Staging, stage migration, and patterns of spread in gastric cancer

Staging, Stage Migration, and Patterns of Spreadin Gastric Cancer Scott A. Hundahl Background concerning tumor node metastasis (TNM) staging of gastric cancer is presented, with special attention to the issue of stage migration. Patterns of spread are also reviewed and

current problems in local-regional control are emphasized.

t least three separate factors determine the prognosis of a malignant neoplasm: host status, the nature of the neoplasm, and treatment. 1:) Unfortunately, current cancer staging fails to encompass host factors, treatment factors, and a variety of other factors impacting on prognosis. For example, the influence of comorbid medical conditions on prognosis weighs large in the survival of cancer patients, 3-jl but has yet to be standardized or systematically incorporated into any scheme. In stomach cancer, "completeness of surgical resection" ranks as one of the most important prognostic factors L,w but is largely ignored in current staging models. Candid assessment of current anatomic-based staging invites inquiry as to its reliability in generating reasonable prognostic estimates, particularly when applied across international boundaries, to widely differing populations subject to disparate selection factors and undergoing sometimes dramatically different treatment. Despite its drawbacks, however, anatomic-based cancer staging represents the clinician's lingua franca, a convenient shorthand for describing extent of disease and disease-oriented severity. Modern treatment guidelines inevitably rely on stage of disease. Within relatively homogeneous, large populations--particularly if good actuarial data permitting relative survival calculations are availablel3.14~stage stratification does allow reasonable comparison of long-term survival. Staging and appreciation of factors influencing staging and patterns of spread are particularly

important for the clinician treating stomach cancer. This review summarizes relevant details.

A

From the Queen's CancerInstitute, and the Universitr of Hawaii, Honolulu, HI. Address correspondence to Scott A. Hundahl, MD, FACS, Medical Director, The Queen's Cancer Institute, 1301 Punchbowl Street, Honolulu, HI 96813. E-maik [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 1053-4296/02/1202-0004535.00/0 doi: 10.1053/srao. 2002.30816

Copyright 2002, Elsevier Science (USA). Aflrightsreserve~

Staging Since 1987, the American Joint Committee on Cancer (A]CC) and the Union Internationale Contra le Cancer (UICC) systems for the staging of cancer have been identical. 15,1GFifth edition AJCC staging for carcinoma of the stomach is summarized in Table 175 Published in 1997, this staging system incorporates a major revision with respect to nodal staging. The rationale for this change relates to the issue of node-related stage migration (see below). The staging of tumor depth, or T staging, for this site has not changed since the AJCC third edition, published in 1988.17 The T staging for this site differs from that of colorectal cancer. Invasion of the lamina propria or submucosa, but not the muscularis propria of the gastric wall, is deemed T1 disease. Invasion of the muscularis propria, or a breach of the muscularis propria without a serosal breach, is deemed T2 disease. A tumor may extend into the lesser omentum or the greater omentum adjoining the stomach, and provided the serosa (ie, visceral peritoneum) is not breached, the tumor is deemed T2. A T3 tumor breaches the serosa, thus placing the patient at increased risk of peritoneal dissemination. Microscopic breach of the serosa can be difficult for the pathologist to detect, but prognostically, presence or absence of such penetration has great impact (eg, one recent study from Hong Kong reports 5-year survival of 64% compared to 10% based on this feature alonela). A T4 tumor invades adjacent structures such as spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, or retroperitoneum. It should be noted that intramural extension to the duodenum or the esophagus is not considered invasion of an adjacent structure; staging of a tumor exhibiting such

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Scott A. Hundahl

Table 1. Fifth Edition AJCC Staging for Gastric Carcinoma PrimaO, Tumor (7) Tx Primary cannot be assessed TO No evidence of primary tumor T1 Tumor invades lamina propria or submucosa T2 Tumor invades muscularis propria or subserosa* T3 Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures* T4 Tumor invades adjacent structures Distant Metastasis (M) MX Cannot be assessed M0 No distant metastasis M1 Distant metastasis

Regional Lymph Nodes (N) NX Cannot be assessed NO No regional node mets N1 Mets in 1-6 nodes N2 Mets in 7-15 nodes N3 Mets in >15 nodes 0 IA IB II

