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Protocol for the Examination of Specimens from Patients with Carcinoma of the EsophagusProtocol applies to epithelial tumors of the esophagus and esophagogastric junction, including all carcinomas and well-differentiated neuroendocrine tumors and all epithelial tumors involving the esophagogastric junction with center no more than 2 cm into the proximal stomach. This protocol does not apply to tumor involving the esophagogastric junction (EGJ) with the tumor midpoint more than 2 cm into the proximal stomach, tumor midpoint less than 2 cm into the proximal stomach but not involving the EGJ, lymphoma, gastrointestinal stromal tumor (GIST), or non-GIST sarcoma. Based on: AJCC Cancer Staging Manual, Eighth Edition pTNM requirementsCAP Cancer Protocol: Esophagus 4.2.0.0CAP Protocol Web Posting Date: June 2021AAPA Macroscopic Examination Template Edition 3.0AAPA Web Posting Date: Revision History: 1st Edition – April 20172nd Edition – December 2018Summary of Changes: This protocol is revised to the 8th edition of the AJCC Cancer Staging Manual and the current version of the CAP Cancer Protocol Esophagus 4.2.0.0.This is a major revision to the protocol. Extensive changes have been made throughout the document.Procedures Covered in this Protocol:Esophagus biopsyEndoscopic resectionEsophagectomyEsophagogastrectomyAuthors:Drew Sciacca, PA(ASCP)CM*, Patrice Brown, PA(ASCP)CM, Lainee Bulawa, PA(ASCP)CM, Heidi Cheek, PA(ASCP)CM, Heather Gaburo, PA(ASCP)CM, Courtney Hyland, PA(ASCP)CM, Monica Kendall, PA(ASCP)CM, Darryl Kinnear, PA(ASCP)CM, Erika Paulsen, PA(ASCP)CM, Molly Person, PA(ASCP)CM, Dennis Strenk, PA(ASCP)CM, Constance Thorpe, PA(ASCP)CM, Jon Wagner, PA(ASCP)CM*Denotes primary author. All other contributing authors are listed alphabetically.Previous Lead Contributors: Patricia Docken (Bascom) PA(ASCP)CM, Susan Faasse, PA(ASCP)CM, Heather Gaburo, PA(ASCP)CM, Simarjit Kaur, PA(ASCP)CM, Mike Kisiel, PA(ASCP)CM, Edgar Masmila, PA(ASCP)CM, Erika Paulsen, PA(ASCP)CM, James Romnes, Sr., PA(ASCP)CM, Deborah Sullivan, PA(ASCP)CM, Brooke Walsh, PA(ASCP)CMArt Director: Jesse McCoy, BFA, MHS, PA(ASCP)CMPhotograph Curator:Lainee Bulawa, MS, PA(ASCP)CMIllustrators:Jesse McCoy, BFA, MHS, PA(ASCP)CMTami TolpaStructured Macroscopic ReportCarcinomas of EsophagusProcedure ____ Esophagus biopsy____ Endoscopic resection ____ Esophagectomy____ Esophagogastrectomy ____ Other (specify): ______________________________________________________________________ Not specifiedNature of Specimen Received____ Fresh +____ Frozen section (intraoperative consultation) +____ Tissue collected for ancillary diagnostic studies, (specify test): _________________________ In fixative Fixative type:___________________________________________________________________+ Cold ischemic time: ____________________________________________________________+ Fixation time (specify if for entire specimen or specific components):__________________________ Other transport media (specify):______________________________________________________Specimen Orientation+____ Specimen oriented+____ Oriented by surgeon (specify):________________________________________________+____ Oriented based on anatomic landmarks+____ Not orientedInk Key+____ Ink applied (provide anatomic site and color applied): ____________________________________Overall Dimensions (cm)___ x ___ x ___ cmSpecimen Anatomical Components and Size____ Esophagus___ cm length x ___ cm circumference___ cm wall thickness____ Proximal Stomach___ (greater curvature) x ___ (lesser curvature) x ___ (width) cm ___ cm wall thickness____ Other (specify): __________________________________________________________________Macroscopic Tumor____ Absent____ PresentTumor Focality____ Unifocal____ MultifocalNumber of tumors _______ Indeterminate (explain): ____________________________________________________________Tumor Site (select all that apply) ____ Cervical / proximal esophagus ____ Mid esophagus, upper thoracic esophagus____ Mid esophagus, middle thoracic esophagus____ Mid esophagus, not otherwise specified ____ Distal esophagus (low thoracic esophagus) ____ Esophagogastric junction (EGJ)____ Proximal stomach / cardia ____ Other (specify): ______________________________________________________________________ Esophagus, not otherwise specifiedRelationship of Tumor to Esophagogastric Junction____ Tumor is entirely located within the tubular esophagus and does not involve the esophagogastric junction____ Tumor midpoint lies in the distal esophagus and tumor involves the esophagogastric junction ____ Tumor midpoint is located at the esophagogastric junction ____ Tumor midpoint is 2 cm or less into the proximal stomach or cardia and tumor involves the esophagogastric junction # ____ Not specified ____ Cannot be assessed # Use the stomach cancer protocol if either (A) the tumor involves the EGJ, but the midpoint is more than 2 cm into the proximal stomach or (B) the midpoint is less than 2 cm into the proximal stomach, but the tumor does not involve the EGJ.Distance of tumor center from esophagogastric junction (specify, if applicable): ___ cmTumor Size Greatest dimension: ___ cm + Additional dimensions ): ___ x ___ cm ___ Cannot be determined (explain): _________________________________________________________Macroscopic Extent of Tumor____ Cannot be assessed ____ No evidence of primary tumor ____ Tumor confined to mucosa ____ Tumor invades the submucosa ____ Tumor invades the muscularis propria ____ Tumor invades adventitia ____ Tumor invades adjacent structures / organs # (specify): ___________________________________# The adjacent structures of the esophagus include the pleura, pericardium, azygos vein, diaphragm, peritoneum, aorta, vertebral body, and airway.Macroscopic Appearance of Tumor +Color _______HomogeneousVariegated+ShapeEndophyticExophyticUlcerated Sessile+Cut surface appearanceHemorrhagicSolidCystic+ConsistencyFibrousFirmFriableMacroscopic Margin InvolvementFor