In this section we discuss oncologic entities of the lower gastrointestinal (GI) tract, comprising the appendix, colon, rectum, and anus, which are less frequently encountered in surgical practice. These pathologies are distinct tumors that are related only by their common location in the lower GI tract and the infrequency of their occurrence. The lower GI tract tumors to be discussed, in descending order of frequency, include anal melanomas, carcinoids, gastrointestinal stromal tumors (GISTs) and other sarcomas, and retrorectal tumors. Owing to the rarity of these tumors, exact incidences are difficult to determine. The incidence of anorectal melanoma is estimated at 1.7 cases per 100,000 population per year based on a review of cancer registries in the United States.¹ There are approximately five new cases of carcinoids diagnosed per year for every 100,000 individuals in the United States. Twenty-five percent of these occur in the lower GI tract (5% in the appendix, 5% to 7% in the colon, and 14% in the rectum), for an estimated incidence of 1.25 per 100,000 per year.² The overall incidence of GISTs is estimated at 1 to 2 per 100,000, with only about 5% in the lower GI tract.³ The incidence of colonic sarcomas has been reported at 0.04 per 100,000 per year, with appendiceal and rectal sarcomas also being incidentally reported.⁴ Retrorectal tumors are so rare that an overall incidence has not been determined; however, it is reported that between one and six patients are diagnosed annually at major referral centers.^5,6 Though all of these lower GI tract tumors are rare, a thorough understanding of their management, as well as a high clinical suspicion for the diagnoses in the correct clinical setting, is essential for the surgical oncologist.

Background

Anal melanoma is a rare subset of mucosal melanoma which represents only 1% to 2% of lower GI tumors, only 1% to 2% of melanomas overall, and fewer than 25% of all mucosal melanomas.^7–9 One-third of anorectal melanomas arise in the anal canal, 42% occur in the rectum, and the remainder are considered to have an indeterminate site of origin.¹⁰ Anal melanoma disease was first described in 1857 by W.D. Moore in the case of a 65-year-old man.¹¹ It remains a disease primarily of the elderly, with a mean age of diagnosis of 60 to 70 years and a female predominance.^10,12–15 HIV infection is a likely risk factor and perineural invasion has been shown to be an independently poor prognostic indicator.^16,17

Varying histologic subtypes of this disease were described in a study out of Memorial Sloan Kettering Cancer Center, which described 62 consecutive patients with anorectal melanoma treated at their institution from 1984 to 2003. They described 44% as being of an epithelioid subtype, 31% mixed type, and 25% classified as spindle cell melanoma.¹⁶ Mucosal melanomas such as anorectal melanomas have proved to be distinct from cutaneous melanomas, with important molecular differences.¹⁸ One of the primary differences is the incidence of BRAF mutations, which occur frequently in cutaneous melanomas and represent a target for systemic therapies such as the small molecule inhibitor vemurafenib. As anorectal melanomas arise in the setting of very little exposure to ultraviolet light, the incidence of BRAF mutations is much lower. Instead, mutation and dysregulation of c-kit, a transmembrane tyrosine kinase receptor, are often observed, suggesting that kinase inhibitors such as imatinib may be of therapeutic benefit.⁹ An appreciation of these molecular differences is essential in developing and recommending systemic therapies, which may provide a survival benefit to patients with this extremely lethal disease.

Clinical Presentation and Diagnosis

The most common presenting symptom of anal melanoma is bleeding, followed by pruritus, a change in bowel habits, tenesmus, pain, and sensation of a mass.^7,14 Diagnosis is often delayed, as over half of anal melanomas are initially mistaken for benign pathologies such as fissures, hemorrhoids, or dermatitis.¹⁹ In contrast to cutaneous melanomas, a large proportion of anal melanomas (up to 87%) are amelanotic, which can confuse the diagnosis.¹⁴ Endoscopy is used to visualize and biopsy anal melanomas for a tissue diagnosis, whereas endoluminal ultrasound and magnetic resonance imaging (MRI) are both useful adjuncts to determine the depth of tumor invasion and nodal status.⁷

A staging system for anal melanoma is not universally agreed upon. A TNM classification system is not described, and the American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma cannot be applied to those that arise from mucosal locations. An alternative is a three-level staging system first put forth by Alando J. Ballantyne in 1970, in the setting of malignant mucosal melanoma of the head and neck.²⁰ In the setting of anorectal melanoma, stage I tumors are limited to the bowel wall or anal skin, stage II disease involves regional lymph nodes, and stage III disease extends beyond surgical resection margins.¹⁴ Studies have demonstrated correlation of this staging system and survival, with a 5-year survival of 24% for stage I disease and 0% for stage II and III disease.¹⁵ It has been reported that 20% to 44% of anal melanomas are lymph node positive at the time of presentation.^7,21