Stage Grouping TisNOM0 T1NOM0 T 1N 1M0 T2NOM0 T 1N2M0 T2N1M0 T3NOM0

IliA IIIB IV

T2N2M0 T3NIM0 T4NOM0 T3N2M0 T4N 1M0 Any N3 Any M1

*Extension into gastrocolic or gastrohepatic ligaments or into greater or lesser omentum without perforation of the visceral peritoneum is classified as T2 disease.

intramural extension is based on the depth of greatest invasion, as described above. Nodal staging in the fifth edition AJCC system is by n u m b e r of involved nodes. Absence of nodal metastasis is considered NO disease. Nodal metastasis in 1-6 nodes is considered N1 disease. Metastasis in 7-15 nodes is considered N2 disease. Metastasis to more than 15 lymph nodes is considered N3 disease, and most regard this extent of nodal disease as incompatible with survival following surgery t r e a t m e n t alone; hence, in the fifth edition system, any N3 case is classified as stage IV. Nodal staging in previous AJCC editions was based on anatomic location of lymph nodes, with N2 disease reserved for either positive nodes > 3 cm from the primary tumor, or nodes associated with celiac or celiac-based vessels (eg, proximal left gastric, c o m m o n hepatic, or splenic arteries). 17,1'3 Distant metastasis is scored as M1 disease and all such cases are deemed stage IV. C o m m o n sites of M1 disease include the peritoneal cavity, extraregional lymph nodes (eg, periiaortic, retropancreatic, portal, retroperitoneal, and mesenteric lymph nodes), liver, ovaries, and less commonly, lung and bone (see section on Patterns of Spread). The tumor node metastasis (TNM) staging matrix for stomach cancer is summarized in Table 1. If one creates a 2 × 2 table with T stages representing rows and N stages representing columns, stage categories generally map to the diagonals (ie, if the sum of T and N is 1, stage I-A; if the sum is 2, then stage I-B; if the sum is 3,

then stage II; if the sum is 4, then stage III-A). Stage III-B is reserved for stage T3N2M0 tumors. All cases with N3 disease, and all cases with a sum of T and N greater than 5 are considered stage IV. Five- and ten-year relative survival rates for US cases anatomically staged according to the fifth edition AJCC system are depicted in Table 2. 2o Comparison of these rates suggests that 10year (as opposed to 5-year) relative survival should be used as the preferred outcome standard for this site. Clinicians in J a p a n and elsewhere sometimes use an alternate staging system derived from a set of "General Rules for Gastric Cancer Study," first published in 1962. A complete version of the 12th edition of this staging system, usually referred to as the "General Rules," has been published in English, complete with color tables and diagrams. 2j This staging system parallels AJCC

Table 2. Five- and Ten-Year Relative Survival for US Cases Treated by Gastrectomy, 1985-1996 (N = 50,169) 5th Edition AJCC Stage

