37 Miscellaneous Neoplasms

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37

Miscellaneous Neoplasms

Richard Devine and Marc Brand

515

Carcinoids

Carcinoid tumors originate from enterochromaffin cells, part of the diffuse endocrine system. Thus, they are considered to belong in the neuroendocrine group of tumors.¹ They are a confusing group of tumors with a wide range of behavior.

Carcinoid tumors may be located in any of a number of locations within and outside the gastrointestinal (GI) tract, may be single or multiple, may produce a wide array of biochemical products, may produce symptoms from the biochemical products or the tumor itself, and exhibit varying degrees of biochemical and aggressive behavior relative to their location.

This section will focus on carcinoid tumors of the small bowel, appendix, colon, and rectum.

History and Terminology

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The clinical and histologic recognition of carcinoid tumors was first described in 1888 by Lubarsch. He had noted two patients with multiple small tumors of the ileum at autopsy.

The term carcinoid (“karzinoid”) was first applied to these tumors in 1907 by Oberndorfer. The term implies that these tumors are similar to carcinoma, but behave somewhat differently. Specifically, carcinoid tumors are histologically similar to carcinoma, but have a more benign clinical course. Gossett and Masson described the argentaffin-reducing properties of appendiceal carcinoids in 1914, and the tumors became known as “argentaffinomas.” The argentaffin reaction is characterized by reduction of silver salts to a black metallic silver stain.

The association between carcinoid tumors and serotonin production was first described by Lembeck in 1953. Around the same time, the first description of the carcinoid syndrome was published by Waldenstrom’s group (1954). Within a few years, Sandler and Snow first recognized a variable nature of carci- noids. They described an “atypical” gastric carcinoid which only produced a serotonin precursor and had staining and flushing patterns different from “typical” carcinoids. The

staining pattern is described as “argyrophilic,” implying that the reduction of silver salts to the black metallic silver stain occurs only in the presence of pretreatment with a reducing agent.

The amine precursor uptake and decarboxylation (APUD) abilities of these tumors were recognized by Pearse in 1969, and carcinoid tumors became known as “APUDomas.”

APUDomas, including carcinoid tumors, are now considered part of a group of tumors known as neuroendocrine tumors.

Neuroendocrine tumors are derived from the diffuse neuroendocrine system. As such, carcinoid tumors share some characteristics with melanomas, pheochromocytomas, medullary carcinoma of thyroid, and pancreatic endocrine tumors.³

Pathology

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The light microscopic appearance of carcinoid tumors is rather bland. They are composed of monotonous sheets of small round cells. The cells themselves demonstrate uniform nuclei and cytoplasm. The ultrastructural appearance of carcinoid tumors demonstrates electron-dense neurosecretory granules which contain small clear vesicles. These neurosecretory granules correspond to the synaptic vesicles found in neurons.

The staining pattern of carcinoid tumors is related to the amines and peptides they produce as well as cytoplasmic proteins they contain. Silver staining was initially used to identify these tumors. Carcinoid tumors that are capable of taking up and reducing silver stains are described as “argentaffin positive,” and this is attributed to the silver reducing ability of serotonin.

Tumors that are only capable of silver uptake, and not silver reduction, may be demonstrated by addition of an external reducing agent. These tumors are described as “argyrophilic.”

Silver staining has been supplanted by immunohistochemical stains for cytoplasmic proteins. Chromogranin, neuron- specific enolase, and synaptophysin are frequently used to identify a tumor as being a neuroendocrine tumor.

Carcinoid tumors have been described to grow in one of five histologic patterns. These histologic patterns have been

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designated as A-D⁴or I-IV,⁵with the fifth pattern in each system being a combination of several patterns. These growth patterns are described in Table 37-1.

Pathophysiology

Carcinoid tumors are known to produce at least 30 bioactive compounds.² These compounds may be amines (including serotonin and histamine), proteins (a wide variety of hor- mones and kinins), and prostaglandins. Serotonin, an amine, is the most well-known of these compounds.

Serotonin is derived from tryptophan, an essential amino acid. The production of serotonin is a two-step process:

hydroxylation of tryptophan to 5-hydroxytryptophan (5- HTP), followed by decarboxylation of 5-HTP to 5-hydrox- ytryptamine (5-HT, or serotonin). Serotonin is then stored and transported in platelets. Metabolism of serotonin occurs in the liver (monoamine oxidase) and then the kidney (aldehyde dehydrogenase) to produce 5-hydroxy-indole-acetic acid (5-HIAA) which is excreted in the urine.

Normally, less than 1% of tryptophan is converted into serotonin. The remainder is used for synthesis of proteins, niacin (vitamin B₇), and nicotinamide (vitamin B₃). Protein malnutrition, hypoproteinemia, and pellagra (vitamin B₃defi- ciency) may develop if large quantities of tryptophan are diverted to serotonin production by carcinoid tumors.

Classification

Numerous classification schemes have been devised to cate- gorize carcinoid tumors. These have been based on several features including site of origin and histologic growth pattern.

The prognosis of carcinoid tumors is somewhat related to these classifications.

Carcinoid tumors are grouped by their site of origin into foregut, midgut, and hindgut tumors. Foregut tumors originate in the thymus, respiratory tract, stomach, duodenum, pancreas, and ovaries. Midgut tumors originate in the jejunum, ileum, appendix, and proximal colon. Hindgut tumors originate in the distal colon or rectum. The histologic classification pattern has already been described (Table 37-1).

Several studies have reviewed the distribution of site of origin of carcinoid tumors. Godwin⁶reported the most frequent

sites of origin as the appendix, ileum, rectum, and bronchus (38%, 23%, 13%, 11.5%, respectively) in a series of 4349 carcinoid tumors. In another large series, Modlin and Sandor⁷ reported the most frequent sites of origin as the bronchus, ileum, rectum, and appendix (32.5%, 17.6%, 10%, 7.6%, respectively) in 5468 carcinoid tumors.

Clinical Presentation

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Carcinoid tumors may be found incidentally or may present as a result of the production of local or systemic symptoms.

Local symptoms are related to the site of origin or site of metastasis, whereas systemic symptoms are related to production of bioactive compounds.

