14 - 85 Upper Gastrointestinal Tract Cancers

85 Upper Gastrointestinal Tract Cancers

Many chemotherapeutic agents are active in metastatic breast cancer, and selection is based on previous adjuvant chemotherapy and patient preference about route and schedule of administration and side effects. The oral agent capecitabine is often used initially because of ease of administration and acceptable side effect profile. However, several studies have demonstrated that a small percent­ age of the population harbors deleterious mutations in the DPYD gene, which is responsible for converting capecitabine to its inac­ tive metabolites for excretion. Such patients are prone to suffering extreme and, in some cases, lethal toxicities, and some guidelines call for routine testing for this gene before initiating capecitabine or other fluoropyrimidines, such as 5-fluorouracil. Other options include taxanes, anthracycline (depending on previous adjuvant exposure), vinorelbine, gemcitabine, cyclophosphamide, metho­ trexate, eribulin, ixabepilone, and platinum-based agents; the last is often considered in TNBC because of evidence of activity of platinums in that subtype. For patients with TNBC that expresses PD-L1, administration of paclitaxel with the checkpoint inhibitor pembrolizumab can be considered because the combination results in better outcomes than taxane alone; activity of other checkpoint inhibitors is under investigation. ADCs are increasingly finding a role in treatment of metastatic breast cancer. Sacituzumab govitecan, an antibody targeted against TROP-2SN-38 coupled to an irinotecan metabolite, has shown activity against TNBC and endocrine-unresponsive ER-positive, HER2-negative breast cancer. A second ADC, trastuzumab derux­ tecan, which couples trastuzumab with the cytotoxic deruxtecan (discussed in greater detail below in the HER2 section) is also active against tumors that express low levels of HER2 (1+ or 2+/fluorescence in situ hybridization [FISH] negative) and were initially labeled HER2 negative and thus ineligible for adjuvant anti-HER2 therapy using other anti-HER2 agents. Development and testing of novel ADCs are very vibrant areas in treatment of metastatic breast can­ cer, and findings are beginning to challenge some of our concepts about targeted therapy. For patients whose tumors have evidence of germline or somatic BRCA mutation, use of single-agent PARP inhibitor with olaparib or taloparib should also be considered, perhaps before the transi­ tion to infusional therapies because of convenience. Management of HER2-Positive Breast Cancer  The landscape of treatment for metastatic breast cancer has changed substantially in the 25 years since the importance of HER2 protein expression as a predictor for response to anti-HER2 therapy was demonstrated. FDA-approved HER2-directed therapies now include monoclo­ nal antibodies (trastuzumab, pertuzumab, margetuximab), smallmolecule tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib), and ADCs (ado-trastuzumab emtansine or TDM-1, trastuzumabderuxtecan), and others are under development. Apart from trastuzumab-deruxtecan, their clinical benefit is seen only in indi­ viduals whose tumors express 3+ HER2 staining by immunohisto­ chemistry or are gene-amplified by FISH. The preferred first-line treatment for metastatic HER2-positive breast cancer is a combination of taxane, pertuzumab, and trastu­ zumab for several months; taxane chemotherapy may be stopped when disease stability is reached, and the anti-HER2 agents are continued as maintenance therapy. In some cases, this approach can lead to long-term remission, and an active area of research is how long to continue anti-HER2 therapy for those with complete response. A randomized clinical trial has established the superior­ ity of trastuzumab-deruxtecan for second-line therapy. Thereafter, serial administration of anti-HER2 agents, in some cases in com­ bination with single-agent chemotherapy, is pursued. Patients who have HER2-positive, ER- and/or PR-positive breast cancer may benefit from concomitant endocrine therapy as well. HER2-positive breast cancers have a propensity for involvement of the central nervous system. Because control of systemic disease with anti-HER2 therapies can be excellent and penetration of the antibody-based agents across the blood-brain barrier is poor,

patients with this disease subtype are often found to have brain metastasis and may require radiotherapy for local disease control. The small-molecule inhibitors may also offer disease control as they cross into the central nervous system.

■ ■FURTHER READING Andre F et al: Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO Guideline Update. J Clin Oncol 40:1816, 2022. Bedrosian I et al: Germline testing in patients with breast cancer: ASCO-Society of Surgical Oncology guideline. J Clin Oncol 42:584, 2024. Benitez Fuentes JD et al: Global stage distribution of breast cancer at diagnosis: A systemic review and meta-analysis. JAMA Oncol 10:71, 2024. Burstein HJ: Systemic therapy for estrogen receptor-positive, HER-2 negative breast cancer. N Engl J Med 383:2557, 2020. Curigliano G et al: Understanding breast cancer complexity to improve patient outcomes: The St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023. Ann Oncol 34:970, 2023. Giordano S et al: Systemic therapy for advanced human epidermal CHAPTER 85 growth factor receptor 2-positive breast cancer: ASCO guideline update. J Clin Oncol 40:2636, 2022. Henry NL et al: Biomarkers for systemic therapy in metastatic breast cancer: ASCO guideline update. J Clin Oncol 40:3205, 2022. Jackson EB, Chia SKL: Sequencing of endocrine therapy targeted ther­ apies in hormone-sensitive, human epidermal growth factor receptor 2-negative advanced breast cancer. J Clin Oncol 41:3976, 2023. Loibl S et al: Breast cancer. Lancet 397:1750, 2021. Nielsen S, Narayan AK: Breast cancer screening modalities, recom­ Upper Gastrointestinal Tract Cancers mendations, and novel imaging techniques. Surg Clin North Am 103:63, 2023. PDQ Screening and Prevention Editorial Board: Breast Cancer Prevention (PDQR). https://www.ncbi.nlm.nih.gov/books/ NBK65884/.  Accessed January 7, 2024. David Kelsen

Upper Gastrointestinal

Tract Cancers Cancers of the upper gastrointestinal tract include malignancies of the esophagus, stomach, and small bowel. Esophageal, gastroesophageal junction (GEJ), and gastric cancers are among the most common of human malignancies, with 1.693 million global new cases diagnosed in 2020; as a measure of the gravity of such a diagnosis, there were an estimated 1.312 million deaths. In the United States, a lower-risk area, it is estimated that in 2023, esophageal cancer will be diagnosed in 21,560 people and cause 16,120 deaths; for gastric cancer, 26,500 new cases will be diagnosed and 11,130 deaths will occur. Small intestine cancers are rare. ESOPHAGEAL CANCER ■ ■GLOBAL DIFFERENCES IN INCIDENCE AND CAUSATIVE FACTORS Two distinct forms of cancer with different epidemiologies, causative factors, and genomic profiles arise within the esophagus: squamous cell cancers (SCCs), which occur more frequent in the upper and mid esophagus; and adenocarcinomas, which are almost always located in the lower esophagus and at the GEJ. The incidence of esophageal

cancer varies up to 20-fold in global geographic distribution: it is relatively uncommon in North America but has a high incidence in Asia (especially China), the Normandy coast of France, and Middle Eastern countries such as Iran. This marked global variation is likely due to different causative factors in the development of the malignancy, leading to two different cancer types within the same organ: glob­ ally, SCCs make up the majority of cases, as they are more common in high-incidence areas, usually with lower of the four-tier Human Development Index (HDI) scores (a measure of economic develop­ ment that includes standard of living, health, and education). Overall, approximately 604,100 new cases of esophageal cancer were diagnosed globally in 2020; esophageal cancer was the tenth most common cause of malignancy and the sixth most common cause of cancer-related mortality, with an estimated 544,076 deaths.

The most established high-risk factors for the SCC subtype in Western countries are alcohol or tobacco abuse; concurrent alcohol and tobacco abuse further increases the risk. Ingestion of extremely hot sub­ stances (such as tea in Iran and mate [maté] in South America) has been proposed as a risk factor; in India, chewing the areca (betel) nut increases the risk of esophageal SCC. Less common risk factors include chronic achalasia, radiation therapy (such as is delivered for treatment of Hodg­ kin’s lymphoma or breast cancer), lye ingestion, and Plummer-Vinson (Patterson-Kelly) syndrome (iron deficiency anemia, glossitis, cheilosis, and the development of esophageal webs). Adenocarcinoma of the lower esophagus and GEJ has been the predominant histologic subtype in the United States and Western Europe for several decades, now making up