5-Year Relative Survival

lO-YearRelative Survival

IA IB II IIIA

78% 58% 34% 20%

65% 42% 26% 14%

IIIB

8%

3%

IV

7%

5%

Data from Hundahl et al2°

Staging, Stage Migration, and Spread Patterns

staging with respect to the various types of staging (eg, clinical staging, surgical staging, and "conclusive" or pathological staging). The T stages in this system are similar to those in the AJCC (and UICC) system but are otherwise different. Nodal staging differs, with node-level definitions ranging from regional N1 and N2 nodal levels to extraregional N3 and N4 levels. The specific definitions for such levels vary according to location of tumor within the stomach (eg, proximal third, middle third, distal third). The system includes macroscopic description of the tumor (eg, early gastric carcinoma type 22 or, if more advanced, Borrmann type23), but such description does not directly impact on final stage assignment. Peritoneal metastases are described separately (eg, P0-P3), as are liver metastases (eg, H0-H3). Other sites are described conventionally (ie, M0, M1). In the overall "General Rules" staging matrix, limited peritoneal or hepatic disease is lumped in stage IV-A, and other distant metastatic disease is classified as stage IV-B. In this Japanese system, nodal disease that one might term extraregional in the AJCC classification (eg, "General Rules" N3 disease), is incorporated into stage III-A or III-B if the depth of invasion is T1 or T2. Fortunately, it is fairly easy to translate from "General Rules" staging to AJCC staging, provided accurate node counts are also available. The Japanese "General Rules" system is of interest primarily because the extent of surgical lymphadenectomy in stomach cancer has been defined according to this system's lymph node classification. Before the mid-1990s, the Japanese described as an "R level" the extent of lymphadenectomy according to the highest echelon of lymph node stations completely dissected by the surgeon. To avoid confusion with the "UICC R factor," which described completeness of resection, extent of lymphadenectomy was described as a "D factor" after the 12th edition of the "General Rules. T M In reviewing earlier literature in gastric cancer, one should be aware of the dual use of "R" terminology. It must be emphasized that the D-level description for level of lymphadenectomy is based on the Japanese nodal classification system (eg, a lymphadenectomy is classified as D4 if all Japanese "General Rules" N1-N4 nodes are surgically removed, D3 if all N1-N3, but not all N4 nodes are cleared, etc.). Some prominent British authors have, perhaps mistak-

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enly, attempted to redefine D level according to earlier edition AJCC/UICC nodal classifications. 24,25 Internationally, most stick with the original Japanese "General Rules" definitions. In the current fifth edition AJCC/UICC staging system, the choice of numerical thresholds for nodal categories represents a point of ongoing controversy. A number of investigators have observed progressive decrease in survival with increasing number of involved nodes, 26y-34,35"37 with an apparent drop-off in survival when more than 3 nodes are involved. 27-34 Another drop-off has been reported when more than 6 nodes are involved. 29,32,34-37 Involvement beyond 15 or 16 nodes has been observed to be largely incompatible with long-term survival. 3°,37 The AJCC based its cutoffs on these observations, but it must be recognized that differences in the pathologic analysis of surgical specimens, and in the extent of surgical lymphadenectomy, can alter thresholds. In a large National Cancer Data Base (NCDB) experience of 50,169 US cases treated between 1985 and 1996, for example, over 98% of the 10-year survivors of gastric carcinoma had 8 or fewer lymph nodes involved, 2° and a subsequent, more detailed, analysis of this issue revealed that the vast majority of 10-year survivors had 3 or fewer nodes involved:~ In the same series, however, only 18% of cases had 15 or more lymph nodes pathologically analyzed, as recommended by the AJCC for proper staging? 5 To avoid the confounding effect of variation in surgical lymphadenectomy and in the pathological analysis of specimens (see next section), some authors have proposed using the proportion of positive nodes as a better scheme for nodal staging. :~9 In the absence of truly standardized surgical and pathologic procedures, this proposal deserves further investigation. Currently, most authors recognize that basing nodal stage categories on the number of involved lymph nodes does generate better prognostic estimates compared to previous versions of the AJCC system? °-42 Additionally, Japanese authors conclude that the new, fifth edition AJCC system appears to generate better prognostic estimates than the Japanese "General Rules. ''41

Stage Migration Feinstein pointed out in the mid-1980s that improvements in diagnostic/detection/staging meth-

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Scott A. Hundahl

odologies can make stage assessments more accurate, thus generating observed increases in stage-stratified survival, without any true increases in overall survival. ~3 He described this effect as the "Will Rogers Phenomenon," based on a joke that the famous Depression-era comedian told about the "Okies" who migrated away from his beloved native state: "When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states." International debate concerning the value of extended lymphadenectomy in stomach cancer led to early recognition that stage migration could well explain apparent increases in stage-stratified survival associated with more radical procedures and more extensive lymph node analysis. 44 Prior to the 1997 fifth edition AJCC staging system, nodal staging was based on anatomic location of involved nodes, rather than their number. Positive nodes >3 cm from the primary tumor, or nodes associated with celiac or cefiacbased vessels (eg, proximal left gastric, common hepatic, or splenic arteries) were deemed N2 nodes. Unfortunately, this anatomic scheme proved problematic, actually undermining the concept of reproducible anatomic staging. For example, following surgical resection, some surgeon-pathologist teams harvested nodes on fresh surgical specimens, whereas others would harvest nodes only after fixation--and substantial cont r a c t i o n - - o f the specimen; the resulting alterations in interpretation of"3 cm from the tumor" confounded staging in an unpredictable way. Also, surgeons working at major cancer centers or experienced in Japanese techniques frequently removed celiac-based N2 nodes; others usually ignored them. This variation in surgical treat-