Local Symptoms

Small bowel carcinoids may produce local symptoms of peri- odic abdominal pain, small bowel obstruction (caused by intussusception or mesenteric fibrosis and small bowel kinking), intestinal ischemia, and GI hemorrhage. Appendiceal carcinoids are often found incidentally at the time of appendectomy.

Rectal carcinoids are often found incidentally at the time of colorectal cancer screening examinations. The symptoms of rectal carcinoids, when present, are related to bleeding and change in bowel habits. Liver metastases may be the initial presentation, manifested by hepatomegaly and right upper quadrant pain.

Systemic Symptoms and the Carcinoid Syndrome

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Systemic symptoms produced by carcinoid tumors are referred to as the carcinoid syndrome. These consist of a combination of vasomotor symptoms (flushing and blood pressure changes), diarrhea, and bronchospasm. These symptoms are brought on by release of active tumor products into the circu- lation. The liver is capable of metabolizing and inactivating large quantities of tumor products. Therefore, the carcinoid syndrome occurs only in the presence of liver metastases (for GI carcinoids), or a primary carcinoid tumor located outside the portal venous system. Episodes of symptoms of the carcinoid syndrome may be precipitated by routine daily experi- ences such as emotional stress, heat, alcohol consumption, or straining at stool.

TABLE37-1. Carcinoid tumor growth patterns Sogo and Martin and

Tazawa⁴ Potet⁵ Pattern Description Frequency Prognosis

Type A Type I Insular Solid nests with peripheral palisading Most frequent pattern Favorable

B II Trabecular Ribbon-like anastomosing pattern Second-most frequent pattern Favorable

C III Glandular Tubular, acinar, or rosette pattern Least frequent pattern Poor

D IV Undifferentiated No recognizable pattern Third-most frequent pattern Poor

Mixed Mixed Any combination of Any combination of the above A +C most frequent mix Most favorable

the above A +B next most frequent Favorable

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Flushing symptoms and hypotension are thought to be caused by a variety of bioactive tumor products. These include catecholamines, histamine, tachykinins, and kallikrein. Four different patterns of flushing have been described, and each is related to a specific site of origin. Type 1 flushing is a diffuse, erythematous rash, which may last up to 5 minutes, and is associated with the early stage of metastases from midgut carcinoid tumors. Type 2 flushing is a violaceous rash with telangiectasias, which may also last up to 5 minutes, and is associated with the later stages of metastases from midgut carcinoid tumors. Type 3 and 4 flushing is associated with bronchial and gastric carcinoid tumors, respectively.

The heart may be affected by carcinoid tumor products, particularly in those patients with midgut carcinoids and liver metastases. It is thought to be caused by the effects of serotonin on the heart. Specifically, serotonin has an effect on myofibroblasts resulting in fibroplasia, increased vascular tone, bronchoconstriction, and platelet aggregation. Together, these effects may cause pulmonary hypertension, tricuspid and pulmonary valve stenosis, and right ventricular hypertro- phy and fibrosis. The left side of the heart is typically pro- tected from the effects of carcinoid products by the lungs, which are capable of inactivating these substances.

Carcinoid crisis is a life-threatening condition. It may be brought on by anesthesia, embolization or manipulation of the tumor, administration of chemotherapy, or occur sponta- neously. Life-threatening manifestations of the carcinoid crisis include profound flushing and hypotension, bronchoconstriction, arrhythmias, and hyperthermia. Other manifestations include diarrhea, confusion, and stupor. The crisis may be limited or avoided by pretreatment with somatostatin and histamine blockade (both H₁- and H₂-receptors) before treat- ments known to induce a crisis.

Diagnostic Studies

Biochemical Studies

Carcinoid tumors are often difficult to diagnose preoperatively, particularly those in the small bowel and appendix. In a study by Thompson and von Heerden,⁸less than 10% of 145 patients with GI carcinoids were accurately diagnosed before surgery, and all had carcinoid syndrome at presentation.

The diagnosis of carcinoid tumor before surgery relies on biopsy of an accessible lesion (in the foregut, hindgut, or liver), or the identification of biochemical products from the tumor. Although carcinoid tumors may produce many substances, the most widely used tests are related to serotonin.

The most widely accepted test currently used to diagnose the presence of a carcinoid tumor is a 24-hour urine specimen analyzed for 5-HIAA (a serotonin metabolite). Urinary 5-HIAA excretion under normal circumstances is between 2–8 mg/24 hours. Excretion exceeding these levels has shown high sensitivity and specificity (73% and 100%,

respectively) in diagnosing carcinoid syndrome.⁹It is impor- tant to avoid foods and medications that can produce a false- positive result by affecting urinary 5-HIAA levels. These are listed in Table 37-2.

Carcinoid tumors vary in their ability to produce serotonin.

Midgut tumors typically produce high levels of serotonin and its metabolites. Foregut tumors typically lack the ability to convert (decarboxylate) 5-HTP (5-hydroxytryptophan) into 5-HT (serotonin), resulting in low urinary levels of 5-HIAA.

However, the kidney may decarboxylate sufficient 5-HTP into 5-HT, thus increasing urinary serotonin levels. Hindgut carcinoids rarely produce 5-HTP or 5-HT, and urine and blood tests are typically negative. Platelet serotonin levels may be more sensitive than urine or blood tests. The results of three different tests in a series of 44 patients with carcinoid tumors is shown in Table 37-3.¹⁰

Imaging Studies

Localization of primary carcinoids in the GI tract is often difficult. Carcinoids in the foregut and hindgut are frequently diagnosed by endoscopy and biopsy.¹¹ However, ileal and appendiceal carcinoids are more common and less easily localized. These primary sites often remain unknown, despite small bowel contrast studies or computed tomographic (CT) scanning, until surgical exploration identifies the primary site.¹²If these studies are positive, it is usually the mesenteric kinking and fibrosis that is evident rather than the mass itself.

Contrast studies may show small bowel obstruction, extrinsic filling defects, or kinking, angulation, and separation of small bowel loops.¹¹

TABLE 37-2. Dietary and medicinal intake affecting urinary 5- HIAA^70–72

Foods rich in serotonin Medicines affecting urine 5-HIAA

Bananas Guaifenesin

Plantains Acetaminophen

Pineapples Salicylates

Plums L-Dopa

Kiwi Walnuts Hickory nuts Pecans Avocados Tomatoes

TABLE37-3. Comparison of urine and platelet biochemical studies in carcinoid patients

Platelet Urine Urine

Number 5-HT (%) 5-HIAA (%) Serotonin (%)

Foregut 14 50 29 55

Midgut 25 100 92 82

Hindgut 5 20 0 60

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Multiple newer imaging techniques have been used in an attempt to identify both the primary tumor as well as metastases. These may be categorized as morphologic and functional imaging studies. Morphologic studies include ultrasound, CT, and magnetic resonance imaging (MRI).