75% of all incident cases. Risk factors for adenocarcinoma include chronic reflux esophagitis leading to inflammation and the development of Barrett’s esophagus (the finding of glandular gastric type mucosa extending into the esophagus). Although obesity increases the risk of reflux esophagitis, a substantial number of patients with newly diag­ nosed adenocarcinoma of the esophagus and GEJ are younger and fit; Barrett’s esophagus may still be found in these patients. In patients with adenocarcinoma of the lower esophagus in which Barrett’s esophagus is not present, the disease may arise without Barrett’s esophagus, or an exten­ sive tumor found at diagnosis may obliterate previous areas of Barrett’s. Genomic alterations may be identified even before the development of frank adenocarcinoma in patients with dysplasia associated with Barrett’s esophagus. These include mutations of TP53, a gene critical in regulating uncontrolled cell division, and aneuploidy in dysplastic regions. Risk of progression of Barrett’s esophagus to cancer is about 0.4–0.5% per year. Management of Barrett’s esophagus is discussed in Chap. 334. PART 4 Oncology and Hematology As opposed to other gastrointestinal malignancies, such as colorec­ tal cancer, inherited cancer susceptibility genes are rarely associated with esophagus and GEJ cancers. An exception is the rare inherited cancer susceptibility gene driving tylosis palmaris and plantaris; a mutation in the RHBDF2 gene is associated with an increased risk for SCC of the esophagus. Both Lynch syndrome and germline BRCA mutation carriers have a modestly increased risk of gastric and poten­ tially GEJ adenocarcinomas. Identification of these germline mutations is important because it guides choices of systemic therapy, as well as counseling of family relatives (see below). ■ ■SCREENING AND SURVEILLANCE OF HIGHER RISK GROUPS Because of its low incidence in North America and the absence of proven blood-based biomarkers for esophageal cancer assays, screen­ ing of the asymptomatic general population using, e.g., upper endos­ copy is not currently recommended in the United States. Periodic endoscopy is used for surveillance of higher risk patients, such as those with Barrett’s esophagus, especially with dysplasia, based on expert opinion guidelines. Early-Onset GEJ and Gastric Cancers  A marked increase in the incidence of early-onset gastrointestinal malignancies (EOGI; cancer occurring in people <50 years of age) has been noted over the past several decades. First noted were early-onset colorectal cancers, occurring particularly in the left-sided colon or rectum; the start of

the steep increase was traced back to the mid-1990s. A similar trend has been noted in upper gastrointestinal tract cancers, particularly in women. The large majority of EOGI patients do not have inherited germline cancer susceptibility gene mutations or a family history of malignancy for colon cancer or small-bowel cancer or inflammatory bowel disease. Driving factors suggested for the steep increase include lifestyle changes such as being more sedentary (less exercise), dietary changes leading to obesity, use of alcohol and tobacco, changes in the microbiome, and exposure to an as not yet identified environmental agent, not previously used, which was introduced to the general popu­ lation in the 1980s or 1990s. Because the absolute number of young people developing GEJ or gastric cancers is still small, surveillance upper endoscopy or imaging is not recommended (for colon cancer screening, current U.S. recommendations are to start at age 45 years). Efforts are underway to develop sensitive and specific early detection biomarkers such as blood-based assays. Because these cancers are uncommon in young patients, symptoms may be attributed to benign illnesses so that advanced stages are common at the time of diagnosis. Physicians should be aware that symptoms in a young person found more typically in older patients, such as dysphagia, odynophagia, or upper abdominal discomfort, may be related to malignancy, leading to the same diagnostic studies as performed in older patients. ■ ■GENOMIC ALTERATIONS Genomic alteration analyses have revealed substantial genomic dif­ ferences between adenocarcinomas and SCCs of the esophagus. The well-known integrated analysis involving several different genomic platforms, performed by The Cancer Genome Atlas (TCGA) Research Network investigators, demonstrated that esophageal SCC more closely resembled SCCs of other primary sites, such as the head and neck, than adenocarcinomas arising in the esophagus. Three molecu­ lar subclasses of SCC were identified (of note, as opposed to SCC of the head and neck, human papillomavirus was not identified in any of the three subgroups). Similarly, a study of 528 Chinese SCC patients, using whole genome sequencing, evaluated structural variations resulting in rearrangements; five types of structural variations were identified, and some of these may be of clinical significance. In adeno­ carcinomas, HER2/ERBB2 is frequently amplified, and microsatellite instability can be found in both esophageal and GEJ adenocarcinomas. Epstein-Barr virus (EBV) infection is a driver in adenocarcinoma. The similar genomic profile for adenocarcinomas of the distal esophagus, GEJ, and cardia of the stomach suggests that proximal gastric and GEJ tumors may have a similar driving factor (see below). A genomewide association study identified 27 risk loci for the development of adenocarcinomas of the esophagus or GEJ, with a difference between adenocarcinoma arising in Barrett’s esophagus versus not. Other stud­ ies comparing transcriptomes of adenocarcinomas and SCC across organs (i.e., the same tumor histology arising in different organs, such as SCCs and adenocarcinomas from the esophagus, lung, and uterine cervix) found that the same histologies among the different organs showed more similarity than between the different histologies within the same organ. In addition to implications regarding driving factors in the initiation and progression of cancer, these genomic alterations are important for therapeutic decisions involving systemic agents given in the neoadjuvant or postoperative adjuvant setting or for advanced metastatic disease. For esophageal adenocarcinoma, genomic abnor­ malities that should be considered in prescribing drug-based therapy include analysis for HER2/ERBB2 amplification, programed death ligand 1 (PD-L1) expression, and hypermutated tumors/microsatellite instability (see Table 85-1, and below). For SCC of the esophagus, the degree of PD-L1 expression may be of importance. CLINICAL FEATURES ■ ■PRESENTING SYMPTOMS The most common symptoms leading to suspicion of esophageal can­ cer are dysphagia or odynophagia and, less frequently, hematemesis or melena. More subtle symptoms include anorexia and weight loss, and

TABLE 85-1  AJCC Prognostic Stage Groups for Esophageal Cancer Using cTNM (Pretreatment)a TNM CLINICAL STAGE PRESENTING AT THIS STAGEb,c SQUAMOUS ADENOCARCINOMA cTis, N0, M0

1.2% 75% 82% cT1-2, N0, M0 I 17% 75% 78% cT1-2, N1-3, M0 IIA 7% 53% 50% cT3-4a, N0, M0 IIB 13% 40% 40% cT3-4a, N1-3, M0c III 31% 25% 25% cT4b, any N, M0 IVA 17% 21% cAny T, any N, M1 IVB 5% 10% 18% Survival by ypTNM Staging After Neoadjuvant Chemotherapy ESTIMATED 5-YEAR SURVIVAL RATE TNM yp STAGE SQUAMOUS ADENOCARCINOMA T1-2, N0, M0 T1, N1, M0 I 46% 52% T3, N0-1, M0 T2, N1-2 M0 T1, N2-3, M0 T4a, N0, M0 II 34% 38% T4a, N1-3 M0 T4b, any N, M0 T3, N2-3, M0 T2, N3, M0 III 22% 27% Any T, any N, M1 IV 10% 12% aAJCC Cancer Staging Manual Version 9 expected in 2024. bSquamous cell and adenocarcinoma histologies combined. CSurgical series; underestimates incidence of M1 disease at presentation. dIncidence includes cT4b and cNanyMO. Sources: Adapted from TW Rice et al: CA Cancer J Clin 67:304, 2017; TW Rice et al: Dis Esophagus 29:707, 2016; and TW Rice et al: personal communication. fatigue and shortness of breath if anemia from gastrointestinal bleed­ ing is present. Because the symptoms of dysphagia or odynophagia are usually not perceived by the patient until substantial obstruction of the esophageal lumen has occurred, the large majority of patients with esophageal cancer are found with locally advanced if not metastatic dis­ ease. Patients with symptoms of dysphagia and/or odynophagia should undergo upper endoscopy to determine the presence or absence of malignancy; biopsy should be performed at the same setting to deter­ mine histology. Depending on the tumor stage, molecular diagnostic or next-generation sequencing (NGS) analysis to assist in determining potential therapies should be performed. PD-LI, which may guide use of immune modulation therapy, is assessed by immunohistochemistry (IHC). NGS requires adequate tumor cellularity, which may be difficult to achieve from endoscopic biopsy. NGS is currently probably the most efficient methodology for genomic analysis (other than PD-L1), and genomic analysis should be done on all patients with metastatic disease because it will guide therapy. Some high-volume U.S. centers routinely perform NGS on all specimens, including from all but the most earlystage primary tumors of patients without metastatic disease. ■ ■STAGING Therapeutic strategy is currently based on the stage of the disease using a system such as the eighth version of the American Joint Committee on Cancer (AJCC) Staging Manual (for esophageal and gastric cancers, the ninth version is expected in 2024) tumor-node-metastasis (TNM) staging system. The T stage is based on the size of the tumor and depth of penetration through the esophageal wall (which for most of its course is not covered by serosa so that invasion through the muscle layer leads directly into periesophageal tissues) (Fig. 85-1). Patients with regional lymph node metastases are still potentially curable. Meta­ static disease is generally treated with palliative intent with rare excep­ tions. Because neoadjuvant (preoperative) therapy is widely employed for esophageal cancer to improve subsequent surgical outcomes, the AJCC TNM staging system includes clinical, pathologic (for patients

5-YEAR SURVIVAL RATE CHAPTER 85 Upper Gastrointestinal Tract Cancers undergoing initial surgery as first treatment), and ypTNM staging assessment for those treated with preoperative therapy. See Table 85-2 for the TNM staging classification for gastric cancer, which is similar to esophageal cancer. Determining tumor extent includes careful physical examination, which may reveal palpable lymphadenopathy or hepatomegaly; imag­ ing studies including computed tomography (CT) and fluorodeoxyglu­ cose (FDG) positron emission tomography (PET)-CT scan are used to assess for metastatic disease. If no metastatic disease is identified, endoscopic ultrasonography (EUS) is commonly performed to more definitively determine depth of penetration of the primary tumor (T) and regional lymph node involvement. Deep learning artificial intel­ ligence methodology may assist the imaging analysis to improve the diagnostic sensitivity and specificity of EUS for both esophageal and gastric cancers. For tumors of the mid and upper esophagus (5% of esophageal cancers are in the upper third of the esophagus, 20% in the middle third, and 75% in the lower third), bronchoscopy may be per­ formed to rule out invasion of the tracheobronchial tree. The finding of invasion of the trachea or bronchus rules out surgical intervention with curative intent. Regional lymph nodes may be biopsied under EUS guidance. For GEJ tumors, as for gastric cancers, laparoscopy is performed at many centers to assess for peritoneal involvement if the T stage is more advanced. If metastatic disease is suspected, biopsy to confirm tumor staging and to obtain adequate tissue for molecular and genomic alterations analysis should be performed. Assay of plasma ctDNA (circulating tumor DNA) can be used to detect genomic altera­ tions before treatment if biopsy tissue is too limited to allow NGS or molecular diagnostics; ctDNA is being studied as a measure of minimal residual disease after definitive regional therapy (surgery or chemora­ diation therapy). If systemic therapy is indicated as a portion of the treatment (for metastatic disease or for preoperative therapy for locally advanced cancers), serial FDG-PET/CT scans, using decrease in FDG avidity as a surrogate measure of effectiveness, are being used to guide whether the initial therapy should be continued or changed.