Management and Outcomes

Anal melanoma represents an extremely aggressive disease with dismal outcomes. A 5-year disease-specific survival rate of 35% has been reported, with decreased survival in the setting of spread beyond local disease.¹⁶ A review of the SEER database from 1973 to 2001 reported a median survival of 34 months for patients with local disease, 13 months for those with regional spread, and 10 months for those with distant disease, and 5-year survivals of 32% for local disease, 17% for regional disease, and 0% for distant disease.¹²

If curative surgery of anal melanoma can be achieved, it offers the best chance for long-term survival. The traditional surgical treatment has been abdominoperineal resection (APR); however, this has changed over time as equivalent survival has been demonstrated after wide local excision (WLE). Therefore, the current recommendation is that APR should be reserved for patients in whom WLE by a transanal approach is not technically feasible.^15,16,22 It is of paramount importance that every effort be made to achieve an R0 resection, as patients who undergo resection with clear margins have demonstrated significantly better 5-year survival than those with involved margins on surgical pathology (19 vs. 6%, p < 0.001).²³ The optimal surgical margins for anal melanoma remain a topic of debate. Proposed guidelines suggest that the extent of the resection and the surgical margins can be calibrated based on the depth of tumor invasion, as with cutaneous melanoma. Thus, tumors less than 1 mm in thickness undergoing resection with 1 to 2 cm margins, tumors 1 to 4 mm in thickness undergoing resection with 2 cm margins, and tumors >4 mm in thickness undergoing resection via APR.²⁴

The management of lymph node spread remains controversial. If lymph node positivity is apparent on physical exam or on cross-sectional imaging at the time of presentation, then regional lymphadenectomy via an ilioinguinal lymph node dissection should be performed. However, if there is no evidence of lymph node metastasis, then it is reasonable to perform a sentinel lymph node biopsy (SNLB) in addition to WLE.¹⁴ It is important to bear in mind that there is no established pattern of typical lymph node drainage from anal melanomas, with the spread to the deep iliac, mesorectal, and presacral spaces all occurring.⁷

The role of adjuvant therapy is yet another area of debate. A report from the University of Texas M.D. Anderson Cancer Center describes a multimodal treatment strategy of sphincter-sparing surgical resection in combination with a hypofractionated adjuvant radiation regimen that provides locoregional control while avoiding the morbidity of an APR. Additional studies have examined the inclusion of the inguinal lymph node basins in the radiation therapy field as well; however, this has demonstrated an increased risk of lymphedema without a demonstrated survival benefit.^25,26 A number of systemic therapies demonstrate a clear survival benefit in cutaneous melanoma, including interleukin-2 (IL-2), dacarbazine, the IgG1 antibody targeting cytotoxic T lymphocyte–associated antigen 4 known as ipilimumab, the BRAF-targeting small molecule inhibitor vemurafenib, and various immunotherapy strategies including tumor-infiltrating lymphocytes and T-cell receptor and chimeric antigen receptor-based therapies. The utility of these therapies in mucosal melanomas, such as anorectal melanoma, remains to be proven.^17,27

Background

Carcinoids are rare, well-differentiated neuroendocrine tumors that can occur throughout the body. The majority of carcinoids are found within the GI tract (55%).^28,29 Although uncommon, they are the most frequently occurring neuroendocrine tumors of the GI tract. Over the past few decades (1973 to 1997), the small intestine has been shown to be the most common site of carcinoids within the GI tract (45%), followed by rectum (20%), appendix (17%), colon (11%), and stomach (7%). The incidence of carcinoids, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database, is approximately 2.5 per 100,000 population per year for white individuals (2.47 for men and 2.58 for women), with a slightly higher incidence in the black population (4.48 and 3.98 per 100,000 population per year for men and women, respectively).³⁰ It is primarily a disease of middle age, with a reported average age at diagnosis of 60.9 years.²⁸ The incidence has increased at a rate of 3% to 10% over the past three decades, though whether this is due to an actual increase in disease versus an increase in diagnosis owing to more sensitive imaging and diagnostic tools remains debatable.^28,31