These studies may be useful, as they are in many types of cancers, in identifying distant metastases. In addition, CT scans may show a characteristic stellate soft-tissue stranding in the mesentery.¹³ Functional studies are based on tumor uptake and scintigraphic imaging of various isotopes. The first of these was metaiodobenzylguanidine (MIBG),¹⁴ but this has since been replaced by newer agents and techniques. The two scintigraphic imaging techniques currently in use are somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET). Both techniques rely on differential uptake of the radiotracer by the tumor relative to normal tissue. SRS relies on somatostatin receptors on the cell surface, whereas PET relies on metabolic utilization of the localizing agent. A recent study by Hoegerle et al.¹⁵compared both morphologic and functional imaging modalities in localizing primary and metastatic carcinoid tumors in 17 patients. The results are summarized in Table 37-4, and suggest that the two approaches are complementary. ¹⁸F-Dopa-PET imaging is more sensitive in localizing primary tumors and lymph node involvement, whereas CT or MRI is more sensitive in identifying distant disease.

Prognosis

The behavior and prognosis of carcinoid tumors are highly variable and are affected by multiple factors including tumor size, depth, presence and location of metastases, and primary tumor location.

The TNM staging of carcinoid tumors is similar to that of GI adenocarcinomas. T-stage is related to depth of penetra- tion, and nodal and metastatic staging are related to its absence or presence. Prognosis is affected by the TNM stage, as shown in Table 37-5. The effect of primary tumor location on prognosis (survival, likelihood of carcinoid syndrome, and additional tumors) is shown in Table 37-6.

Treatment

Tumor-directed Therapy

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The mainstay of treatment for carcinoid tumors is surgical resection. Difficulty arises in selecting the extent of surgery relative to the extent of disease, magnified by two considerations:

1) carcinoid tumors are often located in an area where “local excision” is an option (appendix, rectum), and 2) the benefit of debulking procedures. The surgical decision is based on the likelihood of residual primary disease, lymph node metastases, and the benefit of debulking the tumor burden to reduce the symptoms of the carcinoid syndrome. Guidelines for extent of surgical resection are summarized in Table 37-7.^16,17

TABLE 37-4. Morphologic and functional imaging in carcinoid tumors

PET

Tumor site ¹⁸F-Dopa ¹⁸FDG SRS CT/MRI

Primary 7/8 2/8 4/8 2/8

Lymph nodes 41/47 14/47 27/47 29/47

Distant metastases 12/37 11/37 21/37 36/37

18FDG, ¹⁸F-fluorodeoxyglucose; SRS, somatostatin receptor scintigraphy.

TABLE37-5. TNM staging and survival of GI carcinoid tumors⁷³ TNM stage Definition 5-y survival (%) Comment

T 1 Submucosa 82 Survival differences

2 Muscularis propria related to tumor

3 Subserosa depth in absence

4 Perforated or 52 of metastases

invading neighboring structure

N 0 Absent 95 Survival differences

1 Present 83 related to

presence and proximity of metastases

M 0 Absent —

1 Present 38

TABLE37-6. Effect of primary carcinoid location on prognosis¹⁶

Primary carcinoid Overall 5-y Incidence of Carcinoid Multiplicity of Second primary

location survival (%) metastases (%) syndrome carcinoid tumors (%) cancer (%)

Appendix 99 <1 cm, 0 1–1.9 cm, 11 >2 cm, 30–60 Rare 4.2 13

Small bowel Related to metastasis <1 cm, 20–30 1–2 cm, 80 LN Common 30–50 20–30

(see Table 37-4) 20 liver >2 cm, >80 LN 40–50 liver

Colon 20–52 Frequent Rare Infrequent 25–40

Rectum No mets–92 LN mets–44 <1 cm, 3 1–2 cm, 11 >2 cm, 74 Rare 0–3 7–32

Distant mets–7 LN, lymph node.

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Small bowel carcinoid tumors are frequently associated with lymph node metastases and structural abnormalities (intussusception, mesenteric fibrosis, and small bowel kinking). Lymph node metastases are common, even when the tumors are small. Lesions less than 1 cm in diameter have a 20%–30% incidence of lymph node involvement. Additio- nally, there are often multiple small bowel lesions. Therefore, surgical management involves formal resection and wide mesenteric excision of the associated region of lymph node drainage as well as thorough exploration for additional lesions.^16,17

Appendiceal carcinoids typically behave differently than small bowel carcinoids. They are frequently found during appendectomy, are less likely to have lymph node metastases (0% for lesions less than 1 cm, 11% for lesions between 1 and 1.9 cm, and 30%–60% for lesions greater than 2 cm in diameter) and multicentric disease is rare. Therefore, appendectomy is adequate treatment for lesions less than 1 cm, whereas lesions greater than 2 cm are treated by formal resection (right hemicolectomy). Treatment for intermediate-size appendiceal carcinoids (1–1.9 cm) must be individualized, balancing the risk of a more extensive surgery against the risk of residual disease. Factors that suggest an increased likelihood of residual disease, and are thus used to indicate a formal right hemicolectomy, include lymphovascular invasion, involvement of the mesoappendix (by direct extension or in lymph nodes), or a positive surgical margin.^16,17

Colonic carcinoid tumors generally behave in an aggressive manner and frequently have lymph node metastases and a poor prognosis. Therefore, they are treated with formal resection.^16,17 Rectal carcinoid tumors are minimally aggressive lesions, and behave in a manner similar to appendiceal carcinoids.

They have a similar rate of lymph node metastases and multiple lesions are uncommon. Surgical treatment also shows similarity in that local (transanal) excision is adequate for lesions less than 1 cm in diameter whereas formal proctectomy is advised for lesions larger than 2 cm in diameter.

