Clinical, radiological and pathological staging of gastrointestinal cancer

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accurate staging is undertaken, a diagnosis of cancer is required, which is usually made by histological examination of biopsy material; this may include imaging techniques to localize and sample the lesion. Once a diagnosis of malignancy is established, the extent of local invasion and the presence of distant metastases must be determined; this is usually undertaken using imaging methods (see ‘Imaging and investigation of the gastrointestinal tract’, page 350). Optimal pathological staging can be undertaken only on resection specimens, and there are three major areas of assessment: • size and/or local extent of the primary tumour • involvement of regional lymph nodes • presence or absence of distant metastases. Tumours of the gastrointestinal tract can spread by local invasion, permeation of lymph vessels or blood vessels or seeding across serosal cavities; comprehensive pathological assessment can assess all of these (or the potential for them) in resection specimens. Pathological staging is the most powerful predictor of local recurrence and long-term survival. It is the most important determinant in the decision to give postoperative adjuvant chemo- or radiotherapy in colorectal cancer. Pathological staging depends on the accurate dissection of a resection specimen and there has been a campaign to improve the pathological reporting of cancers to limit inaccuracies. This has been driven by national attempts to improve cancer management and prognosis. The UK Royal College of Pathologists has published ‘The minimum standards for pathological reporting of common cancers’, which incorporates

Clinical, radiological and pathological staging of gastrointestinal cancer Jyoti Gupta Stephen G Cooke Neil A Shepherd Basic principles Staging is the process that determines the spread of a malignant tumour, thereby providing prognostic information. It can be assessed by clinical, radiological and pathological means. Before

Jyoti Gupta is Specialist Registrar in Histopathology at Gloucestershire Royal Hospital, Gloucester, UK. Stephen G Cooke is Consultant Radiologist at Gloucestershire Royal Hospital, Gloucester, UK. Neil A Shepherd is a Consultant Histopathologist at Gloucestershire Royal and Cheltenham General Hospitals, Gloucestershire, and a Visiting Professor at Cranfield University, Cranfield, UK.

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pathological staging for each of the major malignancies of the gastrointestinal tract. A standardized system is necessary for the purposes of cancer registry and exchange of information between treatment centres. There has been an increasing adoption of internationally accepted staging systems such as the TNM system (see below), although the Dukes classification is widely used in the assessment of colorectal cancer.

Staging accuracy of imaging in oesophago-gastric carcinoma Imaging method CT EUS CT + EUS

TNM system

Depth of invasion (T) (%) 40 85 90

Involvement of lymph nodes (N) (%) 50 80 90

Distant metastases (M) (%) 85 40 90

Staging accuracy (%) 45 70 80

EUS: Endoluminal ultrasound.

The TNM staging system is based on the anatomical extent of spread of the primary tumour. It can be determined clinically (helping to select the most appropriate treatment) or pathologically (in turn providing prognostic information and determining which patients would benefit from adjuvant therapy). It can also be applied to imaging and there are specific systems for the assessment of tumours after adjuvant therapy. The letters TNM indicate the: • extent of spread of the primary tumour • presence or absence of spread to regional lymph nodes • presence or absence of distant metastatic disease. Numerals are added to the above three components (e.g. T1, T2, N1, N2) to indicate the extent of disease. Further information can be provided by prefixes or suffixes (e.g. pT infers pathological primary tumour stage) and the addition of other integers in clinical and radiological staging. The TNM system is universally recognized and therefore reproducible, but has disadvantages, as discussed below. • Non-anatomical factors that are important in prognosis are not always considered (e.g. margins, lymphovascular invasion). • Confusion may be caused because the same T denotation implies spread to different layers in different parts of the gastrointestinal tract. • There are prognostic differences despite the same T denotation depending on the anatomical area (e.g. pT4 in the colorectum may indicate serosal involvement or spread to adjacent organs). Another example is the stomach, whereby pT2 previously indicated involvement of the muscularis propria or subserosa (although this deficiency has now been addressed in the 2004 revision (TNM 6). • The system is constantly being refined and therefore one must keep abreast of the latest changes. Many of the changes reflect prognostic data, but there have been some recent changes in the nodal categorization in colorectal cancer, leading to confusion due to poor reproducibility of findings between centres.