Carcinoids were first described in the literature in 1867 by Theodor Langhans, and first described as carcinoma in 1888 by Otto Lubarsch.^32,33 Though characterized as carcinoma, they tend to behave in a more benign manner, with a more indolent clinical course than other malignancies of the lower GI tract—an observation first made by Siegfried Oberndorfer in 1907.³⁴ Like other neuroendocrine tumors, carcinoids arise from the enterochromaffin cells, also known as Kulchitsky cells, found in the crypts of Lieberkuhn throughout the GI tract.³⁵ The hallmark of these cells is membrane-bound secretory granules which contain hormones and bioactive substances, including gastrin, glucagon, adrenocorticotrophic hormone (ACTH), histamine, vasoactive intestinal peptide (VIP), dopamine, norepinephrine and, most commonly, serotonin.³⁶

Clinical Presentation and Diagnosis

The majority of lower GI tract carcinoids are discovered on imaging or during lower endoscopy, either as an incidental finding or during the workup of vague abdominal symptoms.³⁵ When symptoms do arise, they can be attributable to a mass effect, to a desmoplastic reaction, or to the effects of biologically active substances secreted by the tumor. Tumors occurring in the ileum are typically asymptomatic until they reach approximately 1 cm in diameter, and these small tumors are discovered either incidentally or in the workup of known liver metastases. Patients with ileal tumors greater than 1 cm in size typically have a long-standing history of intermittent abdominal pain, which is often misdiagnosed.³⁷ Appendiceal carcinoids are often diagnosed at the time of pathologic examination after appendectomy for presumed appendicitis. Colonic carcinoids most often arise in the cecum and ascending colon; due to the larger diameter of the right colon, they tend to remain asymptomatic until late in the clinical course. Up to two-thirds of patients with colonic carcinoids are metastatic at the time of diagnosis, which often occurs when symptoms such as obstruction, bleeding, pain, or anorexia finally manifest.³⁵ Because most rectal carcinoids are small and submucosal, they tend to be asymptomatic and discovered incidentally during colonoscopy. If symptomatic, they tend to manifest with rectal bleeding, pelvic discomfort, or a noted change in bowel movements.³⁵

In 2010 the World Health Organization published updated guidelines for the classification of GI neuroendocrine tumors. Tumors are classified based on grade as G1, G2, or G3, a categorization that is determined according to proliferation, based on the Ki-67 index, and the mitotic count. G1 tumors exhibit a Ki-67 index of less than or equal to 2% and a mitotic count of less than 2 per 10 high-powered field (HPF). G2 tumors have a Ki-67 index of 3% to 20% and a mitotic count of 2-20/10 HPF, and G3 tumors have a Ki-67 index of greater than 20% and a mitotic count of more than 20/10 HPF. G1 and G2 tumors are classified as well-differentiated tumors, also known as carcinoids, whereas G3 tumors—frequently small cell type and less often large cell type neuroendocrine tumors—are poorly differentiated and highly aggressive, and portend a poor prognosis.^35,38 The WHO 2010 classification also includes T staging based on tumor size and local invasion. T1a tumors are less than 1 cm and do not invade the muscularis propria, T1b tumors are 1 to 2 cm and do not invade the muscularis propria, and T2 tumors are greater than 2 cm and invade the muscularis propria.³⁸ Studies have demonstrated the validity of this classification in predicting the aggressiveness of neuroendocrine tumors that arise in the lower GI tract.³⁸

Imaging, both cross-sectional (CT and MRI) and somatostatin receptor-based (OctreoScan and PET), is utilized in the workup of lower GI tract carcinoids.³⁵ The measurement of plasma chromogranin A is the most sensitive marker for neuroendocrine tumors and the most useful diagnostic test.³⁹ The 24-hour measurement of urinary 5-hydroxyindole-3-acetic acid (5-HIAA), a degradation product of serotonin, is also useful and demonstrates 88% specificity as a marker for neuroendocrine tumors.^29,39 Both 5-HIAA and plasma chromogranin A have demonstrated prognostic value, with high levels correlating with poorer prognosis.⁴⁰ The diagnosis of carcinoid is definitively made by either positive immunohistochemical staining for neuroendocrine markers on histology or by electron microscopy visualization of secretory granules in the cell membrane and dense-core granules in the cytoplasm.²⁹

Carcinoid syndrome represents a distinct clinical entity that is rarely seen with lower GI carcinoids, as it is almost exclusively associated with midgut carcinoids occurring in the ileum and jejunum. The syndrome manifests secondary to the systemic circulation of serotonin, and classically includes diarrhea, cutaneous flushing, bronchoconstriction, and right-sided valvular heart disease with subsequent heart failure. Flushing is the most common symptom, occurring in up to 94% of patients, followed by diarrhea, which occurs in about 80% of patients, and carcinoid heart disease, which occurs in approximately 40% of patients. Rarer symptoms include intermittent bronchial obstruction and pellagra.^37,39 Serotonin is synthesized from tryptophan by enterochromaffin cells and is the most common biologically active substance excreted by carcinoid tumors.²⁹ Carcinoid syndrome most often occurs in the setting of metastatic spread to the liver.³⁵