Treatment for intermediate-size rectal carcinoids (1–1.9 cm) must be individualized, balancing the risk of a more extensive

surgery against the risk of residual disease. Muscular invasion is the factor that suggests an increased likelihood of residual disease, and is thus used to indicate a formal proctectomy.^16,17 Treatment of hepatic metastases is of significant benefit, especially when metastatic disease is confined to the liver.¹⁸ Tumor debulking may be in the form of hepatic resection, ablative therapy (cryotherapy, radiofrequency ablation), radi- olabeled octreotide, or hepatic artery embolization and chemoembolization. The expected 5-year survival rate for patients with carcinoid liver metastases is 20%. Death is often related to liver failure from local tumor progression or carcinoid heart disease. However, several studies have demonstrated a 5-year survival rate approximating 70% when these metastases are treated with a combination of the listed techniques. Similar survival rates have been achieved with the use of liver transplantation in a small number of patients.¹⁹

Systemic Therapy

Medical treatment for patients with carcinoid tumors has two purposes: palliation of systemic symptoms of the carcinoid syndrome, and treatment of metastases. The palliation of symptoms may use medications directed at specific symptoms, or medications causing a generalized reduction in hormone production. Specific agents that may help control symptoms of the carcinoid syndrome are listed in Table 37-8.

Somatostatin analogs are helpful in controlling many of the symptoms of the carcinoid syndrome by reducing synthesis and systemic release of hormone products. Octreotide is a long-acting somatostatin analog with a half-life of 90 minutes. In doses of 400 µg/day, octreotide improved the major symptoms of flushing and diarrhea in more than 80% of patients.³ Lanreotide is another somatostatin analog with a longer half-life than octreotide, and both agents are available in long-acting depot forms.

Chemotherapy has largely been ineffective in patients with metastatic carcinoid tumor.²⁰ Single agent regimens using 5-fluorouracil, streptozotocin, dacarbazine, dactinomycin, doxorubicin, etoposide, cisplatin, and carboplatin have had objective tumor response rates between 0%–30% in small series of patients. Similarly poor results have been found when combination chemotherapy has been used in the adjuvant TABLE37-7. Guidelines for extent of surgical resection

Primary tumor Factor Extent of resection

Appendix <1 cm Appendectomy

1–1.9 cm Individualize, appendectomy, or right hemicolectomy

>2 cm Right hemicolectomy Small bowel Locally limited Resection of primary

disease and metastatic tumors

Extensive disease Resection or bypass of primary tumor Debulking of metastases

Colon Colectomy

Rectum <1 cm Local excision

1–1.9 cm Individualize, local excision, or proctectomy

>2 cm Proctectomy

TABLE37-8. Medical treatment of carcinoid syndrome symptoms^2,3

Symptom Drug category Specific agents

Flushing H₂-Blockade Cimetidine, ranitidine, famotidine α1-Blockade Doxazosin, phenoxybenzamine Phenothiazine Chlorpromazine

Corticosteroid Prednisone

Diarrhea Serotonin blockade Ketanserin, ondansetron, cyproheptadine, methysergide Opiate blockade Codeine, loperamide

Bronchospasm Phenothiazine Chlorpromazine Bronchodilator Salbutamol Corticosteroid Prednisone

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setting or to treat metastatic carcinoid tumor. Interferon has been used in the treatment of metastatic carcinoid tumors with some success. Patients have experienced an objective response rate near 50%, with a duration of 2.5 years. However, interferon therapy produces significant side effects of a flu-like syndrome, fatigue, and fever which may limit its use.

GI Stromal Tumors

In the past, most spindle cell sarcomas arising from the mesenchymal elements of the GI tract were considered smooth muscle neoplasms and were considered leiomyomas, leiomyosarcomas, and leiomyoblastomas. With advances in electron microscopy and immunohistochemistry, it was dis- covered that many of these tumors lacked structural or immunophenotypic features associated with smooth muscle differentiation and the more generic term “stromal tumor”

was introduced.²¹Further advances in immunohistochemistry allowed pathologists to separate these tumors into those that are true smooth muscle tumors (leiomyomas) and those that are thought to arise from GI pacemaker cells (GI stomal tumors).

GI stromal cell tumors (GISTs) are mesenchymal tumors arising from the intestinal wall, omentum, or retroperitoneum that stain positive for the CD117 antigen, a marker for the KIT oncoprotein. Sixty to seventy percent of GISTs also stain positive for CD34, a hematopoietic progenitor cell antigen.²² Leiomyomas are stain negative for KIT and CD34 and positive for desmin or smooth muscle actin.²³

Because of structural and immunohistochemical similari- ties between GISTs and the interstitial cells of Cajal, it is thought GISTs arise from these cells or other pluripotential mesenchymal stem cells. The interstitial cells of Cajal are located in the muscle layer of the GI tract and form a complex network that regulates intestinal motility.

The stomach is the most common location of GISTs (45%–55%) with small bowel the next most common location (25%–35%). Only 10%–20% of GISTs are located in the colon and rectum. The gender distribution is close to equal in all locations.

GISTs occur throughout the colon but are most often located in the rectum. Miettinen et al.^23,24retrieved all cases coded as leiomyomas, leiomyosarcomas, smooth muscle tumors, or stromal tumors at the Armed Forces Institute of Pathology and the University of Helsinki from 1970 to 1996 for rectal tumors and 1970 to 1998 for colon tumors. The most common location was the rectum and anus (80%). Older reports of colorectal leiomyosarcomas (the majority of which were probably GISTs) also show an increased incidence in the anorectal area with about 1/3 occurring in the colon and 2/3 in the anorectal area.²⁵

The most common clinical presentation is hematochezia, abdominal or rectal pain, or a mass found incidentally on physical examination or endoscopically. As might be

expected, how patients present is largely related to the size of the tumor.^26–28

Complete surgical excision, if possible, continues to be the treatment of choice. Because GISTs rarely spread to the lym- phatic system, removal of the regional lymph nodes is not necessary or recommended.²⁹ Wide margins are not necessary, but complete en bloc removal of the tumor and its pseudocapsule should be performed. Because of high local recurrence rates, enucleation of the tumor (leaving the pseudocapsule) or cutting across tumor should be avoided.

