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Early gastric carcinoma with focal advanced cancer: A particular subtype of gastric carcinoma
Early Gastric Carcinoma With Focal Advanced Cancer: A Particular Subtype of Gastric Carcinoma MARIA-CHIARA OSTERHELD, MD, RICARDO LAURINI, MD, AND EMILIA SARAGA, MD Early gastric cancer (EGC) is defined as a carcinoma limited to the mucosa or mucosa and submucosa, irrespective of whether metastasis to lymph nodes has occurred. EGC presents a much more favorable prognosis than advanced gastric carcinoma (AGC), with a 5-year survival rate between 88% and 96% for EGC versus 45% to 50% for AGC. Moreover, s o m e gastric cancers appear as a more or less extended EGC with focal AGC (fAGC). The purpose of this study was to analyze prognostic factors in this intermediate group of tumors. From 1981 to 1992, among the 615 gastrectomy specimens with carcinoma examined at the Institute of Pathology of the University of Lausanne, only 19 tumors corresponded to the criteria of EGC with fAGC. Cfinicopathologic features were studied, and a cytophotometric D N A analysis was performed. Our results show a 5-year survival rate for EGC with fAGC of 61% (11 of 18 patients alive), intermediate
between that of EGC and AGC. N o significant correlations were fotmd between the most known predictive factors and prognosis. Most tumors analyzed (16 of 19) showed a diploid D N A content in the superficial as well as in the invasive areas. Contrary to the findings in the literature, which show a high-ploidy D N A pattern in most AGC, our cases show low-ploidy D N A even in the invasive portion of the tumors. In conclusion, we show that EGC with focal AGC represents a gastric cancer with an intermediate prognosis and, therefore, must be considered as a specific subtype of gastric carcinoma. HUM PATHOL 29:815-819. Copyright © 1998 by W.B. Saunders Company Key words: advanced gastric carcinoma, early gastric carcinoma, pathology, prognosis, ploidy. Abbreviations: EGC, early gastric cancers; AGC, advanced gastric cancer; fAGC, focal invasion of the muscularis propria.
From the early 1960s, a massive screening program in Japan resulted in an increase of the n u m b e r of early gastric cancers (EGC) detected: EGC constitute 30% to 35% of all gastric cancers in Japan, c o m p a r e d with only 10% to 14% in Europe. 1 EGC is defined as a carcinoma limited to the mucosa or mucosa and submucosa, 2 but not extending into muscularis propria, regardless of the presence of lymph n o d e metastasis. 3 EGC presents a much m o r e favorable prognosis than advanced gastric cancer (AGC): a 5-year survival rate of 89% for EGC versus 46% for AGC. 4 Only a few studies concerning the group of gastric tumors situated histologically between the EGC and AGC have been r e p o r t e d in the literature. Our aim was to study clinicopathologic aspects of 19 superficial gastric cancers, presenting focal advanced type of invasion, hypothesizing that they represent a subgroup of gastric carcinoma with a different prognosis. In view of r e p o r t e d differences in ploidy between EGC and AGC, we also p e r f o r m e d DNA analysis, by image cytometry.