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Imaging (Figure 1) Chest radiography is a cost-effective method of determining gross pathology (including pulmonary metastases) and assessing suitability for surgery. CT is the first-line technique for detecting solid metastases in distant organs (particularly in the liver and lung). CT (Figure 2) has limited use for differentiating individual layers of the oesophagus (see below), but can show whether tumour remains within the oesophageal wall (stage T1 and T2), breaches the wall (T3) or invades further (T4). Reported accuracies for overall assessment of T-stage are up to 60% but, in general, published work refers to data obtained using older, incremental CT machines and not the modern spiral multidetector units. Local invasion is shown with greater accuracy than more distant spread (sensitivities of up to 97% and 64% respectively). The mid-tubular portion of the

Staging of oesophageal and gastric carcinoma Clinical staging The clinical staging of oesophageal and gastric cancer is essential to determine clinical management and for planning preoperative chemotherapy. Accurate preoperative clinical staging is vital to select those patients with potentially resectable and curable disease because of the mortality and morbidity associated with oesophagectomy or gastrectomy. Clinical staging is achieved by clinical examination and imaging. When examining the patient, cervical lymphadenopathy, hepatic enlargement or ascites suggest secondary spread of the tumour.

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2 CT of the thorax and upper abdomen (sagittal view) used for staging. An oesophageal adenocarcinoma (black arrow) extends from a sliding hiatus hernia (open arrow) proximally as far as the level of the pulmonary artery.

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oesophagus is most easily imaged; the cervical oesophagus and oesophago-gastric junction are shown less accurately. Lymph node metastases are shown more clearly on the newer CT machines, but prediction of involvement of lymph node is limited to statistical estimation based on node size. MRI is more expensive and less readily available than CT in the UK. It shows similar results to CT for liver and mediastinal metastases, but is significantly less accurate for detecting pulmonary deposits. Endoluminal ultrasound allows the oesophageal and gastric wall to be seen. Sensitivity for detecting mucosal tumours is up to 90%, but is significantly lower for submucosal tumours. As with CT, the tubular portion of the oesophagus is significantly better staged than the oesophago-gastric junction. Lymph node metastases are much better shown than with CT because, in addition to size criteria, other features of malignant involvement are also available, including echo texture, margin definition and contour of lymph nodes. Endoluminal ultrasound is poor for detecting distant metastases because of limited penetration, although overall accuracy for T-stage is about 85%. A stricturing oesophageal cancer may prevent the passage of the endoluminal ultrasound endoscope in one-third of patients; an ultrasound miniprobe may be used if it is thought the findings will influence clinical management in these cases. However, 90% of such cases usually have advanced node-positive disease. Positron emission tomography (PET) has mainstream acceptance in Europe and the USA. The cost of equipment and the availability of positron-emitting radiopharmaceuticals limits its use, but there are hopes for substantial investment to make this imaging method more widely accessible in the UK. The most commonly used PET radiopharmaceutical is 18-fluorodeoxyglucose ( 18 F-FDG). Fluorodeoxyglucose is an analogue of glucose and is metabolized similarly; the imaging process relies on increased glycolysis in cells subject to malignant

transformation, causing accumulation of the tracer. Instead of revealing anatomical delineation of tumour, a functional image of the distribution of metabolic activity is obtained, with the most metabolically active tumour tissue showing the highest uptake (Figure 3). PET is useful in the staging of oesophageal carcinoma, but is less helpful in initial diagnosis because uptake is seen in benign oesophageal conditions, including oesophagitis (monilial and reflux) and Barrett’s oesophagus without malignancy. The reported sensitivity of PET compared with CT is variable, and the combination of CT and endoscopic ultrasound appears to be the most sensitive means to evaluate small peri-oesophageal lymph nodes. The poor sensitivity of PET for detecting regional disease is due to the proximity of peritumoural nodes to the primary tumour, making differentiation between tumour and metastasis difficult due to poor spatial resolution. In most studies, the specificity of PET for regional nodal disease is higher than the sensitivity (>90% in most cases). Focal activity of PET in perioesophageal regional lymph nodes seen on endoscopic ultrasound or CT is highly suggestive of nodal metastasis. The clinical utility of PET for determination of N-stage is controversial, but it does not appear to be sufficiently sensitive for accurate preoperative staging. Therefore, nodal staging in oesophageal cancer requires a multi-method approach. Laparoscopy is essential in the staging of gastric and lower one-third tumours of the oesophagus because it assesses serosal involvement and local invasion. The diaphragm, peritoneum, omentum and liver can also be inspected for secondary deposits. Mediastinoscopy is of limited value and rarely used. Bronchoscopy can detect tracheobronchial involvement in upper and mid-oesophageal tumours. Pathological staging (Figures 4 and 5) During macroscopic examination of the resection specimen, areas

TNM staging classification of oesophageal cancer T1 T2 T3 T4

Tumour involves lamina propria and/or submucosa Tumour involves muscularis propria Tumour involves adventitial tissues Tumour involves adjacent structures