esophagectomy and esophagogastrectomy specimens only:Proximal Margin ____ Cannot be assessed____ Macroscopically uninvolved by tumor+Distance of tumor from proximal margin: ___ cm____ Macroscopically involved by tumorDistal Margin ____ Cannot be assessed____ Macroscopically uninvolved by tumor+Distance of tumor from distal margin: ___ cm____ Macroscopically involved by tumorRadial Margin *____ Cannot be assessed____ Macroscopically uninvolved by tumor+Distance of tumor from radial margin: ___ cm____ Macroscopically involved by tumor*The circumferential / radial margin represents the adventitial soft tissue margin closest to the deepest invasion of tumor.Other Margin(s) (required only if applicable) Specify margin(s): _____________________________________________________________________ ____ Cannot be assessed ____ Macroscopically uninvolved by tumor____ Macroscopically involved by tumorFor endoscopic resection specimens onlyMucosal margin____ Cannot be assessed____ Macroscopically uninvolved by tumor+Distance of tumor from mucosal margin: ___ cm____ Macroscopically involved by tumorDeep margin____ Cannot be assessed____ Macroscopically uninvolved by tumor+Distance of tumor from deep margin: ___ cm____ Macroscopically involved by tumorOther Margin(s) (required only if applicable) Specify margin(s): _____________________________________________________________________ ____ Cannot be assessed ____ Macroscopically uninvolved by tumor+Distance of tumor from margin: ___ cm____ Macroscopically involved by tumor+Macroscopic Appearance of Uninvolved Tissues / Organ(s)+____ Esophageal mucosa:Color____Longitudinal mucosal folds+____ Gastric mucosa if present: Color____ Rugated+____ Esophagogastric junction, if uninvolved:Color____Congestion+____ Diaphragm:Color____SmoothRough+____ PericardiumColor____MembranousSmoothRoughRegional Lymph Nodes ____ No nodes submitted or identified Number of Lymph Nodes Examined: ___ Indeterminate (explain): __________________________________________________________ +Number and location (esophageal, gastric, or other) of lymph nodes: _____________________Number of Lymph Nodes Involved: ___ Indeterminate (explain): __________________________________________________________+Number and location (esophageal, gastric, or other) of involved lymph nodes: ______________Size of lymph nodes in three dimensions: ___ x ___ x ___ cm or range in size: ___ - ___ cm+ Tissue Submitted for Research (specify, if possible):_______________________________________(+) Data elements preceded by this symbol are optional elements which may be clinically important but are not yet validated or regularly used in patient management.Recommended Block Allocation Key Esophagectomy and esophagogastrectomy specimens onlyA1:Proximal margin (en face, perpendicular if < 1 cm)A2-A4:Distal margin (en face, perpendicular if < 1 cm)A5-___: One cassette per 1 cm of greatest dimension of tumor (at least 5 sections OR if small enough, entirely submit) A6:Tumor with closest radial / adventitial margin* A7:Tumor with greatest depth of invasionA8:Tumor with closest esophagogastric junction (EGJ), if possibleA9:Tumor with adjacent uninvolved mucosaA10:Uninvolved esophageal mucosa proximal to tumor A11:Uninvolved esophageal mucosa distal to tumorA12:Representative uninvolved stomach (or stomach with any lesions)A13-A15: Regional lymph nodes*If the patient had neoadjuvant therapy, full-thickness sections of the entire tumor bed must be submitted to evaluate for viable tumor cells.Endoscopic resection specimens onlyUnoriented specimenA1:Ends (en face)A2-A10:Central specimen (A4-5 to include lesion) (perpendicular margins)Oriented specimenA1:Superior end (en face)A2:Inferior end (en face)A3-A10:Central specimen (A4-A5 to include lesion) (perpendicular margins)References:Amin MB, Edge SB, Green FL, Byrd DR, et al. (Eds.) AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.Bejarano PA, Berho M. Examination of surgical specimens of the esophagus. Arch Pathol Lab Med. 2015:139:1446-1454.Lester S. “Gastrointestinal Specimens.” In Manual of Surgical Pathology, 3rd ed. Philadelphia, PA: Elsevier Saunders; July 2010:323-328Specimen Handling / Dissection GuidelinesEsophagus biopsyMeasure and count the number of fragments present.If there is a great disparity in size, separate the fragments into similar sizes and submit together in the same cassette.If applicable, indicate number of tissue fragments in cassette(s).Entirely submit.Endoscopic mucosal resectionOrient the specimen if designation is present.Measure the specimen; surface, with depth of excision.If oriented, state the measurements based on the orientation provided.Assess the integrity of the deep margin, noting any defects.Ink the mucosal and deep margins.If oriented, ink according to institutional protocol.If unoriented, ink the margins one color.Differentially ink defects.Measure the tumor in three dimensions. The third dimension is depth of invasion and is measured after sectioning.Serially section through the specimen perpendicular to the long axis. Examine the cut surface for invasion, using the muscularis propria as a macroscopic landmark.Measure the tumor to the closest mucosal margin.If oriented, state the anatomic location of the closest mucosal margin.Measure the greatest tumor depth of invasion (third dimension of the tumor) and measure the distance of the tumor to the deep margin.Submit the specimen entirely with opposing margins en face and remaining cross sections perpendicular to the remaining margins. Esophagectomy or Esophagogastrectomy specimenIdentify and measure specimen components:Esophagus - length and circumference (or diameter).Stomach - greater curvature length, lesser curvature length, range of circumference.Adipose tissue – thickness or quantitative assessment (minimal, moderate, extensive).Any additional structures present (e.g., diaphragm, pleura, pericardium, etc.).Describe the external surface (color, adhesions, puckering, induration, stricture). Note