gross appearance. 5 Histological examination of the latter g r o u p c o n f i r m e d the presence of 72 cases of EGC, but the o t h e r 19 cases showed EGC with focal invasion of the muscularis propria (fAGC). These 19 cases were selected for o u r study. All available gross and histological material was r e e x a m i n e d by two pathologists, which i n c l u d e d the m a p p i n g of the lesions as described by Mori et al 6 in their p r o t o c o l (Figs 1, 2). Gross findings were classified according to the system p r o p o s e d by the J a p a n e s e Society o f Gastroenterological Endoscopy into type I; type II a, b, and c; or type III. 5 T u m o r s were classified according to the criteria of Lauren, 7 and those of the World H e a l t h Organisation. s T h e T N M classification was used for the d e e p e d g e of the invasive focus. 9 T h e growth pattern of the invasive c o m p o n e n t was classified into four types: A, B, C, or D as described by Mori et al a° (Fig 3). T h e presence of dysplasia, metaplasia, lymphangitis carcinomatosa, and lymph n o d e metastases was r e c o r d e d for each case. For each tumor, the areas in square centimeters of EGC and of the invasive c o m p o n e n t (fAGC) were measured. This allowed us to d e t e r m i n e the ratio between the area of the invasive c o m p o n e n t and that of the EGC. T h e tumors were divided into two groups: less than 10% of surface ratio (fAGC/EGC) and 10% or m o r e of surface ratio. For all of the cases, clinical data, including symptoms, endoscopic findings, and follow-up, were obtained from the pathology reports, referring clinicians, or the Swiss T u m o r Registry. Preoperative biopsy specimens of 16 cases were available for review. Possible correlations between age, sex, areas of fAGC and EGC, p e r c e n t a g e f A G C / E G C , types of tumors, lymph n o d e metastases or lymphangitis carcinomatosa, and prognosis were evaluated by means of the chi-square test. Only a P-value of less than .05 was considered statistically significant. T h e Kaplan-Meier survival curve was also used for these parameters. For cytophotometric DNA analysis, hematoxylin and eosin-stained slides f r o m all tumors were screened to identify the EGC and fAGC c o m p o n e n t f r o m each case, to separate
MATERIALS AND METHODS We reviewed the reports and slides f r o m 615 cases of gastric carcinomas available in the files of our institute between 1981 and 1992. Five h u n d r e d twenty-four cases were classified as AGC, and 91 were classified as EGC based on the
From the Institute of Pathology of the University of Lausanne, Switzerland. Accepted for publication December 2, 1997. Address correspondence and reprint requests to M.C. Osterheld, MD, Institute of Pathology of the University of Lausanne, Rue du Bugnon 25--1011 Lausanne, Switzerland. Copyright © 1998 by W.B. Saunders Company 0046-8177/98/2908-000858.00/0
815
HUMAN PATHOLOGY
Volume 29, No. 8 (August 1998)
analysis system (SAMBA, Alcatel TITN Answare, Grenoble, France). A minimum of 150 nuclei were measured per smear (300 nuclei in most cases). Only well-preserved nuclei were selected by the operator, using the gallery program of SAMBA system (SAMBA, Alcatel TITN Answare, Grenoble, France). As a control, we used human lymphocytes and, when available, neutrophils in the tumor cell sample. Histograms exhibiting a G0/G1 main peak at 2C were considered to be diploid (index, 0.85 to 1.15). A tetraploid tumor was concluded when the DNA index of the peak was between 1.70 and 2.30 and constituted at least 20% of all eventsd 2
RESULTS
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In o u r series, there was a m a l e / f e m a l e ratio of 3:1, with a significant difference in m e a n age at the time of the gastrectomy (69 years for m e n a n d 58 years for women). T h e clinical symptoms were relatively nonspecific, consisting of epigastralgia, weight loss, anemia, and vomiting for most of the patients. T h e duration of these symptoms varied f r o m 5 days to 9 years, with a m e a n of 11 months. In 7 of 16 cases, the preoperative biopsy findings were suggestive of an early stage of the tumor. Most tumors were located in the small curvature of the stomach. The macroscopic pattern c o r r e s p o n d e d mainly to types II and III. T h e m o d e of invasive growth, following the classification of Mori et al, comprised four cases of type A, five of type B, two of type C, a n d eight of type D. According to Lauren et al's 7 classification, eight tumors were diffuse carcinomas, 10 intestinal-type carcinomas; and one patient showed a mixed type of tumor. Eleven cases had an infiltrating carcinoma pT2, and eight h a d a pT3 (Table 1). We f o u n d nine patients with lymphatic p e r m e a t i o n and seven with lymph n o d e metastases. All of the cases presented intestinal metaplasia, and in seven (37%), epithelial dysplasia was seen at the p e r i p h e r y of the tumour. T h e 5-year survival rate in o u r series was 61% (7 of 18 patients). Two other patients died after 6 and 7 years, respectively. O f the nine dead patients, four died of the progression of their carcinoma, whereas in the other five patients the cause of death was cardiovascular failure, major sepsis, or renal failure without evidence of tumour. According to the Kaplan-Meier survival curves (Fig 4), survival correlated significantly only with lymphangitis carcinomatosa (P = .02) and borderline with lymph n o d e metastasis (P = .06) (Fig 3). DNA analysis showed the EGC c o m p o n e n t to be diploid in 18 of 19 cases. DNA analysis was possible for the infiltrating c o m p o n e n t only in 16 cases and was diploid in all of them. Unfortunately, in the one case in which the EGC c o m p o n e n t of the t u m o r presented a tetraploid p e a k (HS85-963), the c o r r e s p o n d i n g fAGC was c o m p o s e d of isolated t u m o r cells that escaped detection by cytometry (Table 2).