Tis (HGD) T1a T1b T2 T3 T4a T4b NO N1 1 or 2 N2 3 to 6 N3 7 or more PART 4 Oncology and Hematology M1 Pleura FIGURE 85-1  Patterns of spread of esophageal cancer and the basis for anatomic staging. HGD, high-grade dysplasia. (Reproduced with permission from TW Rice et al: Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol 12:36, 2017.) TREATMENT Esophageal Cancer Although the prognosis for patients with esophageal cancer (all stages) is still poor, a slow but steady improvement in 5-year survival has been noted. Because no cost-effective early detection methods exist in low-incidence countries, the number of U.S. patients found to have very-early-stage cancers at the time of diagnosis has not markedly increased; the modest improvement in survival is prob­ ably a combination of somewhat improved systemic therapy as well as decreased operative morbidity and mortality when surgery is performed by high-volume surgeons at high-volume centers, as well as improvements in the delivery of external-beam radiation therapy. For patients without evidence of metastatic disease, the goal of therapy is cure, usually by employing combined-modality therapies. Except for patients with early-stage esophageal cancer, who might be treated by surgery alone (or for very-early-stage lesions [Tis or T1a], by endoscopic mucosal resection [EMR] or submucosal dissection [ESD] for smaller [<2 cm] tumors); EMR and ESD are also used as part of initial staging to determine more definitively T stage), preoperative treatment including systemic drug therapy is a standard of care option for patients with esophageal and GEJ cancers. For locally advanced adenocarcinomas of the esophagus and GEJ, systemic therapy alone may be indicated: in the ESO­ PEC trial, preoperative systemic FLOT chemotherapy resulted in improved survival compared to preoperative chemoradiation (using the CROSS regimen). For selected patients with adenocar­ cinomas (e.g., not able to tolerate regimens such as FLOT), and for patients with SCC of the esophagus, chemoradiation remains a standard of care option; for SCC, chemoradiation may be definitive therapy. If surgery is planned after preoperative chemoradiation, a prolonged delay before surgery has been associated with a poorer outcome. For selected patients with GEJ adenocarcinomas, systemic

Lamina propria Epithelium Basement membrane Submucosa Muscularis mucosae Muscularis propria Adventitia Aorta therapy alone may be given before definitive surgical resection. For patients with SCC of the upper and mid esophagus, combined chemotherapy plus concurrent radiation therapy is a standard option, with surgery reserved for patients not achieving a complete radiographic and endoscopic response. Radiation therapy alone is rarely given with curative intent, as chemotherapy plus concurrent radiation was superior to radiation therapy alone in several clinical trials. Increasingly, all systemic therapy with curative intent is given before operation, although if surgery is the initial therapy and the patient is found to have more locally advanced cancer at pathol­ ogy (e.g., regional lymph node metastasis), postoperative systemic therapy is used in the adjuvant setting. Adjuvant chemotherapy is more frequently indicated in patients with adenocarcinoma than SCCs. The CheckMate 577 trial demonstrated that for esophageal or GEJ cancer patients who received preoperative chemoradiation therapy and underwent a R0 (negative margins) resection but who had residual tumor in the resection specimen (i.e., not ypT0N0M0), postoperative adjuvant therapy with nivolumab, an immune-mod­ ulating agent targeting PD-1, significantly improved survival. For patients with metastatic disease, the goal of therapy is symptom palliation and life extension. No randomized trials of supportive care only versus systemic therapy plus best supportive care have been reported in patients with esophageal cancers. For gastric cancer (an adenocarcinoma histology, as are most distal esophageal and GEJ tumors), clinical trials performed in the 1980s and 1990s indicated a modest improvement in 1- and 2-year survival when systemic therapy plus best supportive care was used versus best supportive care only. While the cytotoxic chemotherapy regimens used for palliation have not changed dramatically over the past 10 years (currently including, for first-line treatment, a platinum compound such as oxaliplatin and a fluorinated pyrimidine such as fluorouracil or capecitabine; the FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel] regimen includes docetaxel and is used

TABLE 85-2  Staging System for Gastric Carcinomaa DATA FROM ACS IN THE UNITED STATES NO. OF CASES, % 5-YEAR SURVIVAL, % STAGE TNM FEATURES

TisN0M0 Node negative; limited to mucosa

IA T1N0M0 Node negative; invasion of lamina propria or submucosa

IB T2N0M0 T1N1M0 Node negative; invasion of muscularis propria

II T1N2M0 T2N1M0 Node positive; invasion beyond mucosa but within wall

or T3N0M0 Node negative; extension through wall IIIA T2N2M0 T3N1-2M0 Node positive; invasion of muscularis propria or through wall

IIIB T4N0-1M0 Node negative; adherence to surrounding tissue

IIIC T4N2-3M0

3 nodes positive; invasion of serosa or adjacent structures T3N3M0 7 or more positive nodes; penetrates wall without invading serosa or adjacent structures IV T4N2M0 Node positive; adherence to surrounding tissue

or T1-4N0-2M1 Distant metastases aAJCC Cancer Staging Manual, Eighth Edition. Abbreviation: TNM, tumor-node-metastasis. in very fit patients), subgroups of patients have been identified who benefit from therapies targeting specific genomic alterations

(Table 85-3). Approximately 20–25% of patients with adenocar­ cinoma of the esophagus or GEJ are found to have amplified or overexpressed HER2/ERBB2; trastuzumab plus chemotherapy, or trastuzumab, chemotherapy, plus immune therapy using pembro­ lizumab (for progression-free survival), results in higher response rates and longer progression-free and overall survival compared to chemotherapy alone. For patients whose tumors do not express HER2/ERBB2, immune-modulating therapy using PD-1 inhibi­ tors is a standard option as part of first-line therapy (in combina­ tion with chemotherapy) and as second-line palliative therapy for patients who have esophageal cancers expressing PD-L1. Patients TABLE 85-3  Molecular Diagnostics and Genomic Alteration Analyses Help Guide Systemic Therapy SITE HISTOLOGY FACTOR ASSAY TYPE THERAPY OPTIONS Esophageal SCC PD-L1 IHC Immunomodulation Esophageal Adeno/ GEJ PD-L1 IHC Immunomodulation Esophageal Adeno GEJ ERRB2/HER2 IHC/FISH/NGS Trastuzumab; trastuzumab-deruxtecan Esophageal Adeno GEJ/gastric dMMRP/MSI IHC/NGS Immunomodulation Gastric Adeno Claudin 18.2 IHC Zolbetuximaba aZolbetuximab is currently investigational. Abbreviations: Adeno, adenocarcinoma; dMMRP, deficient mismatch repair protein; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; MSI, microsatellite instability; NGS, next-generation sequencing; PD-LI, programmed death ligand 1; SCC, squamous cell carcinoma.

whose tumors have high PD-L1 combined positive score (CPS) may have greater benefit. For patients with hypermutated or microsat­ ellite-unstable tumors, immune therapy alone is considered, using agents such as pembrolizumab, or nivolumab plus ipilimumab. As noted above, molecular diagnostic or NGS genomic alteration analysis assays to identify these biomarkers should be performed routinely in patients with metastatic esophageal, GEJ, and gastric cancer to help guide therapy.