N1 M1

Regional nodes involved Distant metastases

For tumour of lower thoracic oesophagus M1a Coeliac nodes involved M1b Other distant metastasis For tumour of upper thoracic oesophagus M1a Cervical nodes involved M1b Other distant metastasis

3 Coronal images from whole-body FDG-PET with simultaneous CT (PET– CT). Study was done for biopsy-negative suspected recurrent colorectal carcinoma in the pelvis. In addition to confirming pelvic disease, a small deposit is seen in the right lung. Combining PET with CT to obtain a ‘fusion image’ shows the exact site of disease activity, thereby increasing specificity and reporting confidence. Source: Dr W L Wong, Clinical Head of PET, Paul Strickland Scanner Centre, Middlesex, UK.

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For tumour of mid-thoracic oesophagus M1b Distant metastasis (including non-regional lymph nodes) 4

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bowel arise in the duodenum, jejunum or ileum. In several studies, the 5-year survival rate is as low as 20–25%. The prognosis is extremely poor if tumour involves mesenteric lymph nodes.

TNM staging classification of gastric cancer T1 T2 T2a T2b T3 T4 N1 N2 N3

Tumour involves lamina propria and/or submucosa Tumour involves muscularis propria and/or subserosa Muscularis propria Subserosa Tumour penetrates serosa Tumour involves adjacent structures 1–6 nodes involved 7–15 nodes involved >15 nodes involved

Staging of cancer of the large intestine Clinical staging of cancer of the large intestine There has been increasing emphasis on accurate clinical staging of cancers of the large intestine due to the availability of new techniques (e.g. MRI for rectal cancer) and management protocols (e.g. intraluminal stents as a palliative measure to avoid major surgery in patients with metastatic disease). Clinical staging of colorectal cancer involves a combination of clinical examination, endoscopy and imaging. On clinical examination, an enlarged liver, ascites or a Sister Joseph’s nodule (signifying umbilical involvement by metastatic cancer) raise the suspicion of metastatic disease.

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of the tumour that show the greatest depth of invasion of the oesophageal or gastric wall and areas of likely involvement of the serosa and blood vessels are assessed. A diligent search for lymph nodes is done and their anatomical location recorded. Histological examination confirms the depth of invasion and the number of lymph nodes involved by metastatic cancer, but also assesses other prognostic factors (e.g. tumour grade, vascular invasion, status of circumferential margin). One of the most important prognostic parameters in oesophageal cancer is the presence of tumour within 1 mm of the circumferential margin, which predicts the likelihood of local recurrence in cases with a low metastatic nodal burden; this should be recorded on the histopathological report. Despite the importance of this margin, it is not included in the TNM system. There is controversy in the categorization of tumours that lie close to or at the oesophago-gastric junction. Many of these were previously considered gastric primary tumours, but many authors believe that a high proportion of these junctional tumours share features of true lower oesophageal adenocarcinoma. Siewert et al (see FURTHER READING) have proposed the following classification: • type I carcinomas arise in the distal one-third of the oesophagus, usually against a background of Barrett’s mucosa, and they may or may not involve the gastro-oesophageal junction; they should be staged using the oesophageal classification • type II carcinomas straddle and appear to arise from the true junction between the oesophagus and stomach • type III carcinomas are subcardial gastric cancers that grow proximally to involve the gastro-oesophageal junction and therefore should be staged according to the gastric classification. The choice of staging system for type II tumours is controversial. Many authors believe that type II tumours should be treated in the same way as type III tumours because the pattern of nodal spread is similar. Other studies suggest that they behave more like type I tumours.