EGc fAGC
87029686 FIGURE I, The lesion is evident in the resected specimen (A, B). A map of the resected specimen delimits areas of EGC and fAGC (C).
DISCUSSION
these two components for DNA evaluation by dissection from the corresponding paraffin blocks. All blocks were processed following the technique of Hedley et al. 11 DNA analysis was performed on Feulgen-stained cytospins using an image
In recent years, attempts to improve the detection of EGC in J a p a n have resulted in an increased incidence 816
ECG WITH FOCAL ADVANCED CANCER (Osterheld et al) !:i
ii!iiill
!ii:!ii~i!;;i::¸ ,
F I G U R E 2. ( A ) Low-power view of a histological section cut through an area of EGC with fAGC (small invasion type according to Mori 1990; original magnification x8). (B) Highpower view of the EGC located in the area marked by the long arrows in (A). (Original magnification x130,) (C) High-power view of the area of focal invasion of the muscularis propria marked by the short arrows in (A). (Original magnification x 1300
of this type of tumor. In fact, in Japan, EGC represents 30% to 35% of gastric cancer, whereas the frequency in E u r o p e is below 10% to 14%. 1 T h e 5-year survival rate of EGC (88% to 96%) is distinctly better than that of AGC (45% to 50%). 2,4 Few papers have b e e n published on gastric carcinomas that c o m b i n e features of EGC and AGC. 4:° N a k a m u r a f o u n d for these tumors an intermediate prognosis. For this category of tumors, we f o u n d in our study a 5-year survival rate of 61%, in between that of the EGC and AGC, which corresponds to the data of Nakamura. 4 O u r 3-year survival rate was 74%. This i m p o r t a n t difference in survival stimulated us to search for correlations with well-established prognostic factors. In accordance with Lawrence and Shiu, is no correlation was f o u n d between sex, t u m o r location, endoscopic aspect, growth pattern of fAGC, histological A (small invasion type)
B (ulcer-connected type)
C (vessel permeation type)
D (diffusely inf'dtralivetype)
i ............
;& ..................
type of the tumor, and prognosis. As expected, the i m p o r t a n c e of lymphatic p e r m e a t i o n for prognosis was confirmed. We further hypothesised t h a t the size of the AGC and the ratio between the area of EGC and AGC m i g h t be progalostically significant. However, neither the size of EGC (P = .50) n o r the size of the invasive c o m p o n e n t (P = .74) n o r the fAGC/EGC ratio (P = .57) correlate with survival. T h e n u m b e r of cases (19 patients) limits the power of statistical analysis but even in the four patients who died because of widespread carcinoma, the surface of the invasive c o m p o n e n t was usually very small measuring: only 0.25 cm 2 for two of them. If we consider the whole g r o u p of patients, the prognosis is better than that of p u r e AGC. However, o u r results show that the majority of the established predictive factors do not influence prognosis in individual cases. F u r t h e r m o r e , almost all of our cases were diploid, also in the invasive c o m p o n e n t , which contrasts with what has b e e n observed for usual AGC. O t h e r studies have r e p o r t e d that high ploidy is related to massive infiltration and a p o o r prognosis, 14 whereas low-ploidy is p r e d o m i n a n t l y f o u n d in EGC with long survival and low risk of metastasis) ~46 O u r observations indicate that EGC with fAGC probably does not r e p r e s e n t a transition f r o m EGC to a m o r e aggressive t u m o r but a particular subtype of gastric carcinoma and therefore i m p o r t a n t to be recognized. T h e implications of such a diagnosis for patient
..............
