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Primary adenocarcinoid of the appendix: an update
M. Stamatakos, Ch. Stefanaki, S. Tsaknaki, P. Safioleas, R. Iannescu, M. Safioleas (Chirurgia, 104 (4): 389-392)

Adenocarcinoid, also referred to as goblet cell carcinoid, mucinous carcinoid, microglandular carcinoma, and crypt cell carcinoma, is a pathologic entity involving gastrointestinal and many other sites, which is becoming increasingly recognized as a diagnostic consideration (1-8). The most common presentation is that of acute appendicitis. The diagnosis of appendiceal adenocarcinoma has never been made preoperatively and is frequently an incidental finding at the time of operation for unrelated conditions. The finding of adenocarcinoid (goblet cell carcinoid, mucinous carcinoid, microglandular carcinoma, or crypt cell carcinoma) is usually a clinical and pathological surprise, and the above case was characterized by several unexpected aspects involving this unusual neoplasm. The fact that the small bowel adenocarcinoid was asymptomatic at time of diagnosis, however, is a feature common to the majority of small bowel tumors. As mentioned above, a preoperative diagnosis has never been reported, and the diagnosis is rarely even suspected at the time of laparotomy (3,6-8). Because of the rarity of the disease, its natural history is poorly understood. Benefits from adjuvant radiation, chemotherapy, or a combination have not been reported. Most studies emphasize survival outcome based on procedure option. There are few data and, consequently, much debate on the appropriate management of these lesions (9). The aim of this article is to review this entity and to assess and report new data, through a review of the literature.

Neoplasms of the vermiform appendix are rare, they account for 0.4 – 1% of all gastrointestinal malignancies (10). In a review of over 2000 appendicectomy specimens, histological confirmation of appendiceal neoplasm included carcinoid (0.27 %), adenocarcinoma (0.14%), malignant mucocele (0.005 %) and lymphoma (0.005 %) (11). Most symptomatic appendiceal tumors present as appendicitis, other p esentations have also been described, but are far less common, these tumors may also be encountered unexpectedly in any acute or elective abdominal operation and the correct diagnosis is rarely made pre or intraoperatively, most of these tumors are identified only after histopathological examination of an appendicectomy specimen (some 0.7 – 1.7%) of appendicectomy specimens contain an appendiceal neoplasm (10). A slight male predominance is reported and the en age of presentation is the fifth or the sixth decade, with a range of 13 to 91 years (12-15).

Presentation-Clinical Features
Clinically most appendiceal tumors present as acute appendicitis (79.1% in one series reported (12), another report (16) described the clinical presentations of 74 patients found to have appendiceal tumors, some 49% presented as acute appendicitis, 9.5% were incidental findings, 5.4% presented as pelvic abscesses, 6.4% with gastro- intestinal symptoms, and 6.4% with bowel obstruction. Other less common presentations (1.4% each) included carcinoid syndrome, RIF (Right Iliac Fossa) mass, inflammatory bowel disease and strangulated hernia.
In our review of the literature, some other unusual presentations of appendiceal tumors have also been reported, they included spontaneous skin fistula (17) and disseminated ovarian carcinoma (18).

The diagnosis of adenocarcinoid is usually unexpected by both clinicians and pathologists. In addition to mucin positivity, immunohistochemical stain demonstrated the tumor to be positive for chromogranin, synaptophysin, serotonin, gastrin, and glucagon. Of histogenetic interest, some individual neoplastic cells appeared to be positive for both mucin and chromogranin, and this was confirmed by the electron microscopic finding of microvilli, intracytoplasmic mucin droplets, and neurosecretory granules involving the same neoplastic cells. The clinical presentation is either one of an acute appendicitis with fortuitous discovery of the tumor at pathology examination or a suspected tumor formation, often misdiagnosed as an ovarian tumor (19).