ment also confounded reproducible staging. Skip metastases to celiac-based nodes, an event that does occur in gastric cancer, cannot be identified if such nodes are not submitted for analysis in the first place. The old AJCC system also made international comparisons difficult, because Japanese and German surgeons tended to remove celiac-based nodes, whereas, outside of specialist centers, US and British surgeons often did not. This generated a stage migration effect on an international scale. 45,46-4u Relying on data from the Dutch prospective randomized trial comparing D1 and D2 lymphadenectomy, the magnitude of observed 5-year survival difference based on D1 third and fourth edition AJCC nodal staging versus D2 nodal staging can be estimated: 3% change in observed 5-year survival for stage I, 8% for stage II, 6% for stage III-A, and 12% for stage III-B, with the better staged D2 group having better survival.46.49 Numerically based nodal staging, as in the fifth edition AJCC system, has not eliminated stage migration as a problem. As noted previously, only 18% of US gastric cancer cases have 15 or more lymph nodes pathologically analyzed, as recommended by the AJCC. 2° Deficient nodal analysis is sometimes the fault of the surgeon, who may not remove enough nodal tissue to permit optimal analysis; sometimes the fault of the pathologist, who may not harvest enough lymph nodes from submitted tissue; and sometimes the fault of both. Techniques such as fat clearing can dramatically improve nodal yields from resected tissue and facilitate analysis of small nodes. 5°,51 Such small nodes (ie, nodes 1-3 mm in diameter) not infrequently harbor disease. 52 Unfortunately,

3. Lymphadenectomy-Related Stage Migration: Effect of Number of Lymph Nodes Analyzed on Stage-Stratified Relative Survival

Table

Number of Lymph Nodes Analyzed 1 1-6

7-15 --> 15 --> 25

IA

Five-Year Relative Survival By 5th Edition Stage, Stratified by Number of Nodes Analyzed* IB H IIIA IIIB

78%

58%

34%

75% 81% 79% 79%

48% 60% 68% 68%

26% 34% 44% 44%

*No change in T-stage distribution for these strata. Data from Hundahl et al.2°

IV

20% 14%

8% --

7% 6%

20% 25% 22%

6% 10% 19%

6% 8% 9%

145

Staging, Stage Migration, and Spread Patterns

fat clearing is sufficiently tedious, inconvenient, and labor intensive to preclude its routine use. If one posits that survival differences are the result of a stage migration effect alone, one may estimate the magnitude of survival difference resulting from 1-node staging versus 1- to 6-node staging versus 7- to 15-node staging. Such data have been generated based on NCDB data from the US (see Table 3). ~° Comparing the survival of cases staged with -<15 nodes analyzed versus those with > 1 5 nodes analyzed, one sees differences in stage-stratified survival rates of up to 20%. A Memorial Sloan-Kettering study reveals similar stage-stratified survival differences. ~°

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Patterns of Spread Information concerning patterns of gastric carcinoma growth and dissemination derive from four sources: (1) autopsy series of untreated 5s,54 or treated 55-5a cases, (2) clinical-pathologic findings at time of diagnosis derived from various clinical series and registry reports, (3) "second look" reoperative series following initial surgical treatment, 59,6° and (4) clinical series with comprehensive posttreatment follow-up of cases treated for cure combined with mature failure analyses.26,61-63 In the United States, a substantial proportion of cases present with extraregional disease. Population-based cancer data from the US SEER (Surveillance, Epidemiology, and End Results) Cancer Statistics system document that, at time of diagnosis, gastric cancer has spread to extraregional sites in approximately 35% of cases. 64 A much larger, national, convenience sample of US cases from 1985 to 1993 documents a 39% rate of extraregional disease at the time of diagnosis. 45 In gastric cancer, such extraregional disease is usually intra-abdominal. Peritoneal disease is, by far, the most c o m m o n site of extraregional disease, followed by distant nodal disease. Distant organ metastases in gastric cancer, whether at the time of initial presentation or following prior treatment, rarely occur in isolation and are generally found in the setting of advanced localregional and/or peritoneal disease. Provided one regards ovarian metastasis as a subset of peritoneal dissemination, liver is by far the most common site of distant organ metastasis in gastric cancer, followed as a distant second by lung.