The use of imatinib mesylate (Gleevac in the United States, Glivec in Europe, Novartis Pharmaceuticals) has significantly impacted the treatment of GISTs. The KIT oncoprotein, detected in almost all GIST tumors by positive immunohistochemical staining for the CD117 antigen, is a transmembrane receptor tyrosine kinase encoded for by the C-kit protoonco- gene.^29,30 In GIST tumors, abnormal activation of the KIT oncoprotein results from a mutation in the C-kit gene. This abnormal activation results in unregulated cellular prolifera- tion. Imatinib is a selective tyrosine kinase inhibitor and acts by blocking the abnormal activation of the KIT oncoprotein.

Demetri et al.³¹used imatinib in 147 patients with metastatic or unresectable GIST tumors. Fifty-four percent had a par- tial response with shrinkage of their tumors and 41% of the patients had stable disease. Van Oosterom et al.³²found an objective response in 70% (25 of 36 patients) of patients with KIT-positive metastatic GIST tumors.

The use of imatinib as a postoperative adjuvant to surgery is currently being investigated and patients who have a resected primary GIST should be considered for entry into a clinical trial.²⁹ Patients who present with marginally resectable or unresectable tumors should be considered for a course of preoperative imatinib. Katz et al.³⁰ reported two cases of patients with unresectable GIST tumors treated with imatinib. In both cases there was a dramatic decrease in the size of the tumors and both patients eventually had surgical excision of their tumors.

The incidence of local recurrence or metastatic disease after complete surgical excision is high. About 50% of patients with potentially curative resection will develop a recurrence.²⁹ Of 40 patients with rectal tumors reported by Yeh et al.,²⁷48% developed a recurrence or metastasis. They also found local recurrences were higher in the group that had wide local excision compared with those who had a more radial resection, such as an abdominoperineal resection or anterior resection (55% versus 24%).

Leiomyomas

Leiomyomas of the colon and rectum are usually small (less than 1 cm) nodules arising from the smooth muscle of the muscularis mucosa. They are differentiated from GISTs by staining negative for CD117 (KIT) and positive for desmin and smooth muscle actin.³³ They are almost always found

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incidentally on endoscopy or in surgical resections done for other pathology. Of 88 cases reported by Miettinen et al.,³³ 29% were in the rectum and 49% in the sigmoid colon. The leiomyomas in this series were almost all removed by snare polypectomy. There were no recurrences. Walsh and Mann³⁴ also reported a series of 26 patients who had leiomyomas arising from the muscularis mucosa. Twenty-two tumors had some sort of local excision (12 by biopsy forceps). No recurrence was noted in any of these patients. Small incidental leiomyomas found on endoscopy are benign tumors that are adequately treated by snare polypectomy alone.

Squamous and Adenosquamous Carcinoma

Squamous and adenosquamous carcinomas of the colon are thought to be variants of the same tumor.³⁵Squamous cell cancers have pure epithelial features without glandular elements;

adenosquamous cancers have both epithelial and glandular features. A review of the National Cancer Institute’s database found approximately one in 2000 cases of colorectal cancer was adenosquamous.³⁶By 1999, only 59 cases of squamous cell carcinoma and 56 cases of adenosquamous cell cancer had been published. A review of the National Cancer Institute database added 145 cases of adenosquamous cancer in 1999.

To be considered a primary colon rectal tumor, these tumors should be located proximal to the distal rectum to exclude anal canal cancers that have extended proximally.

Patients with a history of squamous cell cancer elsewhere are also excluded because of the possibility this may represent metastatic disease.

The mean age of patients in reported cases of pure squamous cell cancer is 58³⁷and 66 for a large series of patients with adenosquamous cancer. The anatomic location seems to be similar to that of adenocarcinoma with most lesions found in the proximal and distal colon and few in the middle colon (transverse and descending).^36,37

Patients tend to present with advanced disease. Cagie et al.³⁶ reviewed 145 patients with adenosquamous disease and found only 11% presented with node negative, superfi- cially invasive cancer (Astler-Coller Stage A and B). Forty- four percent had tumors with full-thickness invasion or positive lymph nodes and 40% had distant metastasis. Those patients with T₁, or T_2, N0, M0 lesions appeared to have a prognosis similar to that of patients with adenocarcinoma.

Patients with T₃lesions, positive lymph nodes, or metastatic disease have a worse prognosis.³⁶ In a combined series of squamous and adenosquamous cancer, Frizelle et al.³⁵ reported a 5-year survival rate of 86% for patients with Stage II disease and only 24% for patients with Stage III.

The primary treatment of these tumors is surgical. Because, by definition, these tumors are located in the colon or proximal to mid rectum, a segmental resection with anastomosis should be feasible. In rectal tumors, preoperative adjuvant chemoradiation should be considered. This recommendation

is based on improved control of local disease with preoperative adjuvant therapy in patients with adenocarcinoma and the good response to chemoradiation in patients with squamous cell cancer of the anus.³⁵No recommendations based on data can be made concerning postoperative adjuvant chemotherapy in patients with these tumors. The prognosis, however, is so poor in patients with nodal disease that adjuvant chemotherapy seems a reasonable option. At the very least, these patients deserve to have a consultation with an oncologist.

Lymphomas

Most primary GI lymphomas are located in the stomach or small bowel; only 6%–12% of primary GI lymphomas occur in the colon. Primary colonic lymphomas represent less than 1% of large bowel malignancies.³⁸ Approximately 70%

involve the cecum or ascending colon.^39,40The most common presenting symptoms are abdominal pain, palpable abdominal mass, hematochezia or melena, and weight loss.^39,41

Several authors use Dawson’s criteria to establish a diagnosis of primary intestinal lymphoma as opposed to generalized lymphoma secondarily involving the GI tract. Dawson’s criteria are: 1) absence of enlarged superficial lymph nodes when the patient is first seen; 2) no enlargement of mediasti- nal lymph nodes; 3) the total and differential white count are normal; 4) at laparotomy, only regional lymph nodes have metastatic disease; 5) the liver and spleen are unaffected.⁴²

The majority of lymphomas in the colon and rectum are non-Hodgkin’s lymphomas of B cell origin, diffuse large cell type. In a series of 32 patients reported by Myung et al.,⁴¹22 were of diffuse large cell type and 27 of B cell origin. Other pathologic types that occur in the colon include low-grade lymphoma tissue (MALT lymphomas), mantle cell lymphoma, and T cell lymphoma.^38,43,44