Imaging Colonoscopy or barium enema should be undertaken to exclude synchronous lesions. Chest radiography helps to detect pulmonary deposits and assess fitness for surgery. Ultrasound – the sensitivity of conventional ultrasonography for the detection of liver metastases is relatively poor compared to contrast-enhanced CT or MRI. The exception is if sonographic contrast media is given; reported yields for metastases increase from an average of 63% up to 91%. However, this technique is not widely used in the UK. Most lesions missed on ultrasonography are small (the sensitivity for detecting lesions <1 cm is only 20%) or have similar echogenicity to adjacent normal liver parenchyma. Endorectal or transrectal ultrasound is the first-line imaging method for local staging of rectal carcinoma, but use in the UK is limited because of the need for dedicated equipment and a highly trained operator. In skilled hands, depth of penetration of tumour and perirectal spread are shown with a sensitivity of up to 94% (Figure 6). Involvement of lymph nodes is less easy to show, but endorectal ultrasound is more sensitive than CT for detecting perirectal spread. Endorectal ultrasound is particularly useful for assessing lesions for local excision or non-surgical treatment and, with distal rectal lesions, to show separation from the anal sphincter mechanism before planning surgery. Five distinct sonographic layers can usually be shown, with the key interface being the outer hypoechoic muscularis propria. T1 tumours do not penetrate the muscularis propria, whereas T2 tumours or greater disrupt this layer. CT may provide additional information on the extent of spread of the primary tumour. However, CT is used largely to detect and localize metastases in the liver, and has a sensitivity of 85% (depending on lesion size and morphology). CT assessment of invasion of the bowel wall is good, but sensitivity in evaluating lymph node deposits is about 50%. However, local staging improves as disease stage increases; accuracy also improves after specific preparation of the bowel. CT is the benchmark for initial evaluation because of its speed, availability and ability to show complications that are not always evident clinically (e.g. obstruction, localized perforation). A negative staging abdominal and pelvic CT suggests that metastatic disease is highly unlikely (negative predictive value of >90%). CT is the principal method

Staging of cancer of the small intestine Carcinomas of the small bowel account for only 1% of all gastrointestinal cancers. Preoperative staging of these cancers is unusual because the diagnosis is usually not made until after resection. Chest radiographs and CT help to exclude distant metastases for cancers diagnosed preoperatively (e.g. duodenal cancer). CT has replaced ultrasound for liver assessment in many UK centres. The TNM staging is identical whether carcinomas of the small

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7 Axial T2-weighted MRI of male pelvis. A lobulated rectal tumour extends anteriorly to breach mesorectal fascia (between arrowheads) and invade seminal vesicles to the left of midline. Small nodes with intermediate signal intensity similar to tumour are in the right pararectal space (tumour stage T3b).

6 Endoluminal ultrasound of rectum. The probe is inserted into the rectum with a surrounding waterbath (shown as black) inflated around a rotating crystal. This yields a radial scan showing tumour between 4 o’clock and 10 o’clock. The hypoechoic muscularis propria (open arrows) is not separately delineated deep to the central portion of the tumour in the 7–8 o’ clock position (black arrow). This indicates tumour stage T2 rather than T1. The seminal vesicles are seen anteriorly.

metastases, but the specificity of this finding for regional lymph node metastases is 96% if uptake is shown in pericolic nodes. Specificity is reduced by FDG uptake due to physiological bowel wall accumulation, inflammatory bowel conditions and benign polyps, resulting in ‘false-positive’ scans. PET is also helpful for assessing recurrent disease; postoperative fibrosis or radiation necrosis can look identical to disease recurrence on CT, but is readily differentiated by PET. In a study comparing the sensitivity and specificity of FDG-PET, CT, and serum concentrations of carcinoembryonic antigen, FDG-PET was more sensitive than CT and carcinoembryonic antigen for the detection of disease recurrence; the specificity of FDG-PET was equivalent to that of carcinoembryonic antigen.

for preoperative evaluation of hepatic metastases, but ultrasound is the reference standard for identification of hepatic metastases intraoperatively. MRI offers no clear benefits over CT scan for T-staging, but improvements in MRI technology allow useful information to be obtained for rectal tumours. In the UK, MRI is becoming the standard for preoperative assessment of extent of local tumour in rectal cancer (Figure 7). It can assess the depth of extramural penetration and the relationship between tumour and the mesorectal fascia. This enables identification of patients likely to benefit from total mesorectal excision, with excision of the primary tumour and avoidance of preoperative chemotherapy. If MRI shows involvement of the mesorectal fascia, radiotherapy can be given preoperatively to reduce recurrence rates due to involved resection margins. As with endoanal ultrasound, tumour penetration into perirectal fat is readily shown, but MRI can overstage due to tissue reaction visible in the perirectal fat adjacent to tumours. MRI also shows accuracy in the assessment of involvement of lymph nodes and there is good correlation between MRI staging and final pathological staging. PET –the sensitivity of PET is lower than that of CT for colorectal disease; less aggressive or small (<8 mm) tumours are poorly shown. Sensitivity (up to 97%) and specificity (up to 76%) for metastatic disease are high when PET is combined with simultaneous CT (PET–CT). The technique allows the whole body to be imaged, showing disease spread and incidental lesions (Figure 3). This avoids inappropriate curative surgical treatment for patients with unsuspected metastatic disease and improves survival rates of surgical patients. Poor spatial resolution and low sensitivity for small lesions inevitably results in limited contribution to T-staging in early disease; PET is only 29% sensitive for regional lymph node