Supportive measures to improve nutrition and quality of life include placement of an endoluminal stent in the setting of highgrade obstruction; use of enteral nutrition can also be performed using a percutaneous gastrostomy. Photodynamic therapy and endoscopic laser therapy have been used to treat symptoms of endoluminal obstruction. TUMORS OF THE STOMACH ■ ■ADENOCARCINOMA OF THE STOMACH Incidence and Causative Factors  Since the 1920s, the incidence of gastric cancer has steadily decreased; while the reason for this has not been definitively identified, it coincided with widespread use of refrigeration and a decreased need for food preservatives. In 2023, it is estimated that there will be 27,500 new cases of gastric cancer diagnosed in the United States; while now seen much less frequently, it remains a lethal disease, with 11,130 deaths. As noted above, globally, gastric cancer is the third most common cause of cancer mortality. High-incidence areas, as is the case for esophageal cancers, include large Asian countries such as China, Korea, and Japan; South American countries such as Chile; and Eastern European countries. CHAPTER 85 Upper Gastrointestinal Tract Cancers While the number of new cases of body and distal gastric cancers has decreased in Western, high-tier HDI countries, the incidence of adenocarcinomas of the GEJ has markedly increased in the same areas over the past several decades, including as described earlier in younger patients. For gastric cancer overall, a higher incidence in some coun­ tries may be due to the ingestion of high concentrations of nitrates found in dried, smoked, and salted foods. Chronic inflammation, caused by an infection, is a major cause of gastric cancer. Helicobacter pylori infection is a known driver in many cases of gastric cancer. While H. pylori is extremely common, occurring in approximately half of all humans, gastric cancer occurs in only a small subset of those infected. Higher cancer risk has been associated with certain strains of H. pylori; while analyses of H. pylori are identifying high-risk genomic factors, a specific human genomic profile increasing risk of gastric cancer in the setting of H. pylori has not yet been identified. H. pylori and ingestion of partially decayed bacterially contaminated food may lead to the gen­ eration of carcinogenic nitrites from nitrates. Supportive evidence that H. pylori infection is a causative factor in the development of gastric cancer includes prospective studies demonstrating that treatment of H. pylori infection decreases the overall risk of gastric cancer. For exam­ ple, patients with H. pylori infection who had at least one first-degree relative with a history of gastric cancer (increasing their own risk of stomach cancer) were randomly assigned to placebo or treatment for H. pylori. The group receiving H. pylori eradication showed a signifi­ cant decrease in the incidence of gastric cancer (especially for those in whom H. pylori was successfully eradicated) compared to the control group. Earlier studies had demonstrated that treatment of H. pylori in Korean patients who had a prior very-early-stage gastric cancer decreased the incidence of a second gastric cancer. These data suggest that treat­ ment of asymptomatic H. pylori gastric infection should be considered for patients who have a first-degree relative who has had gastric cancer or who themselves have a prior history of an early-stage gastric cancer. The spectrum of the gastric microbiome beyond H. pylori may also be contributory to an increased risk of gastric cancer, with gastric cancer patients having a higher bacterial load than controls. EBV has also been associated with an increased risk for gastric cancer, and gastric cancer EBV phenotype and genotype have been well described. Another inflammation-driven cause is suspected to be reflux of gastric contents into the esophagus, particularly in obese people, increasing the

risk of GEJ and esophageal adenocarcinomas. Obesity alone is not the cause, as a substantial number of GEJ patients are fit and not overweight.

In addition to chronic inflammatory conditions, inherited cancer susceptibility genes increase the risk of gastric cancer. These include mutations of CDH1, which encodes for the cell cohesion gene e-cadherin; germline CDH1 mutations markedly increase the risk for the diffuse cell (signet cell) gastric cancer subtype (see below for discussion of histologic subtypes). Prophylactic gastrectomy as a risk-reducing sur­ gical procedure is an option for patients with an inherited deleterious CDH1 mutation. CDH1 mutations also increase the risk for lobular breast cancer. Germline mutations in the mismatch repair pathway (Lynch syndrome) and in the homologous repair pathway (BRCA mutations) slightly increase the risk for gastric cancer. Other inherited cancer susceptibility genetic syndromes that increase the risk of gastric cancer include familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome. Surveillance programs for the early detec­ tion of gastric cancer for the higher risk germline cancer susceptibility genes (e.g., CDH1) should be employed. In addition, systemic therapy options for patients with certain germline mutations may be different from those with sporadic gastric cancer (e.g., for Lynch syndrome, immune modulation therapy; and for BRCA, use of DNA-damaging agents such as platinum compounds). Gastric cancer stem cells, mostly located in the isthmus of individual gastric glands and possibly originating in the bone marrow, may play an important role in the development of gastric cancer. H. pylori may be an inciting factor for recruitment of such bone marrow gastric stem cells. If this hypothesis is confirmed, it may have important implica­ tions for therapy of gastric cancers. PART 4 Oncology and Hematology Clinical Features  •  SURVEILLANCE STRATEGIES  As is the case for esophageal cancer, the incidence of gastric cancer in Western patients is relatively low, and early detection methodologies such as endoscopy are not routinely employed. The development of a “pan-cancer” bloodbased biomarker or a biomarker specific for gastric cancer would allow broader screening. At this time, the overwhelming majority of Western patients with gastric cancer are symptomatic at the time of diagnosis. Early detection programs in Japan and Korea, where gastric cancer has been among the most common of malignancies (although its incidence has been decreasing), include upper endoscopy; these programs have increased the number of patients found with early gastric cancer and Cardia GE junction CIN • Intestinal histology • TP53 mutation • RTK-RAS activation Pylorus Antrum GS • Diffuse histology • CDH1, RHOA mutations • CLDN18–ARHGAP fusion • Cell adhesion FIGURE 85-2  Molecular/genomic characterization of subtypes of gastric carcinomas. CIMP, CpG-island methylator phenotype; CIN, chromosomally unstable; EBV, EpsteinBarr virus-associated; GE, gastroesophageal; GS, genomically stable; MSI, microsatellite instability-associated.

decreased mortality rates. This strategy has not been cost effective in populations in which the incidence of gastric cancer is much lower, such as in the United States. As noted above, in high-incidence areas, treatment of symptomatic H. pylori is a preventive measure. PRESENTING SYMPTOMS  Presenting symptoms include vague upper abdominal discomfort, hematemesis or melena, anorexia and early satiety, and unexplained weight loss. For patients with esophagogastric junction cancers, dysphagia or odynophagia may be the presenting symptom. Anemia may be found due to occult bleeding. These symp­ toms and signs lead to upper (and if site of bleeding is uncertain, lower) endoscopy and biopsy. Occasionally, imaging using CT performed to evaluate abdominal symptoms may identify gastric thickening or a gas­ tric mass leading to upper endoscopy. Physical examination can reveal left supraclavicular adenopathy (Virchow’s node), a periumbilical mass (Sister Mary Joseph nodule), a pelvic mass on rectal exam (Blumer’s shelf), ascites, or an ovarian mass (Krukenberg tumor). More com­ monly, physical examination is unrevealing. Upper endoscopy may reveal an ulcer or ulcerated mass, biopsy of which shows adenocarcinoma. For the diffuse subtype of gastric can­ cer, a mass or ulceration may not be seen, but rather, thickened gastric rugae may be noted. Initial biopsy may not reveal diffuse gastric cancer, which may track below the mucosal surface. In these patients, EUS may guide biopsy. Histopathology Classification of Primary Gastric Adeno­ carcinomas  The large majority (~85%) of gastric malignancies are adenocarcinomas or subtypes of adenocarcinoma. Other malignancies, discussed below, include neuroendocrine tumors (carcinoid tumors), primary gastric lymphomas, gastrointestinal stromal tumors (GISTs), and other rare malignancies. Using the Lauren classification, patholo­ gists classify adenocarcinomas on the basis of histopathology as intestinal (more common) or diffuse subtype (~20%). As noted above, the diffuse subtype is associated with inherited CDH1 mutations; in addition, in the TCGA genomic analysis of gastric cancer and in other genomic analysis studies, approximately a third of diffuse subtype cases had somatic CDH1 mutations. The intestinal subtype is associated with H. pylori infection and atopic gastritis. Histologic grade also influences the clinical course. Genomic analysis performed by several groups has resulted in molecular classifications of gastric cancer that may, in the future, Fundus EBV • PIK3CA mutation • PD-L1/2 overexpression • EBV-CIMP • CDKN2A silencing • Immune cell signaling Body MSI • Hypermutation • Gastric-CIMP • MLH1 silencing • Mitotic pathways

inform staging systems; they already provide a better understanding of the driving factors in the development of gastric cancer and important information on treatment options as outlined above (Fig. 85-2). For example, the TCGA group reported the results of a multiplatform analysis of 295 patients with previously untreated gastric cancer; both Western and Asian patients were included in the analysis. Four sub­ types of gastric cancer were identified: high EBV burden, microsatel­ lite unstable with hypermutation, genomically stable (associated with the diffuse subtype), and chromosomal unstable. The Asian Cancer Research Group (ACRG), studying primary tumors from 300 Korean patients, analyzed gene expression profiles and found four subtypes: mesenchymal, microsatellite unstable, microsatellite stable with TP53 expressed, and microsatellite unstable with TP53 mutated. Clinical out­ come was correlated with genomic subtype in both studies, with micro­ satellite unstable tumors having the best outcome (in an era before use of immune modulation therapy) and genomically stable (TCGA) and mesenchymal (ACRG) types having the worst outcome. In addition to histopathology, as is the case for esophageal cancer, molecular diagnostics and genomic alteration analysis using NGS are an important part of the pathology workup. The molecular subtypes have therapeutic implications; for example, as discussed above, ~20% of gastric cancer or GEJ cancer patients’ tumors have overexpression or amplification of HER2/ERBB2, which would lead to the addition of agents such as trastuzumab-based therapy as part of systemic treatment for metastatic disease. Immune modulation therapy would be used in patients with hypermutated tumors, found by NGS (tumor mutation burden) or by polymerase chain reaction (PCR) for microsatellite instability (MSI). An evaluation for overexpression or amplification of HER2/ERBB2, quantification of PD-L1 by IHC, and assessment of MSI by PCR or deficient mismatch repair protein (dMMRP) expression should be a routine part of the pathology workup of patients with meta­ static gastric cancer. Claudin 18.2 has recently been identified as a tar­ get for therapy; if agents targeting Claudin 18.2 are approved by the U.S. Food and Drug Administration (FDA), an assay for this factor should be included in the pathologic evaluation of metastatic gastric cancer. More controversial is whether these assays should also be routinely performed in patients with potentially operable gastric cancer because, for example, the addition of trastuzumab to neoadjuvant chemotherapy has not yet been shown to change outcome. In large-volume centers, NGS is routinely performed on pretreatment biopsies. Currently, the finding on pathologic assays of positive tumor EBV (identified in 8–10% of gastric cancer patients) does not change therapeutic options. Staging  Once a diagnosis of a primary gastric adenocarcinoma is made, algorithms for clinical evaluation of stage include physical exam­ ination and imaging studies (Fig. 85-3; Table 85-2). Tumor-related biomarkers such as carcinoembryonic antigen (CEA) or CA19-9 may be elevated but are nonspecific (may be elevated in a number of other gastrointestinal and other site cancers). Diagnostic CT scan of the chest, abdomen, and pelvis should be performed. If metastatic disease is suspected on imaging, a biopsy of a metastatic site should be strongly considered to confirm stage IV disease, which changes the goals of care from potentially curative to palliative treatment and provides tis­ sue for molecular and genomic analyses. As is the case for esophageal cancer, FDG-PET/CT, which is more sensitive than diagnostic CT scan in identifying sites of metastatic disease, should be performed if the anatomic CT is negative for metastatic disease. Note, however, that FDG-PET may be noninformative (the primary tumor may not be FDG-avid, particularly in diffuse-type gastric cancer). If imaging does not reveal metastatic disease, EUS should be considered to determine depth of penetration of the primary tumor and the presence or absence of regional lymphadenopathy suspicious for metastasis. Lymph node biopsy and, on occasion, biopsy of left hepatic parenchymal lesions found on EUS can be performed at the same setting. Endoscopic biopsies usually provide enough tumor tissue for molecular diagnostic pathology testing for HER2/ERBB2, MSI/MMRP, and PD-L1 assess­ ment; it may not provide enough tissue for NGS genomic alteration analysis. If neoadjuvant therapy is planned, laparoscopy should be considered to allow evaluation of the peritoneal cavity, with peritoneal