Management and Outcomes

Clinically, carcinoids tend to be indolent, slow-growing, and rarely aggressive in comparison with other lower GI tumors such as adenocarcinomas. The mainstay of carcinoid treatment is surgical resection and efforts should be made to resect all primary disease.³⁵ If the disease is not amenable to total resection, debulking should still be undertaken as it has demonstrated therapeutic benefits, and combined treatment modalities should be employed, including hepatic chemoembolization for the treatment of liver metastases and medical therapy.^29,35 The extent of recommended surgical resection of a carcinoid primary tumor depends on tumor location. Ninety percent of appendiceal carcinoids occur at the tip of the appendix, and it has been shown that tumors less than 2 cm in size are unlikely to metastasize. Therefore, tumors that are less than 2 cm in size, and without invasion into lymph nodes or the mesentery, are adequately treated with appendectomy; however, for tumors measuring more than 2 cm or demonstrating local invasion, an oncologic resection of the right colon should be undertaken.^29,35,41 As previously mentioned, colonic carcinoids tend to present late as large masses, with over half (55%) exhibiting metastatic spread at the time of diagnosis.⁴² Surgical resection of the hemicolon along with a total mesocolic excision is recommended for all colonic carcinoids in accordance with oncologic principles established for colonic adenocarcinomas.^29,35,41

In contrast to colonic carcinoids, rectal carcinoids tend to be small (<2 cm) at diagnosis and rarely metastasize. Therefore, for a tumor of that size, resection with negative margins is considered adequate. Resection can be performed either endoscopically or surgically. A transanal approach is the most common. For larger tumors (≥2 cm) that invade lymph nodes or the muscularis propria, surgical resection along the same guidelines as rectal adenocarcinoma is recommended: either low anterior resection (LAR) or abdominoperineal resection (APR), depending on tumor location. Unlike rectal adenocarcinoma, however, there is no role for neoadjuvant chemoradiation in the treatment of rectal carcinoids.^41,43,44

In the setting of metastatic disease, multiple treatment modalities have been employed as adjuncts to surgical resection, including medical therapy with interferon-α, chemotherapy, and liver-directed therapy with radiofrequency ablation, hepatic arterial embolization, and chemoembolization. However, owing to a lack of clinical trials there is no clear consensus on a preferred approach, and furthermore no modality has demonstrated a dramatic therapeutic benefit.^29,35 Single-agent chemotherapy with doxorubicin, 5-FU, and streptozotocin shows response rates of 5% to 10%, whereas combination regimens increase response rates to only 20% to 30%.⁴⁵ Symptoms such as flushing and diarrhea can be controlled with somatostatin analogues such as octreotide; however, these medications have not demonstrated effective inhibition of tumor growth.⁴

Five-year survival rates over the past decades are best for rectal carcinoids (88%), followed by 76% for appendiceal carcinoids, 76% for small bowel carcinoids, 75% for carcinoids of the stomach, and 70% for colonic carcinoids, though survival rates vary widely depending on tumor stage at diagnosis.^28,30 For instance, the 5-year survival rate for appendiceal tumors exceeds 80% in the setting of local or regional disease, but falls to less than 10% if tumors are metastatic at the time of diagnosis.³⁰ Even after complete surgical resection, continued follow-up is recommended for a minimum of 7 years. This may consist of imaging or endoscopic surveillance as well as monitoring of serum chromogranin A and urinary 5-HIAA levels.⁴⁶

Background

Gastrointestinal stromal tumors are the most common sarcomas, accounting for 18% of all sarcomas and 1% of all intestinal neoplasms.⁴⁷ The annual age-adjusted incidence in the United States is seven cases per million, with approximately 5000 new cases per year.⁴⁸ GISTs can arise anywhere along the GI tract, but most commonly in the stomach (50% to 60%) and small intestine (30% to 35%), and less frequently in the colon and rectum (5%), esophagus (<1%), or elsewhere in the abdomen (<5%).^48,49 Given the inherent resistance to chemotherapy and radiation, GISTs are aggressive tumors, with a historical median overall survival in metastatic GIST of approximately 9 months.⁵⁰