GI lymphoid tissue exists in intestinal mucosa, submucosa, and lamina propria. Low-grade B cell lymphomas arising from these specialized lymphoid tissues are referred to as MALT (mucosa-associated lymphoid tissue) tumors. MALT tumors are low-grade tumors with an indolent course and are usually located in the stomach, but cases of colonic involvement have been reported.^45–47 Currently, gastric MALT tumors are thought to arise in response to Helicobacter pylori infection and it has been shown that eradication of the H. pylori infection will lead to complete regression in the majority of cases.⁴⁸ MALT tumors in the colon are usually solitary lesions, but can also present as multiple polypoid lesions. In a series of 17 colonic MALT tumors reported by Yatabe et al.,⁴⁹ treatment consisted of endoscopic (three patients) or surgical excision (14 patients); three of the patients also had chemotherapy. There are two case reports of complete regression of a colonic MALT with either chemotherapy or treatment of a concomitant H. pylori infection.^47,50

Multiple lymphomatous polyposis is a mantle cell lymphoma that involves the GI tract. Multiple lymphomatous

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polyps can involve the GI tract from the stomach to the rectum, but can also involve the colon alone. The most common presenting symptoms are weight loss, diarrhea, abdominal pain, rectal bleeding, and anemia. On endoscopic examination, it can be confused with familial adenomatous polyposis or nodular lymphoid hyperplasia. The treatment is chemotherapy.^51,52

Treatment of localized, primary colonic lymphoma is primarily surgical excision.^40,45 Aviles et al.⁴⁵ followed surgical excision with adjuvant chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin. In 40% of their cases, epirubicin was used in place of doxorubicin. In node negative patients, their event- free survival rate at 10 years was 80%. In two other series of more advanced lesions, the 5-year survival rate was only 33%

and 39% in patients treated with both surgery and chemotherapy.^39,40

Extramedullary Plasmacytoma

The most common type of plasma cell neoplasm is multiple myeloma. Of 1272 patients with a plasma cell neoplasm seen at M.D. Anderson Cancer Center, 94% had multiple myeloma and only 2% (22 patients) had an extramedullary plasmacytoma (EMP).⁵³More than 75% of EMPs occur in the upper respiratory tract, and when they do occur in the GI tract, they are usually found in the stomach or small intestine.^53,54 Therefore, EMPs occurring in the colon are very rare and by 2004, only 22 have been reported in the English language.⁵⁵

To be considered an EMP, metastatic multiple myeloma must be excluded by evaluating the urine for Bence-Jones protein, serum electrophoresis, and bone marrow biopsy.

Pathologic diagnosis is established by histologic and immunohistochemical findings consistent with a localized collection of monoclonal plasma cells.^55,56

Hashiguchi et al.⁵⁵recently reviewed all the reported cases of colonic EMPs. Patient ages ranged from 15 to 90 with a mean of 52.3. The cecum (36.4%) and rectum (22.7%) were the most common sites involved. Treatment consisted of surgery alone in 18 cases (81.8%), radiotherapy in two cases (9%), and both surgery and radiotherapy in one case. In the 22 plasmacytoma cases report by the M.D. Anderson group, only two were in the colon. Radiation treatment alone was used in 18 of the 22 cases with good results. In seven of the 22 cases (32%), multiple myeloma developed after a median of 1.8 years, including one of the two colon cases.⁵⁶

Melanoma

Primary melanomas of the GI tract are rare and the majority are located in either the anorectal area or the esophagus.⁵⁷An electronic search of the medical literature from 1966 to 2004 found only four reports of primary colonic melanoma.^58,59

Malignant melanoma will often metastasize to the GI tract, and autopsy studies have shown malignant melanoma is one of the most common metastatic lesions to involve the GI tract.

Up to 60% of patients dying of melanoma will have metastasis to the GI tract.⁶⁰It is unusual, however, for colonic metastasis to be diagnosed while the patient is alive.

In a recent Mayo Clinic review, 2965 patients were treated between 1960 and 2000 with metastatic melanoma. Only 24 patients (0.8%) had symptoms from metastatic melanoma to the colon. The mean age at diagnosis of metastatic disease was 60.4 and the average time between diagnosis of the primary and metastasis was 8.47 years. The presenting symptoms were bleeding (50%), pain (20%), obstruction (20%), and weight loss (17%). Eighteen of the 24 had segmental resection and the 1-year survival was 37%. The 5-year survival was 21%.⁶⁰

Long-term survival from literature review of patients with isolated colonic metastasis was 58.7 months. Therefore, surgery for metastatic melanoma to the colon with either palliative or curative intent is indicated.

Colonic Complications of Leukemia

Colonic complications of leukemia may be broadly divided into two categories: complications caused by leukemic invasion of the bowel and complications caused by the profound immunocompromise, as a result of the disease and its treatment.

Leukemic infiltration of the colon is not common. In a paper by Hunter and Bjelland,⁶¹13 of 142 leukemic patients had a significant GI complication and only one had evidence of colonic infiltration. In an autopsy study, 16 of 148 patients who died of leukemia had evidence of leukemia infiltrates in the colon.⁶²

Endoscopic and radiologic findings are varied; a small localized ulceration,⁶³ diffuse polyposis,⁶⁴ a colitis-like appearance,⁶⁵ and plaque-like bowel thickening have all been described. The most common CT finding is a diffuse thickening of the bowel wall.⁶⁶

Symptoms of leukemic infiltration are nonspecific, such as abdominal pain, bloating, diarrhea, and hematochezia.⁶⁷The treatment consists of treating the underlying leukemia.

Surgery is indicated only if complications arise.

Neutropenic enterocolitis is a serious life-threatening complication of the chemotherapeutic treatment of leukemias.

Cartoni et al.⁶⁸reported a 6% incidence of neutropenic colitis in 1450 consecutive patients treated for leukemia with a mortality rate of 15%. Hogan et al.⁶⁹reported a 15% incidence of neutropenic colitis in a group of 78 patients treated for acute myelogenous leukemia. In the report by Hogan et al., the median onset of symptoms (fever, pain, diarrhea) was 10 days after the start of chemotherapy and all patients had absolute neutrophil counts of less than 0.5 ×10⁹/L. CT and ultrasound findings consist of thickening of the bowel wall in the ileocecal region. Cartoni et al. showed that detection of bowel wall

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thickening on ultrasound was associated with a worst prognosis than if no thickening was detected (a 29% mortality versus 0% mortality).