FIGURE 3. Growth pattern of the fAGC component as described by Mori (1990), 817
HUMAN PATHOLOGY
TABLE 1.
Volume 29, No. 8 (August 1998)
Pathological Data on Patients With Gastric Cancer (EGC and fAGC)
Patients
Sex
Age
fAGC (cm z)
EGC (cm 2)
AGC/EGC (%)
Lymph. CA
Lymph Nodes
Histology*
Growth Patternf
D e p t h of Invasion
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
M F M M M M M Yi M M M M M M M M F F F
68 48 69 55 63 61 62 66 66 63 75 73 83 82 60 73 86 62 39
8 0.25 3.75 0.24 3.75 0.25 3.75 4.5 4 1.5 1.5 0.09 2.25 0.12 0.75 0.25 0.25 2 33
35 3 24 10.5 30 9 12.25 45.5 41.25 30 22.5 6 30 9 3.75 5 36 90 136
23 8%
+ + + + + + + + + +
+ + + + + + +
I D I I I I D D D D I I I D I I M D D
D B D B D A D D B D A A A D B B C C D
T3 T2 T3 T2 T3 T2 T3 T3 T3 T2 T3 T2 T3 T2 T2 T2 T2 T2 T3
15 2.2 12.5 3 30 10 10 5 7 1.5 7.5 1.3 20 5 0.7 2.2 24
Follow-Up
Months
NS Alive Alive Alive Alive Alive Alive Alive Alive Alive DnRT DnRT DnRT DnRT DnRT DRT DRT DRT DRT
Lost 156 156 108 96 96 96 96 60 60 84 30 24 24 12 72 48 48 12
Abbreviations: D, diffuse type with signet ring cells; I, intestinal type; M, m i x e d type; DnRT, de a t h n o n r e l a t e d to the tumor; DRT, d eath related to the tumor; NS, n o t stated. *Lauren's classification. ~'Growth p a t t e r n of AGC a c c o r d i n g to Mori's classification.
A
AGCIEGC
B
:l.O0-
LYNPHNODES ~..00
-
i
n
n n
/ >.
0.75
8 &
0.50 -
> ~n
0.25
-
0.00
-
I
-
t
I
0.75
II
_
_
1
~
-
t~ 1313
'L
13 13
fl 0.50 -
1
>
0.25
-
0.00
-
12
Survival in months
3L 46 66 7~ o~ ol ~B 1~o ~2 N4 Survival in months
LYMPHANGITZ5
C
2 '~
D
AGC
1.00
-
1.00- ~
0,75
-
0.75 -
n
I
1
m
In
I
I1
IN
11
0.50
-
0.25
-
0.00
-
0.50
-
0.25
-
0.00
-
>
Z
2~ 3L 40 66 72 o~ o~ I~0 I~0 112 N4 Survival in months
Survival in m0ntns
FIGURE 4. Kaplan-Meier survival curves. (A) Group 0: with a ratio of fAGC/EGC < 10%. (B) Group 1: with a ratio of fAGC/EGC -> 10%. (C) Group 0: lymph n o d e negative; group 1: lymph node positive. (C) Group 0: lymphangitis carcinomatosa negative; group 1: lymphangitis carcinomatosa positive. (D) Group 0: fAGC area < 2 cm2; group 1: fAGC area _> 2 c m 2.