washing for cytology if no peritoneal metastases are visible. The perito­ neal cavity is a common site of metastases, especially from diffuse-type gastric cancer. The finding of peritoneal involvement either visibly or by positive cytology is staged as metastatic disease and generally rules out the chance for curative resection.

The AJCC staging classification for gastric cancer is summarized in Table 85-2. Three staging classifications are provided: cTNM clinical staging (before any therapy has been given), pTNM pathologic staging (for patients not undergoing preoperative therapy), and a post–neoad­ juvant therapy classification staging (ypTNM). The three components take into account current standard-of-care options for therapy in which the AJCC prognostic stage groups from clinical staging guide therapeutic decisions. For example, after clinical evaluation, a large percentage of newly diagnosed patients will be found to have higherstage primary cancers (penetrating through the gastric wall [T3 or T4] or lymph node–positive tumors), in which case perioperative (neoad­ juvant) systemic therapy may be chosen. Pathologic examination of the resected specimen for prognostic stage classification must take into account exposure to preoperative therapies that may lead to down­ staging (thus, ypTNM staging). Nomograms have been developed for predicting outcome in patients undergoing surgery as initial treatment. CHAPTER 85 TREATMENT Gastric Cancer POTENTIALLY CURABLE GASTRIC CANCER: SURGERY Surgical removal of the primary tumor with negative microscopic margins (an R0 resection) and with resection of regional lymph nodes is currently the only curative therapy; with surgery alone, overall 5-year survival rates are approximately 25% (higher for very-early-stage tumors). If tumor cells are found at the margin of resection (R1) or if visible cancer is left at the time of surgical removal of the primary tumor (R2), surgery is palliative rather than curative. For patients with early-stage tumors (mostly clinical stage I), surgery without perioperative systemic therapy may be performed. For patients with more locally advanced tumors (clini­ cal stages IIA, IIB, III), who compose approximately 70% of newly diagnosed operable patients, multimodality therapy (surgery and systemic chemotherapy) improves overall survival. Both neoadju­ vant (preoperative) and postoperative systemic therapy are accepted approaches. If staging studies demonstrate a locally advanced can­ cer (or node positive), preoperative treatment is recommended in a medically fit patient. If surgery is performed first and a locally advanced cancer is found, postoperative chemotherapy or che­ motherapy plus chemoradiation is recommended. For selected very-early-stage gastric cancers (primary tumors that are ≤2 cm in diameter, are well to moderately differentiated, do not invade the deep submucosa [T1], and do not show lymphovascular invasion or lymph node metastasis), which are not commonly found in the United States, EMR or ESD may be performed by experienced gas­ troenterologists in place of surgical resection, with favorable results in studies in high-incidence areas such as Japan. Upper Gastrointestinal Tract Cancers For patients in whom the primary tumor is in the distal stom­ ach, a subtotal gastrectomy is the preferred surgical procedure. For tumors of the proximal stomach, the options for resection include total gastrectomy or, alternatively, proximal gastrectomy. Esophago­ gastrectomy is performed for tumors involving the GEJ. In selected patients, a jejunostomy feeding tube may be placed if postoperative radiation therapy is part of the treatment plan. As noted above, laparoscopy is commonly performed at highvolume centers before a final decision regarding the role of surgery. If staging has already demonstrated clinically suspicious lymph nodes or an advanced T stage tumor, but laparoscopy does not demonstrate peritoneal metastasis, perioperative chemotherapy is given before surgical resection. Palliative resection of the primary tumor is usually performed only if symptoms such as uncontrollable bleeding or obstruction are present that cannot be relieved by other means.

No evidence of metastatic disease MI disease suspect FDG-PET/CT No MI disease MI disease PART 4 Oncology and Hematology EUS Stage 1 Consider laparoscopy Consider laparoscopy No peritoneal metastasis No MI peritoneum MI peritoneum Resection Neoadjuvant therapy pT1–2 N0 M0 pT3 Nany M0 Resection Active surveillance Adjuvant therapy FIGURE 85-3  Staging for gastric adenocarcinoma. CT, computed tomography; EUS, endoscopic ultrasound; FDG-PET, fluorodeoxyglucose positron emission tomography. As is the case for colorectal cancer, a correlation exists between the number of lymph nodes removed and sampled and outcome. Sentinel lymph node biopsy is not performed in gastric cancer outside of a research study setting. The goal is to examine at least 15 lymph nodes from the resected specimen; it is more contro­ versial whether more extensive lymph node resection itself affects outcome; the extent of lymphadenopathy can be classified using a D0–D3 system with a higher number meaning more extensive lymphadenopathy. In the United States, a modified D2 (D1+) resection preserving the spleen and avoiding pancreatectomy is recommended but should be performed by experienced surgeons at high-volume centers. Japanese investigators and others have used very extensive lymph node dissections, but studies have not demonstrated an advantage for a D3 resection. Both resection of the primary tumor and its regional lymph nodes can be performed laparoscopically in appropriate patients.

Endoscopy and biopsy positive Diagnostic CT Biopsy if technically feasible Systemic therapy Stage 2/3 Systemic therapy In the hands of experienced surgeons, operative mortality would be anticipated to be ≤2%. NEOADJUVANT AND POSTOPERATIVE ADJUVANT THERAPY FOR RESECTABLE GASTRIC CANCER The large majority of potentially resectable Western gastric cancer patients have locally advanced tumors (cTNM stage IIA/B or III). Multimodality therapy using systemic chemotherapy plus surgery improves 5-year survival rates by 10–15% compared to surgery alone. An older but widely cited study, the MAGIC clinical trial, randomly assigned patients with potentially resectable disease to receive perioperative chemotherapy or to proceed directly to surgery. Five-year overall survival for patients undergoing surgery alone was 23%; for those receiving pre- and postoperative chemotherapy, it was 36%. On the basis of this and other clinical trials, for most medically fit patients with stage cTNM II and III resectable gastric cancers,