Treatment consists of bowel rest, parenteral nutrition, and broad spectrum antibiotics. Surgery should be reserved for complications such as documented evidence of bowel perfo- ration or massive bleeding.

References

1. Creutzfeldt W. Carcinoid tumors: development of our knowl- edge. World J Surg 1996;20:126–131.

2. Lips CJM, Lentjes EGWM, Hoppener JWM. The spectrum of carcinoid tumors and carcinoid syndrome. Ann Clin Biochem 2003;40:612–627.

3. Jensen RT, Doherty GM. Carcinoid tumors and the carcinoid syndrome. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer:

Principles and Practice of Oncology. 6th ed. Philadelphia:

Lippincott Williams & Wilkins; 2001:1813–1832.

4. Soga J, Tazawa K. Pathologic analysis of carcinoids: histologic reevaluation of 62 cases. Cancer 1971;28:990–998.

5. Martin ED, Potet F. Pathology of endocrine tumors of the GI tract. Clin Gastroenterol 1974;3:511–532.

6. Godwin JD. Carcinoid tumors. An analysis of 2,837 cases.

Cancer 1975;36:560.

7. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813.

8. Thompson GB, von Heerden JA. Carcinoid tumors of the gastrointestinal tract. Presentation, management, and prognosis.

Surgery 1998;98:1054.

9. Feldman JM. Carcinoid tumors and syndrome. Semin Oncol 1987;14:237.

10. Kema IP, deVries GE, Sloof MJH, Biesma B, Muskiet FAJ.

Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem 1994;40:86.

11. Thompson GB, van Heerden JA, Martin JK, et al. Carcinoid tumors of the gastrointestinal tract: presentation, management, and prognosis. Surgery 1985;98:1054.

12. Bancks NH, Goldstein HM, Dodd GD. The roentgenologic spectrum of small intestinal carcinoid tumors. Am J Roentgenol Radium Ther Nucl Med 1975;123:274–280.

13. Picus D, Glazer HS, Levitt RG, Husband JE. Computed tomography of abdominal carcinoid tumors. Am J Radiol 1984;143:

581–584.

14. Fischer M, Kamanabroo D, Sonderkamp H, Proske T. Scinti- graphic imaging of carcinoid tumors with I-131-metaiodobenzylguanidine. Lancet 1984;2:165.

15. Hoegerle S, Altehoefer C, Ghanem N, et al. Whole-body 18F- dopa PET for detection of gastrointestinal carcinoid tumors.

Radiology 2001;220(2):373–380.

16. Memon MA, Nelson H. Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 1997;40(9):1101–1118.

17. Stinner B, Kisker O, Zielke A, Rothmund M. Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum. World J Surg 1996;20:183–188.

18. Pasieka JL. Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumors. Can J Surg 2001;44(1):25–33.

19. Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors.

A 31-case French multicentric report. Ann Surg 1997;225(4):

355–364.

20. Kvols LK. Neoplasms of the diffuse endocrine system. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., eds. Cancer Medicine. 6th ed. Hamilton, ON: BC Decker; 2003:1275.

21. Fletcher CDM, Berman JJ, Corless C. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33(5):459–465.

22. Davila RE, Faigel DO. GI stromal tumors. Gastrointest Endosc 2003;58:80–87.

23. Miettinen N, Sarlomo-Rikala M, Sobin LH, Lasota J.

Gastrointestinal stromal tumors and leiomyosarcomas in the colon. A clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. Am J Surg Pathol 2000;24:

1339–1352.

24. Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus. A clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 2001;25:1121–1133.

25. Akwari OE, Dozois R, Weiland L, Beahrs OH. Leiomyosarcoma of the small and large bowel. Cancer 1978;42:1375–1384.

26. Haque S, Dean PJ. Stromal neoplasms of the rectum and anal canal. Hum Pathol 1992;23:762–768.

27. Yeh C, Chen H, Tang R, Tasi W, Lin P, Wang J. Surgical outcome after curative resection of rectal leiomyosarcoma. Dis Colon Rectum 2000;43:1517–1521.

28. Tworek JA, Goldblum JR, Weiss SW, Greenson JK, Appelman HD. Stromal tumors of the anorectum. A clinicopathologic study of 22 cases. Am J Surg Pathol 1999;23:946–954.

29. Eisenberg BL, Judson I. Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. Ann Surg Oncol 2004;11:465–475.

30. Katz D, Segal A, Alberton Y, et al. Neoadjuvant imatinib for unresectable gastrointestinal stromal tumor. Anticancer Drugs 2004;15:599–602.

31. Demetri GD, Von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–480.

32. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumors: a phase 1 study. Lancet 2001;358:1421–1423.

33. Miettinen M, Sarlomo-Rikala M, Sobin LH. Mesenchymal tumors of muscularis mucosae of colon and rectum are benign leiomyomas that should be separated from gastrointestinal stromal tumors: a clinical pathologic and immunohistochemical study of eighty-eight cases. Mod Pathol 2001;14(10):

950–956.

34. Walsh TH, Mann CV. Smooth muscle neoplasms of the rectum and anal canal. Br J Surg 1984;71:597–599.

35. Frizelle FA, Hobday KS, Batts KP, Nelson H. Adenosquamous and squamous carcinoma of the colon and upper rectum. A clinical and histopathologic study. Dis Colon Rectum 2001;44:341–346.

36. Cagie B, Nagy NW, Topham A, Rakinic J, Fry RD. Adeno- squamous carcinoma of the colon, rectum, and anus: epidemiol- ogy, distribution, and survival characteristics. Dis Colon Rectum 1999;42:258–263.

(10)

37. Juturi JV, Francis B, Koontz PW, Wilkes JD. Squamous cell carcinoma of the colon responsive to combination chemotherapy:

report of two cases and review of the literature. Dis Colon Rectum 1999;42:102–109.

38. Lee HJ, Han JK, Kim TK, et al. Primary colorectal lymphoma:

spectrum of imaging findings with pathologic correlation. Eur Radiol 2002;12:2242–2249.