818
ECG WITH FOCAL ADVANCED CANCER (Osterheld et al)
TABLE 2. DNA Ploidy Values in the EGC and fAGC Components (19 Cases) Patients
EGC
HS81-26955 HS82-30913
Diploid Diploid, tetraploid peak 10%
HS83-16396 HS84-6284 HS85-11162 HS85-963 HS86-18411 HS87-10752 HS87-17781 HS87-29686 HS87-31943 HS87-33706 HS87-34860 HS88-708 HS88-17339 HS91-20782 HS91-27242 HS92-20673 IIS92-12630
Diploid Diploid Diploid Diploid, tetraploid, peak 38% Diploid Diploid Diploid Diploid Diploid, tetraploid peak 12.6% Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid
REFERENCES
fAGC * Diploid, tetraploid peak 7% Diploid Diploid Diploid Diploid t Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid * Diploid Diploid
*Insufficient material for cytometry. tIsolated cells escaped detection by cytometry.
management impose the need for more detailed gross and histological examination of gastrectomy specimens according to the protocol discussed in this article. In conclusion, our study (1) defines a variant of early gastric carcinoma characterized by a superficial growth pattern with focal invasion of the muscularis propria, regardless of extent or pattern of infiltrative growth and displaying better prognosis than AGC; and (2) confirms the importance ofDNA ploidy assessment in gastric carcinoma as an independent predictor of prognosis.
Acknowledgments. T h e authors thank P r o f ET. Bosman for critical review of the manuscript, S. Burki a n d J . Maillardet for photography, and G. Van Melle for statistical assistance.
819
1. Ohta H, NoguchiY, Tkagi K, et al: Early gastric carcinoma with special reference to macroscopic classification. Cancer 60:1099-1106, 1987 2. Itoh H, Yoshihiro O, Nakamura K, et al: Complete ten-year postgastrectomy follow-up on early gastric cancer. Am J Surg 158:1416, 1989 3. Japanese Research Society for Gastric Cancer: The general rules for gastric cancer study in surgery and pathology. Jpn J Surg 11:127-139, 1981 4. Nakamura K, Ueyama T, Yao T, et al: Pathology and prognosis of gastric carcinoma. Cancer 70:1030-1037, 1992 5. Murakami T: Pathomorphological diagnosis: Definition and gross classification of early gastric cancer, in Early Gastric Cancer. Gann Monograph on Cancer Research No 11. Tokyo, Japan, University of Tokyo Press, 1972, p 53 6. Mori M, Adachi Y, Kakeji Y, et al: Superficial flat-type early carcinoma of the stomach. Cancer 69:306-313, 1992 7. Lanren P: The two main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Immnnol Scand 64:31-49, 1965 8. Oota K, Sobin LH: Histological typing of gastric and oesophageal tumours, in International Histological Classification of turnouts, No 18, WHO, Geneva, 1977 9. Kennedy BJ: TNM classification for stomach cancer. Cancer 26:971-984, 1970 10. Mori M, Adachi Y, Nakamura K, et al: Advanced gastric carcinoma simulating early gastric carcinoma. Cancer 65:1033-1040, 1990 11. Hedley DW, Friedlander ML, Taylor IW, et al: Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. J Histochem Cytochem 31:1333-1335, 1983 12. Bowman R, Angelini G, Cabral C, et al: Interobserver and intraobserver variation in tumor DNA index as analysed by static image cytometry: A pilot study. Cell Vision 3:291-296, 1996 13. Lawrence M, Shiu MH: Early gastric cancer. Ann Surg 213:327-334, 1991 14. Johnson H, Belluco C, Masood S, et al: The value of flow cytometric analysis in patients with gastric cancer. Arch Surg 128:314317, 1993 15. Korenaga D, Okamura T, Saito A, et al: DNA ploidy is closely linked to tumor invasion, lymph node metastasis and prognosis in clinical gastric cancer. Cancer 62:309-313, 1988 16. Sasaki O, Soejima K, Haraguchi Y: Intra-mmor DNA ploidy distribution pattern and its relation to histologic type in gastric carcinoma. Pathol Res Pract 188:545-549, 1992
between that of EGC and AGC. N o significant correlations were fotmd between the most known predictive factors and prognosis. Most tumors analyzed (16 of 19) showed a diploid D N A content in the superficial as well as in the invasive areas. Contrary to the findings in the literature, which show a high-ploidy D N A pattern in most AGC, our cases show low-ploidy D N A even in the invasive portion of the tumors. In conclusion, we show that EGC with focal AGC represents a gastric cancer with an intermediate prognosis and, therefore, must be considered as a specific subtype of gastric carcinoma. HUM PATHOL 29:815-819. Copyright © 1998 by W.B. Saunders Company Key words: advanced gastric carcinoma, early gastric carcinoma, pathology, prognosis, ploidy. Abbreviations: EGC, early gastric cancers; AGC, advanced gastric cancer; fAGC, focal invasion of the muscularis propria.
