiltration, the simple appendectomy is most often curative, while the extended resection (right hemicolectomy) must be considered on the basis of different variables such as the evidence of infiltration of the appendiceal base or of the lymph-vascular or mesoappendicular district, in carcinoids bigger as 2cm (or tumors where the size cannot be determined), in incomplete tumor resection, and during special histological features (medium and high grade, pleomorphism and mixed histology). The right hemicolectomy by laparoscopy is the gold standard in the young patient.

The prognosis depends on the stage of the disease (tumor size, degree of infiltration, angiolymphatic invasion, overcoming of subserosa, involvement of the mesentery and of the regional lymph nodes and metastases). Response to the therapeutic strategy depends on the age and to the co-morbity; the size of the tumor is the most important prognostic indicator of metastatic potential.

In advanced disease, if on the one hand the treatment is indicated in those cases where the tumor may be reasonably eradicated (R0), the therapy directed to the liver and that of debulking, in selected and symptomatic patients, allows an increase of the survival in short term, a greater control of symptoms, a reduction of severe complications related to the permanence of the primary tumor, and therefore an improvement in the quality of life.

For what concerns the medical therapy, often the best option is the utilization of the octreotide while, in cases of disease progression, the addition of interferon may be considered as a possible alternative; the adjuvant chemotherapy, or other classes of inhibitors such as monoclonal antibodies, have not shown significant efficacy for survival, usually considered for those patients “rebels” to the traditional treatment options.

Finally, despite the need for further studies, from the data of recent literature emerging indications for a conservative and ‘less aggressive’ approach in selected patients (especially in children); in the presence of an appendicular tumor of size greater than 2cm, in correlation to intrinsic and general characteristics (rarely relapsed and infrequently metastatic), the simple appendectomy, the clinical observation and the biohumoral dosage should represent a possible alternative to the extended surgical approach.

Authors' Contribution

ZW: Conducted the study, did the literature search and prepared the manuscript.
DL: Literature review and prepared the manuscript.
AI: Helped in contributed to preparation of manuscript.
PR: Literature review and prepared the manuscript.
CA: Helped in contributed to preparation of manuscript.
CL: Revision of the manuscript for publication.
All authors have seen the final manuscript and approve its publication.

Conflict of Interests

The authors declare that there are no conflicts of interests.

Ethical Considerations

A informed consent was obtained from the patient for publication of this case report

References

[1]. Zuccon W, D’Angelo C, Giorgetta C, Tagliabue F, Balduzzi V, Bonandrini L. A rare case of ileal carcinoid tumour: clinical consideration and treatment. Ann Ital Chir 2007; 78: 311-14. [Pubmed].

[2]. O’Donnell M, Carson J, Garstin W. Surgical treatment of malignant carcinoid tumours of the appendix. Int J Clin Pract 2007; 61: 431-37. [Pubmed].

[3]. Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix and cecum. Pancreas 2010; 39: 753-66. [Pubmed].

[4]. Guraya Y, Khairy G, Ghallab A, Al Saigh A. Carcinoid tumors of the appendix. Our experience in a University Hospital. Saudi Med J 2005; 26: 434-37.

[5]. Modlin IM, Lye KD, Kidd M. A 5 decade analysis of 13.715 carcinoid tumors. American Cancer Society 2003; 934-58. [Pubmed].

[6]. Wheeler MH, Maddox P, Maddineni S, Jordan S, Amer K, Butchart E. Surgical treatment of carcinoid tumours. Przegl Lek 2000; Suppl 5: 95-7. [Pubmed].

[7]. Goede AC, Caplin ME, Wislet MC. Carcinoid tumour of the appendix. Br J Surg 2003; 90: 1317-22. [Pubmed].

[8]. Fornaro R, Frascio M, Sticchi C, De Salvo L, Stabilini C, Mandolfino F, Ricci B, Gianetta E. Appendectomy or right hemicolectomy in the treatment of appendiceal carcinoid tumors?. Tumori 2007; 93: 587-90. [Pubmed].

[9]. Varisco B, McAlvin B, Dias J, Franga D. Adenocarcinoid of the appendix: is right hemicolectomy necessary? A metanalysis of retrospective chart review. Am Surg 2004; 90 : 593-9. [Pubmed].