preoperative systemic chemotherapy followed by resection and, if tol­ erable, postoperative chemotherapy is a standard approach. Because it is challenging to give postgastrectomy systemic therapy using currently employed regimens (<50% of patients receive or complete postoperative treatment), total neoadjuvant therapy is favored at some centers. For patients with MSI/hypermutated tumors, immune modulation therapy (PD-1/PD-L1 or PD-1 plus CTLA-4 agents) can be considered in place of chemotherapy, although substantial pathologic response rates were seen in a small number of patients in the DANTE trial using FLOT alone. Preoperative chemoradiation as given for esophageal cancers is usually used for GEJ tumors. If an R1 or R2 resection is performed, postoperative chemoradiation can be considered. Use of postoperative chemoradiation therapy, with exceptions outlined above, did not improve outcome when com­ pared to systemic chemotherapy alone. Preoperative chemotherapy followed by chemoradiation is under study. For patients being treated with multimodality therapy, close interactions among the surgeon, medical oncologist, and radiation oncologist are essential. Clinical trials have compared different preoperative cytotoxic chemotherapy regimens, most of which include a platinum com­ pound—either cisplatin or oxaliplatin. Currently, a platinum compound plus a fluorinated pyrimidine, such as fluorouracil or capecitabine, given for three to four cycles before surgery is a standard-of-care option. Drug combinations are favored; for very fit patients, a combination of FLOT may be chosen. An alternative is, for example, the FOLFOX regimen, which includes fluorouracil, leucovorin, and oxaliplatin. Addition of trastuzumab to preop­ erative chemotherapy has not improved outcomes for patients with HER2-positive cancers. Careful monitoring of chemotherapyrelated toxicities with appropriate dose modifications is important. For patients receiving preoperative systemic chemotherapy and undergoing an R0 D2/D1+ dissection, postoperative chemoradia­ tion therapy has not improved outcome. For patients in whom the primary tumor has been resected and who did not receive preoperative chemotherapy, who are found to have stage II or III cancers, or who have <15 lymph nodes found in the resected specimen (less than D2 resection), postoperative che­ motherapy or chemoradiation is a treatment option. Chemotherapy and chemoradiation therapy may also be given for unresectable cancers in selected patients. As noted above, plasma ctDNA as a measure of minimal residual disease (regional or metastatic cancer not identifiable by current imaging modalities) is being studied. Data from other gastrointestinal tumors suggest that conversion of a positive ctDNA assay to negative after systemic postoperative therapy is associated with a better outcome. PALLIATIVE THERAPY FOR INCURABLE GASTRIC CANCER Patients with clinical stage IV gastric cancers with an adequate per­ formance status should be offered systemic drug therapies. Small clinical trials performed in the 1980s and 1990s showed a survival benefit for systemic therapy compared to best supportive care only. As discussed above, genomic and molecular diagnostic analysis has identified several distinct cohorts of gastric cancer patients. These analyses guide therapy. While the cytotoxic chemotherapy regimens most commonly employed are still based on a platinum compound and a fluorinated pyrimidine (e.g., FOLFOX, as is used in the peri­ operative setting), a major advance has been the demonstration that immune modulation therapy plus chemotherapy improves outcome (including overall survival) compared to chemotherapy alone. In the CheckMate 649 trial, 1581 patients with HER2/ERBB2-negative advanced gastric or GEJ cancers were randomly assigned to receive nivolumab plus chemotherapy (oxaliplatin plus capecitabine or FOLFOX) versus chemotherapy alone. Overall survival, progres­ sion-free survival, and response rates were significantly better for patients receiving nivolumab plus chemotherapy; this effect was most marked for patients with PD-L1 CPS of >5. CheckMate 649 and other data have led to guidelines recommending use of immune modulation therapy plus chemotherapy as an option for first-line treatment for patients with HER2/EBB2-nonexpressing, PD-L1 CPS

5 metastatic gastric and gastroesophageal cancers; chemotherapy plus immune modulation therapy may also have benefit for patients with lower PD-L1 CPS scores. Those whose tumors have overex­ pressed or amplified HER2 should receive HER2-targeted agents such as trastuzumab or trastuzumab, pembrolizumab, plus cyto­ toxic chemotherapy. Beyond first-line therapy, additional HER2targeted therapy using agents such as trastuzumab-deruxtecan, a monoclonal antibody-drug conjugate, is recommended for patients whose tumors have amplification of HER2/ERBB2. For patients with metastatic MSI/dMMRP gastric cancers, immune modulation therapy using either PD-1 inhibitors such as pembrolizumab or combinations such as nivolumab plus ipilimumab may be employed as first-line therapy; guidelines include the option of immune therapy plus chemotherapy.

When disease progresses after first-line treatment, other therapies include the combination of a VEGF receptor–targeted agent, ramu­ cirumab, either alone or in combination with paclitaxel. Immune modulation inhibitors are an option for second-line therapy for patients whose tumors are microsatellite unstable (e.g., nivolumab plus ipilimumab if single-agent pembrolizumab was used as firstline therapy). For patients with microsatellite stable gastric cancers (the large majority), immune modulators are an option if not used in the first-line setting, if PD-L1 is positive. As above, for patients with HER2/ERBB2-amplified tumors, trastuzumab-deruxtecan can be used. Several other cytotoxic agents have activity in the thirdline setting including trifluridine-tipiracil and irinotecan. Even with improvements in therapy including immune modulation therapy, the best results from clinical trials indicate overall survival for treated patients with stage IV disease is still only 12–15 months. Investiga­ tional studies include targeting Claudin 18.2, a cell surface type junc­ tion molecule that is overexpressed in ~50% of gastric cancers. In the SPOTLIGHT trial, previously untreated, HER2/ERBB2-negative patients assigned to zolbetuximab (targeting Claudin 18.2) plus FOLFOX chemotherapy had an improvement in survival compared to those receiving FOLFOX chemotherapy alone. Zolbetuximab plus chemotherapy may become another first-line option for advanced gastric cancer. Additional studies targeting Claudin 18.2 including those using chimeric antigen receptor (CAR) T cells are underway. CHAPTER 85 Upper Gastrointestinal Tract Cancers Radiation therapy using shorter regimens may be employed to palliate bleeding. For patients with advanced incurable disease, other supportive measures include placement of a duodenal stent to relieve gastric outlet obstruction; in selected patients, surgical pro­ cedures for gastric outlet obstruction may be performed. Radiation therapy might be used if not previously given. Enteral feeding using a jejunostomy tube may support nutritional needs. GASTRIC LYMPHOMAS Lymphomas of the stomach are an uncommon (~3%) but important subgroup of gastric malignancies. They are extranodal non-Hodgkin’s lymphomas (NHL). The gastrointestinal tract is the most common site for extranodal NHL, and the stomach is the most common site within the gastrointestinal tract. The presenting symptoms can be similar to those of the much more common adenocarcinoma of the stomach described above, including pain, anorexia, and bleeding. Symptoms of fever and night sweats occur in 10–15% of patients with gastric NHL. Because the treatment options are so different, obtaining adequate tis­ sue for definitive pathologic examination is crucial in diagnosing both gastric lymphomas (as opposed to adenocarcinoma) as well as defin­ ing the subtype of lymphoma. On occasion, this may be challenging because, similar to diffuse subtype adenocarcinoma, lymphomas may track below the mucosal surface. A fine-needle aspirate may not be suf­ ficient; multiple deep biopsies or mucosal resection may be needed to provide enough tissue for definitive pathologic assessment. Potential driving forces in the development of gastric lymphomas include active or prior H. pylori infection, which is associated with mucosa-associated lymphoid tissue (MALT) subtype gastric lympho­ mas and has been described as a potential driver in some patients with diffuse large B-cell lymphomas (DLBCLs). MALT lymphomas may

develop in nearly any organ, but the stomach is the most frequent pri­ mary site, accounting for ~35% of all MALT lymphomas. Identifying a MALT lymphoma is important because antibacterial therapy directed against H. pylori alone can be a highly effective treatment. Other infec­ tions should be considered either as driving factors or as risks from treatment, such as reactivation of hepatitis B virus (HBV); testing for HBV is recommended before initiation of lymphoma therapy. Hepatitis C infection has been associated with DLBCL and with marginal zone lymphomas. Other forms of NHL may involve the stomach either as primary gastric lymphoma or as a secondary site of disease, including both B-cell (e.g., mantle cell lymphoma, Burkitt’s lymphoma, and fol­ licular lymphoma) and T-cell lymphomas (e.g., enteropathy-associated T-cell lymphoma, anaplastic large-cell lymphoma, and peripheral T-cell lymphoma).

Staging is performed using similar imaging modalities as for gastric adenocarcinoma, but the staging systems are different (see below, and presented in more detail in the chapter on lymphomas [see Chap. 113]). As a staging study, FDG-PET/CT is performed, as well as a contrastenhanced, diagnostic-quality CT. FDG-PET/CT is used both as an initial staging study and to assess response. EUS may be used to deter­ mine depth of invasion in patients in whom no evidence of metastatic disease is noted. Examination of the peripheral blood and bone mar­ row aspirate should be considered as part of the workup. In all patients with gastric lymphoma, H. pylori infection status should be evaluated. If H. pylori testing is negative by histopathology, noninvasive testing by either stool antigen test or urea breath test should be used. PART 4 Oncology and Hematology ■ ■STAGING The TNM staging system is not employed for gastric lymphomas. Several classification systems are used for lymphomas, including the Lugano staging system (a modification of Ann Arbor staging), the revised World Health Organization (WHO) Fifth Edition of the WHO Classification of Haematolymphoid Tumours (WHOHAEM5), and the International Consensus Classification (ICC). These are discussed in Chap. 113 on lymphomas. The Lugano staging system for gastroin­ testinal lymphomas is still widely used; it divides patient groups into stages I, II, III, and IV. Stage I tumors are limited to the gastric wall; stage II tumors have regional lymph node involvement or invasion of local structures; stage III tumors have lymph node involvement above and below the diaphragm. Stage IV tumors have either more extensive lymph node involvement or have distant metastasis, including to the bone marrow or other extranodal sites. ■ ■PATHOLOGIC CLASSIFICATION The two most common histologic subtypes of gastric lymphoma are marginal zone B-cell lymphomas (gastric marginal zone B-cell lympho­ mas or MALT; ~40% of newly diagnosed patients) and DLBCLs (~55%). The distinction is critical because therapeutic options are different. The large majority of MALT cases are associated with H. pylori infection. The finding of a t(11;18) translocation identifies a subgroup less likely to respond to H. pylori eradication (or in non-H. pylori–associated MALT). This translocation may be detected using PCR or fluorescent in situ hybridization (FISH); it creates a chimeric protein composed of the amino terminal of API1 (apoptosis inhibitor) and the carboxy terminus of MALT1, leading to activation of nuclear factor-κB signaling. Note that even H. pylori–negative MALT tumors may respond to anti–H. pylori therapy. Other, rarer subtypes of primary gastric lymphomas include those of T-cell lineage. TREATMENT Gastric Lymphoma Unlike adenocarcinoma of the stomach, surgical resection has no role in the treatment of primary gastric lymphoma in the absence of complications of therapy such as perforation or uncontrollable bleeding. Resection of gastric lymphoma does not improve clinical outcomes. For patients with MALT lymphoma, eradication of H. pylori with antibiotics is highly effective therapy. If tests for H. pylori are