No consensus has been determined for appendiceal adenocarcinoid treatment in the world literature because of the low prevalence of this pathology, with experience based only on small series. There is still debates as to whether they should be treated by appendectomy alone, as for most carcinoids, or it right hemicolectomy is indicated as for appendiceal adenocarcinoma For patients who are found to have appendiceal neoplasm on histopathological examination, if the lesion is benign or carcinoid less than 2 cm and confined to the appendix, then appendicectomy alone is sufficient. Those who present with a perforated, though macroscopically removed, epithelial tumor should have baseline tumor markers (CEA, CA-125, CA-19-9), CT scan and colonoscopy. Depending on the stage and the grade of the tumor, the overall 5- year survival reported for adenocarcinoma of the appendix is in the region of 55 percent (10). Radiotherapy in general has no role in the treatment unless the margins are involved and like colorectal cancer, Chemotherapy is offered to patients with positive lymph nodes.
Appendiceal neoplasms are also noted to be associated with a significant incidence of synchronous and metachronous colorectal neoplasms (10). Patients with colorectal cancer have 3-5 percent risk of synchronous and 2-3 percent risk of metachronous neoplasia (20), and a recent report has observed similar incidences of synchronous and metachronous tumors of the appendix and the colon. The authors go on to suggest that because of the inability to assess the appendiceal mucosa postoperatively, the routine removal of the appendix in patients undergoing colorectal cancer resection is justified (20).
The long-term results of surgical treatment was analyzed for appendiceal adenocarcinoids. Data indicate that appendectomy alone is curative for patients presenting with small adenocarcinoids (< 1 cm) not expanding beyond the appendix and with a low mitosis rate. Otherwise, extended resection (i.e., right colectomy) should be proposed. Adenocarcinoids and goblet cell carcinoids share histologic features of both conventional carcinoids and colonic type adenocarcinomas. Its most frequent site of occurrence is the appendix. Although 40 years after its first description the histologic characteristics of this tumor have been well described its biologic behavior is still not clearly defined. Its malignant potential has been reported as between that of a carcinoid and a colonic adenocarcinoma.
Adenocarcinoid have a propensity for ovarian metastasis and peritoneal carcinomatosis. Recently, the natural history of peritoneal carcinomatosis from appendiceal adenocarcinoid has been shown to be similar to that of adenocarcinoma.
In accordance with these data, the results support the idea that appendectomy alone is associated with good results in patients with a small (< 1 cm) adenocarcinoid not expanding beyond the appendix and a low mitosis rate. By contrast, adenocarcinoids > 1 cm in size, with a mitosis count of > 2/10 HPF, and/or spreading beyond appendiceal adventitia are probably better treated with an extended resection (i.e., right colectomy in accordance with Varisco et al. Although experience with adjuvant treatment of adenocarcinoid is sparse, two recent reports have shown encouraging results for peritoneal carcinomatosis treatment: cytoreduction and intraperitoneal chemotherapy or for metastatic cases Folfox chemotherapy. Patients treated for appendiceal tumors, including carcinoids, have an increased risk of a second cancer. The high risk for developing synchronous or metachronous colorectal adeno-carcinoma in patients with adenocarcinoid is intriguing.
Patient follow-up should include an endoscopic surveillance program, coloscopy every 5 years, after appendiceal adenocarcinoid treatment (21).
Histologically,the adenocarcinoid tumor has two components, carcinoid and adenocarcinoma (1,6). The two cell populations can be distinguished by their particular morphology and specific labeling as observed in some cases (3). Prognosis is probably somewhere between that of adenocarcinoma and true carcinoid, although it is not
eworthy that, unlike carcinoid tumors, the prognosis of adenocarcinoid tumors is not related to the size of the tumor (2). These tumors appear to have a particular predisposition for developing ovarian metastasis (22). The ovarian metastasis is often the first inaugural manifestation, sometimes developing several months before the appendicular tumor, and may be the only metastatic localization. Due to this fact, it is advisable to perform wide resection with right hemicolectomy and bilateral ovariectomy. Appendiceal neoplasms could be found at any acute or elective abdominal surgery, management plan should then be based on the intraoperative findings (23). Murphy et al (10) suggested that for tumors found incidentally at operation, if the tumour was confined to the appendix, smaller than 2 cm, without evidence of mesoappendiceal involvement and not involving the base of the appendix, appendicectomy is appropriate. Any neoplasm greater than 2 cm and any involving the base of the appendix or mesoappendix should be considered for immediate right hemicolectomy for an optimal outcome.
Clinically, adenocarcinoid is a relatively indolent neoplasm not associated with carcinoid syndrome which is usually discovered in association with acute appendicitis, as was the case in 70% of patients in our series.
Moreover, no definitive staging system has been validated for appendiceal adenocarcinoid, and the value of the TNM staging system has never been tested. The malignant potential of appendiceal adenocarcinoids is evaluated similar to appendiceal carcinoids: tumor size and mitosis rate. The results of published series on surgical treatment of adeno- carcinoid are summarized in the following table.
In series, three of seven (43%) patients treated for appendiceal adenocarcinoid developed colorectal adeno-carcinoma. None of these patients had a known pathologic condition predisposing to colorectal carcinoma. Thus colonoscopic examination plays an important role in patients with incidentally discovered appendiceal adenocarcinoid; this diagnostic modality seems to be particularly indicated in patients in their sixth to eighth decades.
Complete remission during chemotherapyis exceptional, even with new drugs such as oxaliplatin or irinotecan. In a recent trial of first-line treatment for metastatic colorectal cancer, de Gramont et al had a 49.5% response rate with oxaliplatin and only 1.4% complete remission (9). However, the unusual long duration of complete remission in some patient suggests the possibility of total tumor necrosis (19).
In summary, in addition to carcinoid and adenocarcinoma, adenocarcinoid is a potentially aggressive malignant tumor of the appendix. Surgery is the treatment of choice. However, occasionally the adjuvant therapy with new anticancer drugs (LV, 5FU, Oxaliplatin), can lead to excellent therapeutic results (23).

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