any defects / perforations present and their relation to the tumor.Ink the adventitial surface and serosa overlying the EGJ, differentially inking any defects / perforations. If the tumor is less than 1.0 cm from the proximal or distal margin, differentially ink that margin.Open the specimen; avoid cutting through the tumor.Photograph the opened specimen.State the location of the tumor (proximal, mid, distal esophagus).Specify if the tumor involves the EGJ and / or proximal stomach.Specify if the midpoint of the tumor is in the esophagus, EGJ or within the proximal 2 cm of the stomach. (If the midpoint is in the stomach > 2 cm of the EGJ, this is considered a stomach tumor). (Figure 1, page 12)Describe the tumor.Measure in three dimensions, the third dimension being the deepest invasion, specifying the maximal longitudinal dimension.Measure the tumor to the proximal, distal, and adventitial / radial margins.State the percentage of the esophageal wall circumference involved by tumor.State location of epicenter of tumor, and distance / relationship to EGJ.State relative proportions of tumor in the esophagus versus the stomach.Describe shape, color, consistency, and appearance of the cut surface.*Note: If there is prior treatment, the presence of residual tumor may not be obvious. There may be an area of mucosal induration / erosion and the subjacent cut surface may be firm and fibrous.Document the depth of invasion through mucosa, muscularis, adventitia / serosa or adipose tissue. (Figure 2, page 13)The amount of invasion related to the muscularis propria will distinguish the stage of the tumor. Provide a statement describing the depth of invasion using the muscularis propria as a landmark (i.e., “Does not involve the muscularis propria,” “invades into but not through the muscularis propria,” or “invades through the muscularis propria into the adventitia”). Respectively these descriptions will distinguish between a pT1, pT2, and pT3 tumor.If there is no definitive tumor identified, state the appearance of the cut surface.If there is visible tumor present, submit one section per centimeter of the mass’s greatest dimension, including the greatest depth of invasion, relationship to the adventitial margin, EGJ, uninvolved mucosa, and other adjacent structures.If there is no visible tumor present, most likely in treated specimens, it is necessary to submit the entire area of suspected tumor to determine the effectiveness of the treatment. The area of tumor may appear fibrotic with areas of mucin present.Microscopic foci of cells are important to grading treatment effect and can easily be missed if the entire area is not examined. Per institutional protocol, the tumor site may be mapped out on a photograph of either the intact specimen or the individual slices after sectioning. Submission of the remaining (EGJ) may be required if:No tumor is identified, and initial biopsy and imaging reports tumor present at the EGJ.A tumor is present at the EGJ and after submission of sections previously listed, the remaining EGJ can be submitted in < 5 blocks.Institutional protocols require submission of the entire EGJ.Describe the remaining esophageal and gastric mucosa.Dissect adventitial and perigastric adipose tissue for lymph nodes. The periesophageal soft tissue should be dissected thoroughly to maximize the lymph node yield. Describe and submit all lymph nodes found, designating them as periesophageal or perigastric.Esophageal CarcinomaIntroductionThe two main histological classifications of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. These two subtypes differ in their prognosis, tumor location, pathology, and epidemiology. Adenocarcinoma typically is found below the tracheal bifurcation and has a better prognosis compared to SCC. It is the most common esophageal carcinoma subtype in the United States, accounting for over half of the cases. Conversely SCC is usually found near the tracheal bifurcation, shows an earlier lymphatic spread, and has a worse prognosis. Outside of the United States squamous cell carcinoma has historically been the most common subtype. Other less common subtypes include mucoepidermoid carcinoma, adenosquamous carcinoma and undifferentiated carcinoma. Neuroendocrine tumors, ranging from well-differentiated to poorly-differentiated are also seen in the esophagus.Incidence and EpidemiologyEsophageal adenocarcinoma prevalence varies 60-fold worldwide from high to low incidence regions. The highest incidence of esophageal adenocarcinoma can be found in the region spanning from northern Iran through central Asia and into northern China. Esophageal adenocarcinoma occurs 7 times more frequently in Caucasian men than women. Long standing gastroesophageal reflux disease (GERD) and Barrett’s esophagus are the most common contributing factors to esophageal adenocarcinoma. Individuals with Barrett's esophagus have a 30-60 times greater risk of developing adenocarcinoma. The most common risk factors for Barrett’s esophagus, and thus, esophageal adenocarcinoma, include high body mass index, chemotherapy, and genetic dispositions such as cystic fibrosis. Worldwide SCC is the most common subtype of esophageal cancer with the highest incidence occurring in central and eastern Asia. This higher incidence has been linked to environmental risk factors especially tobacco and alcohol use but also low intake of fresh fruits and vegetables, low socioeconomic status, and drinking hot beverages. In the United States squamous cell carcinoma (SCC) occurs 4 times more frequently in men than women, is six times more common in people of African descent than people of European descent and is often found in adults older than 45 years of age. Smoking is a major risk factor for SCC, occurring 5 times more in smokers than non-smokers. Additional risk factors include alcohol consumption, achalasia, previous thoracic radiation, caustic esophageal injury, frequent consumption of hot beverages, and tylosis (autosomal