positive and t(11;18) translocation assay is negative, one of the cur­ rently accepted antibiotic regimens for treating H. pylori should be the initial therapy. H. pylori eradication is associated with high response rates including complete remissions in the majority of patients. Treatment with an anti–H. pylori regimen may induce remission even in patients in whom standard testing for H. pylori, described above, is negative. The time to remission may be pro­ longed (in some studies averaging 15–16 months); therefore, careful monitoring is important before determining that a MALT tumor is not responding to anti–H. pylori therapy. For patients in whom the t(11;18) translocation assay is positive, options for therapy include anti–H. pylori antibiotic therapy plus involved-field radiation ther­ apy or, if radiation is contraindicated, the use of single-agent ritux­ imab, a monoclonal antibody targeting CD20. For patients who are H. pylori negative, in whom anti–H. pylori therapy may have been used without response, moderate-dose (24–30 Gy) involved-site radiation therapy or single-agent rituximab is a treatment option. For selected, more advanced, stage IV MALT patients who

have not responded to or who have progressed after receiving anti–H. pylori antibiotic therapy and/or rituximab, cytotoxic che­ motherapy regimens such as R-CHOP (rituximab, cyclophospha­ mide, doxorubicin, vincristine, and prednisolone), dose-adjusted R-EPOCH (an infusional regimen of rituximab, etoposide, prednis­ olone, vincristine, cyclophosphamide, and doxorubicin), or ritux­ imab and lenalidomide may be considered. DLBCL may be a result of transformation from more indolent MALT lymphoma or may arise de novo. De novo tumors are more likely to be BCL2 and CD10 positive. MALT lymphomas that have transformed to DLBCLs are more frequently BCL2 and CD10 negative. For patients with DLBCL, earlier-stage tumors may be treated by combination chemotherapy alone or chemotherapy plus involvedfield radiation therapy. For more advanced gastric DLBCL tumors, chemotherapy using the R-CHOP or R-EPOCH regimen is stan­ dard therapy. Some reports have suggested that eradication of H. pylori is effective treatment for early-stage DLBCL when the patient also has H. pylori. UNCOMMON TUMORS OF THE ESOPHAGUS AND STOMACH ■ ■GASTROINTESTINAL STROMAL TUMORS GISTs are rare tumors of the gastrointestinal tract associated with activating somatic mutations in the cKIT (the majority) or PDGFRA genes; in a minority of cases, neither gene is mutated. GISTs arise from Cajal cells, which bridge between the autonomic nerves to the muscle layer of the bowel. The stomach is the most frequent primary site (~60%), followed by the small bowel in about 25%. As endoscopy for other indications has become more widely used, otherwise asymp­ tomatic and probably clinically insignificant small GISTs have been identified more frequently; it is not clear that the actual incidence has substantially increased. Symptoms associated with GISTs include acute gastrointestinal bleeding leading to melena and/or hemateme­ sis. Anemia may be reflected in generalized weakness. With larger tumors, abdominal distention and pain may be presenting symptoms. At endoscopy, a nonspecific smooth bulging mass covered by normal mucosa is the most frequent finding. Initial biopsy may not reveal a mesenchymal neoplasm. The radiologic features found on diagnostic CT scan (which may identify an asymptomatic tumor) may raise the question of a GIST tumor. EUS can be performed, but if biopsy is done, it may not provide an adequately cellular specimen to allow genomic sequencing, which is required to help guide systemic therapy (if needed). Histologically, a spindle cell neoplasm is the most common subtype (~70%), with epithelioid cells making up 20%; 10% of cases are mixed histology. KIT expression is found in ~95% and PDGFRA in ~80% of cases. NGS is usually used to assess for gain-of-function KIT, PDGFRA, or other, rarer mutations.

For nonmetastatic GIST tumors, risk of recurrence assessment (guiding use of postoperative therapy) is based on the size of the pri­ mary tumor, mitotic index, and location in the gastrointestinal tract. For gastric GISTs, resected tumors ≤2 cm with a mitotic index of ≤5% have a near 0 risk of progression. For larger tumors, especially those ≥10 cm, with a mitotic index >5%, the risk is moderate to high. Post­ operative adjuvant imatinib for 3 years is a standard-of-care option. Avapritinib is used for tumors with certain PDGFRA mutations. For patients with metastatic disease, imatinib (for KIT mutation–bearing tumors) or avapritinib (targeting PDGFRA) is used; the location of the KIT mutation (exon 11 vs 9) is associated with degree of effectiveness. However, resistance almost invariably develops, and the development of newer agents effective in tumors with secondary mutations is a high priority; ripretinib, which targets both KIT and PDGFRA, is now also FDA approved. ■ ■SMALL-BOWEL NEOPLASMS Small-bowel neoplasms make up ~3% of gastrointestinal tumors; in 2023, 12,000 new cases are expected in the United States. The spectrum of malignant small-bowel neoplasms includes neuroendocrine tumors (NETs; carcinoid), adenocarcinomas, lymphomas, and GISTs. In the United States, NETs, which have increased in incidence, are slightly more frequent (40–45%) than adenocarcinomas (30–40%), with the remainder mostly lymphomas and ~8% GISTs. The duodenum is the most common portion of the small bowel in which malignancies develop (~50%), with ~30% occurring in the jejunum and 20% in the ileum. NETs are the most common benign and malignant tumors of the ileum. Risk factors for the development of small-bowel adeno­ carcinoma include inflammatory bowel disease (Crohn’s disease); inherited germline mutation syndromes such as Lynch syndrome, familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome; and celiac disease (which is also associated with an increased risk for lymphomas). While an asymptomatic small-bowel primary adenocarcinoma might be found during surveillance in patients at high risk (e.g., FAP), for many small-bowel tumors, the finding of positive stool occult blood, unexplained anemia, or small-bowel obstruction leads to the diagnosis. Both adenocarcinoma and lymphomas might present with perforation. Evaluation by diagnostic CT imaging may reveal a smallbowel lesion. CT and/or magnetic resonance enterography (CTE or MRE) have a high positive predictive value (for adenocarcinoma, MRE appears to be more accurate). A variety of endoscopic techniques are used for diagnostic evaluation of the small bowel, including deviceassisted enteroscopy (DAE), e.g., double-balloon enteroscopy; smallbowel capsule endoscopy (SBCE) may also be employed. DAE allows tissue diagnosis; a tattoo helps localize the small bowel neoplasm (SBN) for resection; DAE may also allow stent placement for palliation of obstruction. SBCE is contraindicated in the setting of obstruction. As is the case for gastric imaging studies, deep learning artificial intelli­ gence is being studied to improve the analysis of small-bowel imaging. For NETs, a gallium-68 or copper-64 DOTATATE scan may identify both the primary site as well as metastatic disease. Blood tumor bio­ markers are nonspecific for the primary site (e.g., CEA or CA19-9 for adenocarcinoma); these assays are better used to monitor response or progression of disease rather than for diagnosis. The median age at diagnosis for sporadic small-bowel adeno­ carcinoma is in the seventh or eighth decade of life, but genetically predisposed patients and those with inflammatory bowel disease may be diagnosed at a much earlier age. African Americans have a higher incidence of small-bowel cancer than whites. While systemic therapies are usually modeled on agents used to treat colorectal cancer, genomic analyses have indicated that small-bowel adenocarcinoma has distinct genomic alterations compared to either colorectal or gastric cancers. Genomic alterations less frequent in small-bowel than in colorectal cancers include TP53, BRAF V600E, and APC mutations, whereas the rate of KRAS mutations is similar to colorectal cancer (a genomic analysis of Chinese small-bowel cancer patients, mostly duodenal cancers, noted a somewhat different profile than U.S. patients). Within small-bowel sites, the most striking difference is the higher rate of

ERBB2 alterations (of which a minority are amplifications) in duodenal cancers. Not surprisingly, because Lynch syndrome increases the risk of small-bowel adenocarcinoma, 15–20% of these tumors are MSI high or mismatch repair deficient; small-bowel adenocarcinoma associated with celiac disease also may have an increased rate of MSI-high tumors. MSI/MMRP status should be assessed in all patients with small-bowel adenocarcinoma. Somatic tumor genomic analysis may suggest a germline mutation, but appropriate genetic testing for a germline driver mutation should be performed in all patients with small-bowel adenocarcinoma.