From the early 1960s, a massive screening program in Japan resulted in an increase of the n u m b e r of early gastric cancers (EGC) detected: EGC constitute 30% to 35% of all gastric cancers in Japan, c o m p a r e d with only 10% to 14% in Europe. 1 EGC is defined as a carcinoma limited to the mucosa or mucosa and submucosa, 2 but not extending into muscularis propria, regardless of the presence of lymph n o d e metastasis. 3 EGC presents a much m o r e favorable prognosis than advanced gastric cancer (AGC): a 5-year survival rate of 89% for EGC versus 46% for AGC. 4 Only a few studies concerning the group of gastric tumors situated histologically between the EGC and AGC have been r e p o r t e d in the literature. Our aim was to study clinicopathologic aspects of 19 superficial gastric cancers, presenting focal advanced type of invasion, hypothesizing that they represent a subgroup of gastric carcinoma with a different prognosis. In view of r e p o r t e d differences in ploidy between EGC and AGC, we also p e r f o r m e d DNA analysis, by image cytometry.
gross appearance. 5 Histological examination of the latter g r o u p c o n f i r m e d the presence of 72 cases of EGC, but the o t h e r 19 cases showed EGC with focal invasion of the muscularis propria (fAGC). These 19 cases were selected for o u r study. All available gross and histological material was r e e x a m i n e d by two pathologists, which i n c l u d e d the m a p p i n g of the lesions as described by Mori et al 6 in their p r o t o c o l (Figs 1, 2). Gross findings were classified according to the system p r o p o s e d by the J a p a n e s e Society o f Gastroenterological Endoscopy into type I; type II a, b, and c; or type III. 5 T u m o r s were classified according to the criteria of Lauren, 7 and those of the World H e a l t h Organisation. s T h e T N M classification was used for the d e e p e d g e of the invasive focus. 9 T h e growth pattern of the invasive c o m p o n e n t was classified into four types: A, B, C, or D as described by Mori et al a° (Fig 3). T h e presence of dysplasia, metaplasia, lymphangitis carcinomatosa, and lymph n o d e metastases was r e c o r d e d for each case. For each tumor, the areas in square centimeters of EGC and of the invasive c o m p o n e n t (fAGC) were measured. This allowed us to d e t e r m i n e the ratio between the area of the invasive c o m p o n e n t and that of the EGC. T h e tumors were divided into two groups: less than 10% of surface ratio (fAGC/EGC) and 10% or m o r e of surface ratio. For all of the cases, clinical data, including symptoms, endoscopic findings, and follow-up, were obtained from the pathology reports, referring clinicians, or the Swiss T u m o r Registry. Preoperative biopsy specimens of 16 cases were available for review. Possible correlations between age, sex, areas of fAGC and EGC, p e r c e n t a g e f A G C / E G C , types of tumors, lymph n o d e metastases or lymphangitis carcinomatosa, and prognosis were evaluated by means of the chi-square test. Only a P-value of less than .05 was considered statistically significant. T h e Kaplan-Meier survival curve was also used for these parameters. For cytophotometric DNA analysis, hematoxylin and eosin-stained slides f r o m all tumors were screened to identify the EGC and fAGC c o m p o n e n t f r o m each case, to separate
MATERIALS AND METHODS We reviewed the reports and slides f r o m 615 cases of gastric carcinomas available in the files of our institute between 1981 and 1992. Five h u n d r e d twenty-four cases were classified as AGC, and 91 were classified as EGC based on the