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Table 5. Patterns Of Recurrence Following Surgical Treatment

Failure Pattern

Wangensteen's 2nd Look* Series, 86 failures/107 cases Ant' Component of Failure

Local-regional Diffuse peritoneal Distant (not peritoneal) Undescribed TOTAL

87% 53% 26% 4% > 100%

Mass Gen. Clinical Series** NCC Tokyo Clinical Series, * ** 687failures~I,976 cases" Clinical!r 88failures~130 cases Any Dominant Failure Component of Failure

56% 34% 60% --

> 100%

23% 44% 24% 8%

100%

*From Gunderson and Sosin6° **From Landry et a126 ***From Katai et al~3 Locally, gastric cancer spreads by way of intramural lymphatics in the gastric wall; spread up to 6 cm from the primary tumor has been described. 65 For exophytic and polypoid tumors of the stomach, a resection margin of 2 cm usually clears intramural disease, but for ulcerating or infiltrating tumors, a margin of 5 cm or more is often required to secure a tumor-free resection margin. Local spread also involves ever-deeper penetration of the gastric wall. A key event in the natural history of gastric cancer occurs when the serosa (ie, visceral peritoneum) is breached, thus setting the stage for widespread intraperitoneal dissemination. Such intraperitoneal spread is common, particularly in the setting of diffusetype gastric cancer. 63 Gastric cancer spreads readily to regional (and extraregional) lymphatics. A number of elegant lymphangiographic studies and carbon particle injection studies have nicely illustrated the lymphatic drainage of the stomach. 66-68 The actual frequency of gastric cancer regional nodal metastasis among 3,843 cases treated with D2 lymphadenectomy at the National Cancer Center in Tokyo has been described and a searchable database has been created and computerized. 69-71 Table 4 illustrates computerized predictions from this searchable database (aka the "Maruyama Program") for a 65-year-old male with a 5-cm, transserosal, poorly differentiated gastric adenocarcinoma in the specified locations. Not shown are predictions for extraregional peri-aortic sites, where, especially for anterior wall and lesser curvature tumors of the proximal and middle stomach, incidence among surgical candidates is as high as 6% to 8%. Clinicians wishing to use the Maruyama Program as an informational tool to guide biopsies and treatment may now access it through a commercially available CD-ROM. 7~

Table 5 summarizes data from three key series describing patterns of failure following surgical treatment. 26,6°,63 Owen Wangensteen's famous reoperative series deserves special emphasis, because this study has generated the best first-siteof-failure data available. Following radical surgical treatment for the (generally advanced) tumors treated by Wangensteen and his team at the University of Minnesota, local-regional disease as the only site of initial failure occurred in 54% of cases. By contrast, distant organ metastasis as the sole site of initial failure occurred in only 6% of cases (data not shown in Table 5). 6o Recognition of high rates of local-regional failure as the first site of failure has fueled interest in regional intraoperative radiotherapy and regional chemoradiatherapy as adjuvant modalities in this disease. 72,73 To summarize, I use a horticultural analogy: Gastric cancer starts like inexorably encroaching bamboo, erupts beyond its original site, and then seeds like a dandelion in the wind. Like bamboo, it is hard to eliminate, even with radical measures. Summary

Fifth edition AJCC staging for gastric cancer results in improved prognostic estimates compared to earlier AJCC versions and Japanese "General Rules" staging. Future refinements in anatomical staging will probably revolve around either the alteration of numerical thresholds for nodal categories or the use of proportional thresholds for such categories. Node-based stage migration remains an issue in the fifth edition AJCC system. Given its propensity to local-regional recurrence following surgical treatment, and less frequent early dissemination to distant organs relative to

Staging, Stage Migration, and Spread Patterns

other cancers (eg, breast), better means of localregional control might favorably impact on the prognosis of this disease.

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