Small-bowel adenocarcinoma has its own staging classification in the eighth edition of the AJCC Cancer Staging Manual. TREATMENT Small-Bowel Adenocarcinomas Surgical resection with negative microscopic margins (R0), as is the case for other gastrointestinal tumors, is the best chance for cure. For duodenal adenocarcinomas, a Whipple procedure may be needed; for more distal duodenal cancers and jejunal adenocar­ cinomas, a segmental resection with adequate margins should be performed. Distal ileal tumors may require right hemicolectomy. CHAPTER 85 Small-bowel cancers are frequently found with locally advanced disease at the time of diagnosis. If the tumor is resectable, post­ operative adjuvant systemic therapy is currently recommended for lymph node–positive patients, using regimens such as those employed for colorectal cancer (capecitabine and oxaliplatin or FOLFOX). Benefit from adjuvant therapy has not yet been proven. Small-bowel cancers developing in patients with Lynch syndrome probably have a better prognosis; if colorectal cancer is a model, postoperative adjuvant therapy for patients with Lynch syndrome may include consideration of immune modulation therapy. For duodenal cancers, chemoradiation is considered if the resection margins are still positive. Upper Gastrointestinal Tract Cancers For patients with advanced metastatic disease, in the absence of Lynch syndrome or a hypermutated tumor, similar cytotoxic regi­ mens as deployed for gastric (duodenal) or colon cancers (jejunum or ileum) have been widely used. For tumors that are MSI high or dMMRP positive, immunotherapy is indicated; for tumors that are HER2 amplified or BRAF mutated, targeted therapy may be useful. ■ ■SMALL-BOWEL GASTROINTESTINAL STROMAL TUMORS Like small-bowel adenocarcinomas, small-bowel GISTs may pres­ ent with obstruction or bleeding. Diagnostic techniques are those employed for other small-bowel neoplasms. While the pathological criteria for malignant potential are somewhat different than those used for gastric GISTs, postoperative management and treatment of meta­ static disease are the same as those described above for gastric GIST. ■ ■BENIGN NEOPLASMS OF THE SMALL BOWEL As is the case for malignant small-bowel tumors, benign neoplasms of the small bowel are rare. In addition to cancers, the precursor lesion adenomas or hamartomas (from which cancers develop) may be driven by inherited cancer susceptibility genes (e.g., FAP, Lynch syndrome, Peutz-Jeghers syndrome). Other benign neoplasms include lipomas, leiomyomas, neurofibromas, and benign lymphoid nodular hyperplasia. Patients with benign small-bowel neoplasms not associated with an inherited cancer susceptibility gene (in which case, a benign tumor may be found during surveillance) are usually asymptomatic. A mass may be noted on an imaging study (usually a CT) ordered for another reason. Workup for occult or overt bleeding or intussusception of the bowel may lead to the discovery of a benign small-bowel neoplasm. Diagnostic evaluation is similar to that described above for malig­ nant tumors. In general, benign neoplasms, if found during surveil­ lance, are removed endoscopically, if technically feasible, to decrease the risk of intussusception in Peutz-Jeghers syndrome. Mucosectomy may be used to treat bleeding hemangiomas.

NEUROENDOCRINE TUMORS OF THE ESOPHAGUS, STOMACH, AND SMALL BOWEL Neuroendocrine neoplasms include NETs (more well differentiated, classified as grades 1–3) and neuroendocrine carcinomas (NECs). Neuroendocrine neoplasms including pancreas NETs are described in detail in Chap. 89. The following describes NET and NEC of the esophagus, stomach, and small bowel.

■ ■ESOPHAGEAL AND GASTRIC NEUROENDOCRINE TUMORS NETs of the esophagus are rare, accounting for <1% of gastrointestinal NETs. Presenting symptoms are similar to those of SCC or adenocarci­ noma of the esophagus, with dysphagia or odynophagia or with more nonspecific symptoms such as substernal discomfort or burning consis­ tent with reflux esophagitis. A potential driving factor of NEC is smok­ ing. The initial diagnostic evaluation includes upper endoscopy and biopsy. Pathology may reveal a well-differentiated NET (grades 1–3; grade guided by percent Ki-67 positivity) with a low to relatively low metastatic potential; at the other end of the spectrum are small-cell or large-cell NECs, which are fully malignant and frequently metastasize. In the absence of metastatic disease, EUS to assess depth of penetra­ tion and presence or absence of regional lymph node metastasis is fre­ quently performed. Imaging studies include CT; for high-grade NEC, an FDG-PET/CT scan to assess for metastatic disease is done. For NET, somatostatin receptor imaging studies such as gallium-68 or copper-64 DOTATATE scans may be performed if metastatic disease is suspected. PART 4 Oncology and Hematology Gastric NETs (also called gastric carcinoid tumors) represent 7–9% of gastrointestinal NETs but <1% of gastric neoplasms; several types have been described, based in part on whether there is associ­ ated achlorhydria and hypergastrinemia. For all gastric NETs, initial evaluation includes upper endoscopy and biopsy. EUS may be help­ ful in assessing depth of invasion for larger tumors and for assessing regional lymph node metastases in higher grade tumors. Somatostatin analogue imaging using DOTATATE scanning may be performed if metastatic disease is suspected. As is the case for other NETs, the finding of unresectable metastatic disease that is DOTATATE avid not only provides staging information but also guides potential therapy using somatostatin receptor–targeted therapy. See Chap. 89 for a more detailed discussion. TREATMENT Esophageal Neuroendocrine Tumors For early-stage, lower-grade NETs, endoscopic resection including EMR or ESD may be performed. Surgery may be employed for more advanced-stage locoregional but not metastatic NET. Smallcell or large-cell NECs that are not metastatic are usually treated with chemotherapy plus external-beam radiation therapy using chemotherapy regimens similar to those employed for small- and large-cell neuroendocrine cancers of the lung (Chap. 83). For metastatic NETs, somatostatin receptor DOTATATE scans guide therapy. See below discussion for small-bowel NETs for discus­ sion of use of somatostatin receptor blockade with agents such as octreotide or lanreotide and the use of peptide-related radiation therapy (PRRT). Systemic therapy for metastatic small- and largecell esophagogastric NECs is also modeled on therapy for small- and large-cell thoracic NECs. TREATMENT Gastric Neuroendocrine Tumors Type 1 tumors can be treated endoscopically with polypectomy or endomucosal resection. For larger tumors (>2 cm) or tumors invad­ ing through the muscularis or to regional lymph nodes, surgical resection is recommended. Type 2 tumors have a higher risk for regional lymph node metastasis and are usually treated surgically,

although selected patients may have a combination of endoscopic resection and limited surgical resection. Type 3 tumors are not asso­ ciated with elevated gastrin levels and have a higher propensity for regional lymph node metastasis and distant metastasis. Surgery is the treatment of choice for localized type 3 tumors, although EMR has been used in selected patients. Adenocarcinoma of the stomach may be found in 5–10% of type 3 tumors. The role of surgery in mixed NEC-adenocarcinoma neoplasms is not well established. ■ ■NEUROENDOCRINE TUMORS (CARCINOID)

OF THE SMALL BOWEL In the United States, NET are the most common small-bowel neo­ plasms. For not yet identified reasons, the incidence of small-bowel carcinoid tumors has markedly increased over the past several decades. A recent study found a 9% incidence of inherited germline cancer susceptibility genes in patients with small-bowel NET; however, it is unlikely that this is the cause of the increased incidence (Chap. 89). Even with an increase in incidence, small-bowel NETs are still uncom­ mon (~12 cases per million in the United States); the disease is more common in African Americans than whites. Anatomically, the ileum is the most common part of the small bowel affected (~49%), followed by the duodenum and the jejunum. The same grading system, based on histology and the Ki-67 prolifera­ tive index or mitotic count, as for other gastrointestinal NETs is used. In the absence of metastatic disease to the liver in the subgroup of patients whose tumors are functional (i.e., produce a hormone, usually serotonin; a duodenal NET may produce gastrin), presenting symp­ toms may be vague abdominal discomfort until or unless small-bowel obstruction occurs. Carcinoid syndrome (including diarrhea and/ or flushing) may occur in patients whose tumors are diagnosed with already established hepatic metastasis. Because the liver is very efficient at clearing serotonin on first pass, carcinoid syndrome as a result of small-bowel carcinoid tumors usually does not occur in the absence of hepatic metastasis. Clinical evaluation includes a diagnostic-quality CT or MRI of the abdomen and pelvis. For duodenal NET, upper endoscopy with EUS is also performed. For ileal NET, colonoscopy with evaluation of the terminal ileum is performed. Imaging studies are similar to those used for diagnosis and localization of small-bowel adenocarcinomas. Somatostatin analogue imaging using gallium-68 or copper-64 DOT­ ATATE PET/CT is helpful in assessing extent of disease in patients whose tumors are somatostatin analogue avid, as well as in identify­ ing patients who may benefit from therapy targeting the somatosta­ tin receptor. Plasma or urine assay for 5-hydroxyindoleacetic acid (5-HIAA) is performed to assess for a functional small-bowel NET. The AJCC Ninth Edition Cancer Staging Manual has a specific small-bowel NET TNM stage classification (for the duodenum and ampulla and for the jejunum and ilium). The majority of patients present with locoregional disease, with approximately 40% having identified lymph node metastasis. Ten to 15% of patients have metastatic disease (usually to the liver) at the time of initial diagnosis. Initial management should be surgical resection with curative intent; for patients with extensive adenopathy involving the root of the mesen­ tery, vascular reconstruction may be required. Since small-bowel NETs may involve multiple tumors (15–30% of patients), the entire small bowel should be carefully examined at surgery. For patients with func­ tional carcinoid tumors, somatostatin analogue therapy using agents such as octreotide should be given before the induction of anesthesia to avoid a carcinoid crisis. For patients with hepatic metastasis, resec­ tion or regional therapy including ablation or hepatic artery emboliza­ tion for functional tumors may provide effective palliation. Carcinoid syndrome may also be palliated by somatostatin receptor–targeted therapy in the patients in whom DOTATATE scanning is positive (the majority of patients with carcinoid syndrome), including agents such as octreotide or lanreotide, or by peptide-directed radiation therapy using agents such as lutetium-177. Everolimus, an mTOR kinase inhibitor, has modest activity in metastatic small-bowel carcinoid tumors.