dominant disorder characterized by hyperkeratosis of palms and soles). Plummer Vinson syndrome is also a risk factor which is characterized by a classic triad of dysphagia, iron deficiency anemia, and esophageal webs. Another known association is SCC found in other locations including the oropharynx and larynx, some of which show clear-cut evidence of high-risk human papillomavirus (HPV) infection. Patients with Bloom syndrome (mutation in the BLM gene) can be affected by various leukemias and lymphomas as well as SCC of the esophagus after 20 years of age. Fanconi anemia is also a risk factor with specific genes involved based the specific complementation groups A-E. These mutations increase the frequency of SCC of the esophagus and other squamous epithelium.Morbidity and MortalityWorldwide, esophageal cancer is the 7th most common cancer and 6th leading cause of cancer-related deaths. Within North America in 2019, it was the 20th most common cancer and 11th cause of cancer-related deaths. The 5-year survival rate varies for every stage. Clinical PresentationClinical presentation consists of dysphagia, odynophagia, weight loss, hematemesis, chest pain, and vomiting. Occasionally, the first symptoms are caused by aspiration of food via a tracheoesophageal fistula. Adenocarcinoma may be found during routine evaluation for gastroesophageal reflux disease or Barrett’s esophagus. A small number of patients may present with hypercalcemia secondary to parathyroid hormone-related protein production by the tumor. Up to 3% of patients with esophageal SCC have concurrent head and neck SCC. Imaging Considerations After a history and physical examination, the patient is evaluated using upper GI endoscopy / biopsy to determine the presence and location of any suspicious lesions. A double contrast barium study may also be useful in diagnosis, as it can identify benign and malignant structures and evaluate the motility of the esophagus. Motility of the esophagus is important to evaluate as patients with conditions such as achalasia, which is a disorder of the esophageal sphincter and smooth musculature of the esophageal body, were found to have a 16-fold increase in esophageal cancer. Benign lesions appear as narrow areas with smooth contours and tapered proximal and distal margins while malignant lesions appear as ulcerated mucosa with asymmetric narrowing with abrupt, shelf-like margins and irregular contours. Endoscopic ultrasound is useful in locoregional staging as detailed images demonstrate the surrounding strucutres and layers of the esophageal wall allowing for idenification of tumor invasion. Computed tomography (CT) scan of the chest / abdomen and potentially the pelvis is used to clinically stage the disease and determine which patients may be suitable for surgical resection. If the tumor appears to be T1a or T1b, based on imaging findings, an endoscopic resection will be performed. Potential areas of metastatic disease seen on imaging will be biopsied. CT is the best initial modality for detection of the distant?metastasis, gross direct invasion, and enlarged lymph nodes. Pertinent AnatomyEsophagogastric Junction vs Squamocolumnar JunctionThe esophagogastric junction (EGJ) is the point at which the tubular esophagus meets the wider stomach. The squamocolumnar junction (SCJ) is the point at which the smooth white-tan esophageal stratified squamous mucosa transitions into the granular pink-tan gastric columnar mucosa. It is important to know that the SCJ may not be present at the EGJ, as seen in Barrett’s esophagus. When assessing the location of the tumor, it is the EGJ that is used as a reference point, not the SCJ. It is important to document when the SCJ is proximal to the EGJ and measure the distance between the two.Location of tumorClinically, the location of the tumor is defined by the position of the upper end of the tumor in the esophagus, as measured from the incisors. Cervical (Proximal) esophagus – 15 cm to 20 cm from incisorsMid esophagus, Upper thoracic – 20 cm to 25 cm from incisorsMid esophagus, Middle thoracic – 25 cm to 30 cm from incisorsDistal esophagus (Lower thoracic) – 30 cm to 40 cm from incisorsEsophagogastric junction (EGJ)Proximal stomach / cardia and esophagogastric junctionThe surgical anatomic divisions of the esophagus are defined by anatomical boundaries and relationships to other structures that may not be included in the surgical specimen. Therefore, it may not be possible to determine the exact esophageal location of the tumor in the surgical resection unless there is specific orientation by the surgeon. If the resection specimen includes the EGJ, pathologic measurements should be recorded from the macroscopic EGJ. (Figure 1)Depth of invasionAfter taking cross sections through the tumor, determine the depth of invasion and measurement or involvement to the adventitia / additional structures. (Figure 2, page 13)Lymph nodesRegional lymph nodesRegional lymph nodes in the esophagus can extend from periesophageal cervical lymph nodes to celiac lymph nodes. This includes superior and inferior mediastinal, aortic, hilar lymph nodes, and lymph nodes in continuity with the esophagus. If the proximal stomach is included, greater and lesser curvature lymph nodes may be present. The number of involved lymph nodes has consistently emerged as a prognostic indicator on multivariate analysis. Data demonstrate that in general, the more lymph nodes resected, the better the survival, which may be the result of either improved N categorization or a therapeutic effect of lymphadenectomy. Based on worldwide data from the AJCC Staging Manual, it is recommended to examine a certain number of regional lymph nodes based on T stage. For pT1, approximately 10 nodes must be resected to maximize survival; for pT2, 20 nodes; and for pT3 or pT4, 30 nodes or more.Based on different data and analysis methods that focus on maximizing sensitivity, others have suggested that an adequate lymphadenectomy requires