From the Institute of Pathology of the University of Lausanne, Switzerland. Accepted for publication December 2, 1997. Address correspondence and reprint requests to M.C. Osterheld, MD, Institute of Pathology of the University of Lausanne, Rue du Bugnon 25--1011 Lausanne, Switzerland. Copyright © 1998 by W.B. Saunders Company 0046-8177/98/2908-000858.00/0
815
HUMAN PATHOLOGY
Volume 29, No. 8 (August 1998)
analysis system (SAMBA, Alcatel TITN Answare, Grenoble, France). A minimum of 150 nuclei were measured per smear (300 nuclei in most cases). Only well-preserved nuclei were selected by the operator, using the gallery program of SAMBA system (SAMBA, Alcatel TITN Answare, Grenoble, France). As a control, we used human lymphocytes and, when available, neutrophils in the tumor cell sample. Histograms exhibiting a G0/G1 main peak at 2C were considered to be diploid (index, 0.85 to 1.15). A tetraploid tumor was concluded when the DNA index of the peak was between 1.70 and 2.30 and constituted at least 20% of all eventsd 2
RESULTS
"~"
"-~.
:"
~
"!~4
.
[]
In o u r series, there was a m a l e / f e m a l e ratio of 3:1, with a significant difference in m e a n age at the time of the gastrectomy (69 years for m e n a n d 58 years for women). T h e clinical symptoms were relatively nonspecific, consisting of epigastralgia, weight loss, anemia, and vomiting for most of the patients. T h e duration of these symptoms varied f r o m 5 days to 9 years, with a m e a n of 11 months. In 7 of 16 cases, the preoperative biopsy findings were suggestive of an early stage of the tumor. Most tumors were located in the small curvature of the stomach. The macroscopic pattern c o r r e s p o n d e d mainly to types II and III. T h e m o d e of invasive growth, following the classification of Mori et al, comprised four cases of type A, five of type B, two of type C, a n d eight of type D. According to Lauren et al's 7 classification, eight tumors were diffuse carcinomas, 10 intestinal-type carcinomas; and one patient showed a mixed type of tumor. Eleven cases had an infiltrating carcinoma pT2, and eight h a d a pT3 (Table 1). We f o u n d nine patients with lymphatic p e r m e a t i o n and seven with lymph n o d e metastases. All of the cases presented intestinal metaplasia, and in seven (37%), epithelial dysplasia was seen at the p e r i p h e r y of the tumour. T h e 5-year survival rate in o u r series was 61% (7 of 18 patients). Two other patients died after 6 and 7 years, respectively. O f the nine dead patients, four died of the progression of their carcinoma, whereas in the other five patients the cause of death was cardiovascular failure, major sepsis, or renal failure without evidence of tumour. According to the Kaplan-Meier survival curves (Fig 4), survival correlated significantly only with lymphangitis carcinomatosa (P = .02) and borderline with lymph n o d e metastasis (P = .06) (Fig 3). DNA analysis showed the EGC c o m p o n e n t to be diploid in 18 of 19 cases. DNA analysis was possible for the infiltrating c o m p o n e n t only in 16 cases and was diploid in all of them. Unfortunately, in the one case in which the EGC c o m p o n e n t of the t u m o r presented a tetraploid p e a k (HS85-963), the c o r r e s p o n d i n g fAGC was c o m p o s e d of isolated t u m o r cells that escaped detection by cytometry (Table 2).
EGc fAGC
87029686 FIGURE I, The lesion is evident in the resected specimen (A, B). A map of the resected specimen delimits areas of EGC and fAGC (C).