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Pathological staging of colorectal cancer Numerous pathological staging systems have been applied to cancers of the large intestine, although the TNM and Dukes classifications are the most widely used in the UK. The Dukes classification was introduced in 1932 for staging of rectal cancers but, after several modifications, it is now applied to all cancers of the large intestine. The modified Dukes–Bussey staging system is the most recognized system used in the pathological reporting of cancers of the large intestine (Figure 8). The resection specimen must be examined and dissected meticulously. All the lymph nodes must be harvested; the presence of positive lymph nodes determines if the tumour is Dukes stage C. The presence or absence of involvement of lymph nodes is the most important factor in the decision to institute adjuvant therapy. The most important pathological prognostic factors in colorectal carcinoma are: • number of lymph nodes involved • extent of local spread • involvement of margins (particularly the radial/circumferential/mesorectal margin in rectal carcinoma) • extramural venous spread 386

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Modified Dukes–Bussey staging system for colorectal cancer Stage A

B

C1 C2

Tumour within bowel wall, but not penetrating completely the muscularis propria; lymph nodes are not involved Tumour penetrating through the full thickness of the muscularis propria into extramural tissue; lymph nodes are not involved Metastasis(es) to regional lymph nodes, with the ‘highest’ node uninvolved Metastasis(es) to regional lymph nodes, with the ‘highest’ node involved

TNM staging classification of anal cancer T1 T2 T3 T4 N1 N2

Five-year survival (%)* 95%

75% N3

40%

Tumour size ≤2 cm Tumour size >2 to 5 cm Tumour size >5 cm Involvement of adjacent organ(s) Involvement of perirectal nodes Involvement of unilateral internal iliac/ inguinal nodes Involvement of perirectal and inguinal/ bilateral internal iliac/inguinal nodes

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10%

node metastasis if the nodule has the form and smooth contour of a lymph node; it is classified under the pT category under vascular invasion if it has an irregular contour. This is a rather subjective assessment and these changes have not been adopted in the UK.

*Rates vary in different series depending on series, treatment and other factors.

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Staging of carcinomas of the anal region (Figure 10) Carcinoma of the anus comprises about 2% of cancers of the large bowel. Squamous cell carcinoma is the predominant cancer type, whereas adenocarcinoma is the most common type of malignancy in other parts of the gastrointestinal tract (see CROSS REFERENCE). 

• peritoneal involvement • tumour perforation. Not all of these factors are incorporated in staging systems, therefore they must be recorded in the histopathological report. National and international guidelines recommend the use of Dukes and TNM staging systems (Figure 9) for reporting colorectal carcinomas. The use of adjuvant chemotherapy for Dukes B carcinomas is unclear. Histopathological assessment can distinguish ‘good’ from ‘bad’ Dukes B tumours; the latter include tumours that show extramural vascular spread, peritoneal involvement, tumour perforation and margin involvement. Changes in the the sixth edition of the TNM classification (2004) have altered some pathological assessments and led to some confusion. Previously, an extramural tumour nodule at some distance from the main lesion that was >3 mm in diameter was interpreted as involvement of lymph nodes; this was an objective assessment based on the nodule size. In the sixth edition, a pericolic or peri-rectal tumour nodule without histological evidence of residual lymph node is classified in the pN category as a lymph

CROSS REFERENCE Gupta J, Vipond M N, Shepherd N A. The clinical and pathological staging of gastrointestinal cancer. Surgery 2002; 20(10): iii–vii.

TNM staging classification of colorectal cancer T1 T2 T3 T4 N0 N1 N2

FURTHER READING Goh V, Halligan S, Bartram C I. Local radiological staging of rectal cancer. Clin Radiol 2004; 59: 215–26. Rohren E M, Turkington T G, Coleman R E. Clinical applications of PET in oncology. Radiology 2004; 231: 305–32. Siewert J R, Stein H J. Classification of carcinoma of the oesophagogastric junction. Br J Surg 1998; 85: 1457–9. Sobin L H, Wittekind C. TNM classification of malignant tumours. 6th edition. New York: Wiley-Liss, 2002. Weaver S R, Blackshaw G R, Lewis W G et al. Comparison of special interest computed tomography, endosonography and histopathological stage of oesophageal cancer. Clin Radiol 2004; 59: 499–504.

Tumour involves only submucosa Tumour involves submucosa and muscularis propria Tumour involves mesorectum or subserosa (i.e. nonperitonealized pericolic/perirectal tissues) Tumour involves peritoneum (pT4a) or other organs or structures (pT4b) No lymph nodes involved ≤3 regional lymph nodes involved >3 regional lymph nodes involved

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