resecting 12-23 lymph nodes.Macroscopic Features of Tumor (Figures 3-7)Macroscopically, esophageal tumors can vary based on the stage and response to chemotherapy. Squamous cell carcinomas (SCC) can be present throughout the esophagus but are most common in the middle to lower thirds while adenocarcinoma usually originates near the EGJ. SCC can vary in appearance from exophytic, circumferential, and obstructive to invasive, ulcerative, and stricturing. Viable tumors have sharply demarcated borders and can be exophytic with ulceration present in more invasive cases. Tumors responsive to treatment have a white flattened appearance with a fibrous cut surface. Figure 3: Distal Esophageal Squamous Cell Carcinoma with Stomach Photograph courtesy of Mayo Clinic, Rochester, MN. Figure 4: Ulcerative Squamous Cell Carcinoma, EsophagusPhotograph courtesy of Mayo Clinic, Rochester, MN.Figure 5: Verrucoid Squamous Cell Carcinoma, EsophagusPhotograph courtesy of Mayo Clinic, Rochester, MN.Figure 6: Adenocarcinoma, Distal EsophagusPhotograph Courtesy of E. Heidi Cheek, PA(ASCP)CM, Mayo Clinic, Rochester, MN. Figure 7: Treated Adenocarcinoma, Distal EsophagusPhotographs courtesy of Rachel Larsen, PA(ASCP)CM and Lainee Bulawa, PA(ASCP)CM, Mayo Clinic, Rochester, MN.Treatment / Therapy GuidelinesTraditionally, radiation therapy has been the most common form of treatment for carcinoma of the upper two-thirds of the esophagus, and surgery (esophagogastrectomy) the usual approach for carcinoma of the lower third. The current approach favors combined preoperative radiation therapy followed by surgery or the combination of chemotherapy and radiation therapy with or without surgery. The general recommendations for treatment options consist of the following:Endoscopic mucosal resection Less than cT1a-Surgical resection (for non-cervical lesions)cT1b-cT2, N0 and lesions < 3 cm Neoadjuvant chemoradiation followed by esophagectomy for the following: cT2, N0 high risk lesions ( ≥ 3 cm lesions, LVI [lymphovascular invasion])cT1b-cT2, N+cT3-cT4a - (if local disease is still present)Palliative therapy cT4b Locally advanced or metastatic diseaseTreatment EffectEndoscopic resection (ER) The goal of this method is removal and hopefully eradication of early-stage disease usually on small, superficial lesions with no lymph vascular invasion. For lesions < 2 cm an ER is encouraged over an endoscopic biopsy as a more accurate depth of invasion can be assessed. Larger resection of lesions > 2 cm can be performed but are associated with a greater risk of complications. Lesions with no poor differentiation grade and a pathologic staging diagnosis of pT1a or pT1b with no evidence of lymph node invasion can by fully treated with ER. However, additional ablation therapy may be necessary if residual Barrett’s esophagus is present. Following the pathologic diagnosis if greater depth of invasion is seen or there is presence of a larger tumor, a discussion between the surgeon and patient is preferred to consider the risk of an esophagectomy versus recurrent disease. Following the procedure, endoscopic surveillance at least 6 weeks post procedure is encouraged to examine for recurrence of disease. Esophagectomy / EsophagogastrectomySeveral surgical methods are listed below with descriptions of each. Determination of the proper surgical approach is determined by many factors including preference of surgeon, location of tumor and available conduit choices ranging from the preferred gastric to colon and jejunum. Other factors such as the Siewert II and III classification may benefit from laparoscopy procedures (Ivor Lewis, McKeown, and Transhiatal) due to detection of radiographically occult metastatic disease. Often procedures utilize thoracoscopy to exclude metastatic disease and identify relevant anatomic structures. Ivor Lewis Laparotomy with right thoracotomy. Anastomosis between the esophagus and stomach in the upper chest.Minimally invasive. Small abdominal incisions and right thoracoscopy incisions. Anastomosis between the esophagus and stomach in the upper chestIndicationsCancers of the distal esophagus and gastroesophageal junction.Length of gastric conduit is insufficient for a neck anastomosis (McKeown approach).Unfavorable approach to neck incision including prior radiation, spine arthritis.TranshiatalUpper midline incision and left neck incision. Anastomosis between the esophagus and stomach in the neck.IndicationsCancer of the gastroesophageal junction and lower third of the esophagus.McKeown (Three incision)Laparotomy, right thoracoscopy and left neck incision. Anastomosis between the esophagus and stomach in the neck. The esophagus above the azygous vein is separated from the trachea with the neck incision allows for greater proximal esophageal resection.IndicationsCancer of the upper, middle, and lower third of the esophagus.Robotic minimally invasiveThe area of treated tumor may appear fibrotic and sizable pools of acellular mucin may be present after chemotherapy or radiation. These pools should be mentioned but should not be interpreted as residual tumor. Although grading systems for tumor response have not been established, the modified Ryan scheme is suggested which has been shown to provide good interobserver reproducibility. Modified Ryan Scheme for Tumor Regression ScoreDescriptionTumor Regression ScoreNo viable cancer cells (complete response)0Single cells or rare small groups of cancer cells (near complete response)1Residual cancer with evident tumor regression, but more than single cells or rare small groups of cancer cells (partial response)2Extensive residual cancer with no evident tumor regression (poor or no response)3Prognosis and Prognostic FeaturesOverall, the 5-year survival rate for esophageal cancer is 20% due to improvement in treatments, compared to the 1970s, when the 5-year survival rate was 5%. Other factors such as tumors confined to the esophagus, metastasis to surrounding organs and / or regional lymph nodes