39. Zibhelboim J, Larson MV. Primary colonic lymphoma. Clinical presentation, histopathologic features, and outcome with combination chemotherapy. J Clin Gastroenterol 1994;18(4):291–297.

40. Fan CS, Changchien CR, Wang JY, et al. Primary colorectal lymphoma. Dis Colon Rectum 2000;43:1277–1282.

41. Myung SJ, Kwang RJ, Yan SK, et al. Clinicopathologic features of ileocolonic malignant lymphoma: analysis according to colonoscopic classification. Gastrointest Endosc 2003;57(3):

343–347.

42. Dawson IM, Cornes JS, Morson BC. Primary malignant lymphoid tumors of the intestinal tract. Br J Surg 1961;49:80–89.

43. Chim CS, Shek TWH, Chung LP, Liang R. Unusual abdominal tumors. Case 3. Multiple lymphomatous polyposis in lymphoma of the colon. J Clin Oncol 2003;21(5):953–955.

44. Isomoto H, Maeda T, Akashi T, et al. Multiple lymphomatous polyposis of the colon originating from T-cells: a case report.

Dig Liver Dis 2004;36:218–221.

45. Aviles A, Neri N, Huwerta-Guzman J. Large bowel lymphoma:

an analysis of prognostic factors and therapy in 53 patients. J Surg Oncol 2002;80:111–115.

46. Arima N, Tanimoto A, Hamada T, et al. MALT lymphoma arising in giant diverticulum of ascending colon. Am J Gastroenterol 2000;95:3673.

47. Avner HW, Beham-Schmid C, Lidner G, et al. Successful non- surgical treatment of primary mucosa-associated lymphoid tissue lymphoma of colon presenting with multiple polypoid lesions.

Am J Gastroenterol 2000;95:2387.

48. Yoon SS, Coit DG, Portlock CS, Karpeh MS. The diminishing role of surgery in the treatment of gastric lymphoma. Ann Surg 2004;240:28–37.

49. Yatabe Y, Nakamura S, Nakamura T, et al: Multiple polypoid lesions of primary mucosa-associated lymphoid tissue lymphoma of colon. Histopathology 1998;32:116–125.

50. Raderer M, Pfeffel F, Pohl G, Mannhalter C, Valencak J, Chutt A.

Regression of colonic low-grade B-cell lymphoma of the mucosa associated lymphoid tissue type after eradication of Helicobacter pylori. Gut 2000;46:133–135.

51. Isomoto H, Maeda T, Akashi T, et al. Multiple lymphomatous polyposis of the colon originating from T-cells: a case report.

Dig Liver Dis 2004;36:218–221.

52. Lam KC, Yeo W, Lee J, Chow J, Mok TSK. Unusual abdominal tumors. Case 4. Multiple lymphomatous polyposis in mantel cell lymphoma. J Clin Oncol 2003;21:955–956.

53. Liebross RH, Hu CS, Cox JD, Weber D, Delusalle K, Alexanian R. Clinical course of solitary extramedullary plasmacytoma.

Radiother Oncol 1999;52:245–249.

54. Lattuneddu A, Farneti F, Lucci E, et al. A case of primary extramedullary plasmacytoma of the colon. Int J Colorectal Dis 2004;19:289–291.

55. Hashiguchi K, Iwai A, Inoue T, et al. Extramedullary plasmacytoma of the rectum arising in ulcerative colitis: case report and review. Gastrointest Endosc 2004;59:304–307.

56. Mendenhall WN, Mendenhall CM, Mendenhall NP. Solitary plasmacytoma of bone and soft tissue. Am J Otolaryngol 2003;24:395–399.

57. Schuschter LM, Green R, Fraker D. Primary and metastatic dis- eases in malignant melanoma of the gastrointestinal tract. Curr Opin Oncol 2000;12:181–185.

58. Avital S, Romaguera RL, Sands L, Marchetti F, Hellinger MD.

Primary malignant melanoma of the right colon. Am Surg 2004;70:649–651.

59. Sarah P, MaNiff JF, Madison MD, Wen-Jen Poo H, Bayar S, Sallem RR. Colonic melanoma, primary or regressed primary.

J Clin Gastroenterol 2000;30:440–444.

60. Tessier DJ, McConnell EJ, Young-Fadok T, Wolff BG.

Melanoma metastatic to the colon. Case series and review of the literature with outcome analysis. Dis Colon Rectum 2003;46:

441–447.

61. Hunter RB, Bjelland JC. Gastrointestinal complications of leukemia and its treatment. AJR Am J Roentgenol 1984;142:

513–518.

62. Prolla JC, Kisner JB. The gastrointestinal lesions and complication of the leukemias. Ann Intern Med 1964;61:

1084–1099.

63. Matsushita M, Hajiro K, Okazaki K, et al. A minute erosion rep- resenting leukemic infiltration of the colon. Endoscopy 1997;29:55–56.

64. Utsunomiya A, Hanada S, Terada A, et al. Adult T-cell leukemia with leukemic cell infiltration into the gastrointestinal tract.

Cancer 1988;61:824–828.

65. Gos P, Rosito MA, Tarta C, et al. Leukemic rectosigmoiditis.

Endoscopy 2000;32:520.

66. Khalil RM, Singer AA. CT appearance of direct leukemic invasion of the bowel. Abdom Imaging 1997;22:464–465.

67. Rabin MS, Bledin AG, Lewis D. Polypoid leukemic infiltration of the large bowel. AJR Am J Roentgenol 1978;131:723–724.

68. Cartoni C, Dragoni F, Micuzzi A, et al. Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol 2001;19:756–761.

69. Hogan W, Letendre L, Litzow M, et al. Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Mayo Clin Proc 2002;77:

760–762.

70. Nutall KL, Pingree SS. The incidence of elevations in urine 5-hydroxyindoleacetic acid. Ann Clin Lab Sci 1998;28:167.

71. Feldman JM, Butler SS, Chapman BA. Interference with meas- urement of 3-methoxy-4-hydroxymadelic acid and 5-hydroxyindoleacetic by reducing metabolites. Clin Chem 1974;20:607.

72. Feldman J, Lee E. Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid. Am J Clin Nutr 1985;42:639–643.

73. Neary P, Redmond PH, Houghton T, Watson GRK, Bouchier- Hayes D. Carcinoid disease: Review of the literature. Dis Colon Rectum 1997;40(3):349–362.