as well as distant metastasis can affect the 5-year survival rate to 47%, 25%, and 5% respectively.The prognosis of esophageal cancer is affected by histopathologic grade with SCC having a worse prognosis than adenocarcinoma. A better prognosis is found in individuals with tumors found distal in the esophagus.Additional factors contributing to a worse prognosis consist of the following:Increase in tumor size and depthStatus of surgical marginsAngiolymphatic invasionDistant metastasis Increasing histologic gradeAdvancing ageDue to lymphatic channels present in the lamina propria, metastases can arise from superficial cancers otherwise confined to the mucosa. For this reason, tumor involvement of lymph nodes is an important prognostic indicator. Extranodal extension is also clinically significant and associated with a poor prognosis.Metastatic SitesSites of distant metastases are those that are not in direct continuity with the esophagus and include non-regional lymph nodes. Metastases to distant organs are also frequent, particularly to liver, lung, and adrenal glands. Direct extension of tumor into the pleura, pericardium, diaphragm, aorta, vertebral bodies, or trachea would not qualify as M1. If en bloc, or radical resection, list when tumor involvement breaches into the “M” criteria.References:Amin MB, Edge SB, Greene, FL, Byrd DR, et al. (Eds.) AJCC Cancer Staging Manual, 8th ed. New York; NY: Springer; 2017. Araki K, Ohno S, Egashira, A, et al. Pathologic Features of Superficial Esophageal Squamous Cell Carcinoma with Lymph Node and Distal Metastasis. Cancer. 2002;94:580-575.Chanjuan S*, Berlin J, Branton PA. Protocol for the Examination of Specimens from Patients with Carcinoma of the Esophagus. 2017 Available at cancerprotocolsChen YJ, Schultheiss TE, Wong JY, Kernstine KH. Impact of the number of resected and involved lymph nodes on esophageal cancer survival. J Surg Oncol. 2009;100(2):127-132.Corley, DA, Buffler PA. Oesophageal and gastric cardia adenocarcinomas: analysis of regional variation using the Cancer Incidence in Five Continents database. Int J Epidemiol. 2001 Dec;30(6):1415-1425Cossention MJ, Wong RK. Barrett's Esophagus and risk of esophageal adenocarcinoma. Semin Gastrointest Dis.2003 Jul;14(3):128-35.Engel LS, Chow WH, Vaughan TL, Gammon MD, Risch HA, Stanford JL, Schoenberg JB, et.al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1404-1413.Esophageal Cancer: Statistics. . Updated January 2020. Accessed March 2020.Iyer R, Dubrow R. Imaging of esophageal cancer.?Cancer Imaging. 2004;4(2):125–132. Published 2004 Sep 9. doi:10.1102/1470-7330.2004.0022Kamangar F, Chow WH, Abnet CC, Dawsey SM. Environmental causes of esophageal cancer. Gastroenterol Clin North Am. 2009;38(1):27-vii. doi:10.1016/j.gtc.2009.01.004Kumar V, Abbas A, Aster J. “The Gastrointestinal Tract.” In Robbins and Cotran Pathologic Basis of Disease, 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:768-775.Kuwano H, Mortia M, Tsutsui S, Kido Y, Morei M, Sugimachi K. 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Cancer of the esophagus and esophagogastric junction-Major changes in the American Joint Committee on Cancer eight edition cancer staging manual. American Cancer Society Journals. 2017;67(4):304-17.Rizk NP, Ishwaran H, Rice TW, et al. Optimum lymphadenectomy for esophageal cancer. Ann Surg. 2010;251(1):46-50.Rosai J, Ackerman LV. Rosai and Ackerman's surgical pathology. 10th ed. Edinburgh, London: Mosby; 2011:594-595.Ruschoff J, Hanna W, Bilous M, et al. Her2 Testing in Gastric Cancer: A Practical Approach. Modern Pathology. 2012;25:637-50.Sandler RS, Nyrén O, Ekbom A, Eisen GM, Yuen J, Josefsson S. The risk of esophageal cancer in patients with achalasia. A population-based study. JAMA. 1995 Nov 1;274(17):1359-62. PMID: 7563560.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. American Cancer Society Journals. 2019; 69(1):7-34.Steyerbert EW, Neville BA, Kopper LB, et al. Surgical mortality in patients with esophageal cancer:development and validation of a simple risk score. J Clin Oncol. 2006;24:4277-4284Thornton R, Yee J. Eso. Esophageal Cancer imaging. . Updated February 2020. Accessed March 2020.APPENDIX ITNM CriteriaDefinition of Primary Tumor (pT)pT CategorypT CriteriapTXCannot be assessedpT0No evidence of primary tumorpTisHigh-grade dysplasia, defined as malignant cells confined to the epithelium by the basement membranepT1Tumor invades the lamina propria, muscularis mucosae, or submucosa pT1aTumor invades the lamina propria or muscularis mucosae pT1bTumor invades the submucosapT2Tumor invades the muscularis propriapT3Tumor invades adventitiapT4Tumor invades adjacent structures pT4aResectable tumor invading pleura, pericardium, azygos vein, diaphragm, or peritoneum pT4bTumor invades other adjacent structures, such as the aorta, vertebral body, or airwayUsed with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science and Business Media LLC, .Definition of Regional Lymph Nodes (pN)pN CategorypN CriteriapNXRegional lymph nodes cannot be assessedpN0No regional node metastasispN1Metastasis in one or two regional lymph nodespN2Metastasis in three to six regional lymph nodespN3Metastasis in seven or more regional lymph nodesUsed with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science and Business Media LLC, .Definition of Distant Metastasis (pM) (required only if confirmed pathologically)pM CategorypM CriteriaM0No distant metastasispM1Distant metastasisUsed with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science and Business Media LLC, .TNM Descriptors:pT(m)NM: For multiple primary tumors, the T score is modified, with the suffix “(m)” recorded in parentheses following the pT indicator (pT indicating primary tumor). Each tumor should be assessed independently of the others. Variability in histologic features should be considered with adequate sampling performed to either assure or exclude histologic variability. With regard to the T score, for staging purposes, the pT score is established based on the primary tumor showing the greatest degree of invasion.ypTMN: If neoadjuvant therapy has been utilized the T score will be modified with the prefix “y”. The “y” categorization is not an estimate of tumor prior to multimodality therapy (i.e., before initiation of neoadjuvant therapy). Rather, the extent of tumor actually present at the time of examination must be disclosed. If neoadjuvant therapy renders macroscopic examination of tumor involvement inconclusive, dissection methods should be considered, which allow for mapping of the treated area, emphasizing the areas of potential deepest invasion.rTNM: The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval.aTNM: The “a” prefix designates the stage determined at autopsy.Residual Tumor (R) CategoryThe absence or presence of residual tumor at the primary tumor site after treatment is denoted by the symbol R. The R categories for the primary tumor site are as follows:R CategoryR DefinitionRXPresence of residual tumor cannot be assessedR0No residual tumorR1Microscopic residual tumorR2Macroscopic residual tumor at the primary cancer site or regional nodal sites Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science and Business Media LLC, .Assessment of the surgical margin (R category) applies only to a surgically resected specimen. In addition to proximal and distal margins or resection, the status of the radial or circumferential margin of resection determines whether the tumor has been completely excised. Presence of tumor cells at the inked radial margin constitutes a positive margin by CAP criteria.APPENDIX IIAncillary TestingMolecular ConsiderationsHER2 (ERBB2) TestingThe HER2 protein is overexpressed in multiple cancer types, including ~15% of patients with esophageal cancer. Though the prognostic significance of HER2 status in esophageal and EGJ cancers is unclear, overexpression / amplification of HER2 (HER-2 positivity) can direct treatment in certain patients. HER2-overexpressing unresectable locally advanced, recurrent, or metastatic esophageal and esophagogastric junction cancers are eligible for treatment with trastuzumab (Herceptin). HER2 (ERBB2) status may also determine eligibility for clinical trials.? Assessment for HER2 overexpression in esophageal and EGJ cancer patients using immunohistochemistry (IHC) and FISH / other ISH is recommended by CAP and NCCN. IHC should be performed first, followed by ISH methods in cases showing 2+ (equivocal) expression by IHC. Positive (3+) or negative (0 1+) results do not require further testing. When diagnostic tissue is limited and the patient is unable to undergo additional procedures, next-generation sequencing (NGS) can be considered to assess numerous mutations (such as amplifications, deletions, TMB, and MSI) simultaneously, instead of sequential IHC / FISH testing. Similar to breast specimens tested for HER2, fixation time should be between 6 and 48 hours and documented in the macroscopic description. HER2 is performed on formalin-fixed, paraffin-embedded tissue by IHC, FISH (when IHC is equivocal) or NGS.Mismatch Repair / Microsatellite Instability (MMR / MSI)Testing of metastatic esophageal and EGJ cancers for dMMR / MSI-H is recommended by NCCN, as pembrolizumab is approved a second line therapy for unresectable or metastatic MSI-H / dMMR esophageal and EGJ tumors. Patients with a microsatellite instability-high (MSI-H) phenotype in their cancer tissues may have a germline mutation in one of several DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, or PMS2) or an altered EPCAM (TACSTD1) gene.? Microsatellite instability (MSI) testing is used routinely to cost-effectively screen colorectal cancer patients for possible Lynch syndrome. Currently, a correlation between esophageal / EGJ cancers and Lynch syndrome has not been made, but the spectrum of cancers associated with Lynch syndrome continues to expand with increased use of next-generation sequencing. Patients with dMMR / MSI-H esophageal and EGJ tumors should be referred to a genetics counselor for further assessment.MMR testing is performed on formalin-fixed, paraffin-embedded tissue via immunohistochemistry (IHC). MSI testing is performed on formalin-fixed, paraffin-embedded tissue?via?polymerase-chain reaction (PCR) or next-generation sequencing (NGS).? An advantage of using MMR IHC for testing is that the results will help identify the specific protein / gene that may be affected. If MMR IHC testing has not been done but MSI has and shows an MSI-H phenotype, MMR IHC testing is recommended because this information will help identify the gene that is most likely to have a germline (or somatic) mutation. Using NGS for MSI testing can be useful in patients with metastatic disease who require HER2 and NTRK testing. PD-L1Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1(PD-1) / PD-L1 immunotherapy.? PD-L1 testing is recommended in patients with locally advanced, recurrent, or metastatic esophageal and EGJ cancers who are candidates for second- or third-line treatment with PD-1 inhibitors, such as pembrolizumab. It is recommended as a second line treatment in patients with esophageal SCC with a PD-L1 expression level by CPS >=10, and as a third line treatment in patients with esophageal and EGJ adenocarcinoma with a PD-L1 expression level by CPS >=1. PD-L1 is tested via IHC on FFPE tissue.NTRK gene fusionThe FDA granted approval for the use of select TRK inhibitors (entrectinib and larotrectinib) for NTRK gene fusion-positive solid tumors. TRK inhibitors only have activity in tumors with NTRK fusions, not mutations. NTRK fusions can be detected via IHC, FISH, DNA-based NGS or RNA-based NGS.? ?OtherMolecular studies suggest that the progression of Barrett esophagus to adenocarcinoma occurs over an extended period through stepwise acquisition of genetic and epigenetic changes. Chromosomal abnormalities, mutation of TP53, and downregulation of the cyclin-dependent kinase inhibitor CDKN2A are detected at early stages. During progression, there is amplification of EGFR, ERBB2, MET, cyclin D1, and cyclin E genes. Biomarker-directed Therapies & Clinical TrialsThere are multiple FDA-approved?biomarker-directed therapies for locally advanced, recurrent, or metastatic esophageal and EGJ cancers. Trastuzumab (Herceptin) is approved for first-line treatment in patients with HER2 overexpression. Pembrolizumab is approved for the second-line treatment of patients with MSI-H / dMMR esophageal tumors, second-line treatment of patients with esophageal SCC with PD-L1 expression levels by CPS >= 10, and third-line treatment of esophageal and EGJ adenocarcinoma with PD-L1 expression levels by CPS >= 1. Entrectinib or larotrectinib are approved for NTRK gene fusion-positive tumors. Lutetium 177 Dotatate is approved for the treatment of patients with metastatic esophageal neuroendocrine tumor (NET) with somatostatin receptor (SSTR)-positive tumors (SSTR tested for via IHC). ERBB2 / HER2, PD-L1, dMMR genes are the most frequent gene inclusion criteria for adenocarcinoma of the gastroesophageal junction clinical trials.A cold ischemia time of 1 hour or less is recommended to meet the most current molecular testing needs for cancer patient specimens.? It is recommended actual cold ischemia times or, at a minimum, deviations from the 1-hour recommendation are recorded in the pathology report.Molecular tests, including solid tumor next generation sequencing (NGS), can be performed on formalin fixed paraffin embedded (FFPE) tissue sections and fresh frozen tissue.? Contact your reference laboratory for specific specimen requirements.?For those tests that have multiple testing modalities, it is assumed that only one of these testing modalities would be used per case unless one test yields equivocal results.??FISH and immunohistochemical analysis can be performed on formalin fixed paraffin embedded (FFPE) tissue sections. Tissue should be fixed for 6 to 48 hours in 10% neutral buffered formalin. The macroscopic description should provide the fixative used. References:Bartley AN, Washington MK, Ventura CB et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345-1363.Biller LH, Syngal S, Yurgelun MB. Recent advances in Lynch syndrome.?Fam Cancer. 2019;18(2):211-219. doi:10.1007/s10689-018-00117-pton C, et al. Preanalytics and Precision Pathology: Pathology Practices to Ensure Molecular Integrity of Cancer Patient Biospecimens for Precision Medicine. Archives of Pathology & Laboratory Medicine. 2019;143(11):1346-1363.Chanjuan S, Berlin J, Branton PA. Protocol for the Examination of Specimens from Patients with Carcinoma of the Esophagus. Cancer Protocol Esophagus 4.1.0.0. 2017.National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – Esophageal and Esophagogastric Junction Cancers, Evidence Blocks - Version 3.2020. . Accessed August 2020.Vanderbilt-Ingram Cancer Center.? My Cancer Genome – Malignant Esophageal Neoplasm.??. Accessed August 2020.APPENDIX IIIFrozen Section ConsiderationsAn esophagectomy or esophagogastrectomy specimen is commonly sent for frozen section for margin assessment. If the proximal margin is requested for frozen section analysis, ensure all layers are present in the frozen section sample, as the mucosa tends to retract upon transection. If the tumor is visible and far from the margins, a gross intraoperative consult without frozen section may be considered.APPENDIX IVSample Narrative Macroscopic DescriptionEsophagogastrectomySubmitted [fresh / in formalin] in one container for gross and microscopic examination, labeled with the patient’s name, [ ], medical record number, [ ], and “[specimen designation],” is an esophagogastrectomy specimen consisting of an esophagus ( ___ cm [length] and ___ cm [circumference]) with attached stomach ( ___ x ___ x ___ cm) OR ___ cm [greater curvature length], ___ cm [lesser curvature length], ___ cm [circumference]) and attached perigastric adipose tissue( ___ cm in thickness). The radial adventitial surface is [rough / intact / disrupted] and is inked [color]. The gastric serosa is [color and smooth / rough / focally disrupted]. Opening shows, a ___ x ___ x ___ cm [color / describe] mass [within the esophagus / involving the esophagogastric junction / crossing the esophagogastric junction and involving the stomach]. The midpoint of the mass is [within the esophagus / within the stomach], ___ cm [proximal / distal] to the esophagogastric junction. The mass is ___ cm from the proximal esophageal margin, ___ cm from the distal gastric margin and involves ___% of the [esophageal / gastric] circumference. Upon sectioning, the mass is [color / describe] and [does not invade into the muscularis propria / invades into but not through the muscularis propria / invades into and through the muscularis propria and into the adventitial soft tissue]. The mass is ___ cm from the adventitial margin (submitted perpendicularly) and ___ cm from the serosal surface. The remaining esophageal mucosa is [color] with normal longitudinal folds. The remaining gastric mucosa is [color] with normal rugal folds and no additional masses or polyps identified. The esophageal wall is ___ cm in thickness, and the gastric wall is ___ cm in thickness. Within the adipose tissue are ___ lymph nodes ranging from ___ to ___ cm in greatest dimension, all with tan smooth cut surfaces. Cold ischemic time: _______Formalin fixation time: _______Representative sections are submitted as follows: FSA1:Esophageal margin en face - frozen section remnantA2-A4:Gastric margin closest to tumor, en face (perpendicular if < cm from tumor)A5:Closest adventitial margin (perpendicular)A6-A10:One cassette per cm of tumor including greatest depth of invasion, adjacent normal mucosaA11:Additional EGJA11: Uninvolved gastric mucosaA12-15:All lymph nodes, indicating if they are periesophageal or perigastric Copyright:? 2021 American Association of Pathologists’ Assistants. 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