DISCUSSION
these two components for DNA evaluation by dissection from the corresponding paraffin blocks. All blocks were processed following the technique of Hedley et al. 11 DNA analysis was performed on Feulgen-stained cytospins using an image
In recent years, attempts to improve the detection of EGC in J a p a n have resulted in an increased incidence 816
ECG WITH FOCAL ADVANCED CANCER (Osterheld et al) !:i
ii!iiill
!ii:!ii~i!;;i::¸ ,
F I G U R E 2. ( A ) Low-power view of a histological section cut through an area of EGC with fAGC (small invasion type according to Mori 1990; original magnification x8). (B) Highpower view of the EGC located in the area marked by the long arrows in (A). (Original magnification x130,) (C) High-power view of the area of focal invasion of the muscularis propria marked by the short arrows in (A). (Original magnification x 1300
of this type of tumor. In fact, in Japan, EGC represents 30% to 35% of gastric cancer, whereas the frequency in E u r o p e is below 10% to 14%. 1 T h e 5-year survival rate of EGC (88% to 96%) is distinctly better than that of AGC (45% to 50%). 2,4 Few papers have b e e n published on gastric carcinomas that c o m b i n e features of EGC and AGC. 4:° N a k a m u r a f o u n d for these tumors an intermediate prognosis. For this category of tumors, we f o u n d in our study a 5-year survival rate of 61%, in between that of the EGC and AGC, which corresponds to the data of Nakamura. 4 O u r 3-year survival rate was 74%. This i m p o r t a n t difference in survival stimulated us to search for correlations with well-established prognostic factors. In accordance with Lawrence and Shiu, is no correlation was f o u n d between sex, t u m o r location, endoscopic aspect, growth pattern of fAGC, histological A (small invasion type)
B (ulcer-connected type)
C (vessel permeation type)
D (diffusely inf'dtralivetype)
i ............
;& ..................
type of the tumor, and prognosis. As expected, the i m p o r t a n c e of lymphatic p e r m e a t i o n for prognosis was confirmed. We further hypothesised t h a t the size of the AGC and the ratio between the area of EGC and AGC m i g h t be progalostically significant. However, neither the size of EGC (P = .50) n o r the size of the invasive c o m p o n e n t (P = .74) n o r the fAGC/EGC ratio (P = .57) correlate with survival. T h e n u m b e r of cases (19 patients) limits the power of statistical analysis but even in the four patients who died because of widespread carcinoma, the surface of the invasive c o m p o n e n t was usually very small measuring: only 0.25 cm 2 for two of them. If we consider the whole g r o u p of patients, the prognosis is better than that of p u r e AGC. However, o u r results show that the majority of the established predictive factors do not influence prognosis in individual cases. F u r t h e r m o r e , almost all of our cases were diploid, also in the invasive c o m p o n e n t , which contrasts with what has b e e n observed for usual AGC. O t h e r studies have r e p o r t e d that high ploidy is related to massive infiltration and a p o o r prognosis, 14 whereas low-ploidy is p r e d o m i n a n t l y f o u n d in EGC with long survival and low risk of metastasis) ~46 O u r observations indicate that EGC with fAGC probably does not r e p r e s e n t a transition f r o m EGC to a m o r e aggressive t u m o r but a particular subtype of gastric carcinoma and therefore i m p o r t a n t to be recognized. T h e implications of such a diagnosis for patient
..............
FIGURE 3. Growth pattern of the fAGC component as described by Mori (1990), 817
HUMAN PATHOLOGY
TABLE 1.
Volume 29, No. 8 (August 1998)
Pathological Data on Patients With Gastric Cancer (EGC and fAGC)
Patients
Sex
Age
fAGC (cm z)
EGC (cm 2)
AGC/EGC (%)
Lymph. CA
Lymph Nodes
Histology*
Growth Patternf
D e p t h of Invasion
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
M F M M M M M Yi M M M M M M M M F F F
68 48 69 55 63 61 62 66 66 63 75 73 83 82 60 73 86 62 39
8 0.25 3.75 0.24 3.75 0.25 3.75 4.5 4 1.5 1.5 0.09 2.25 0.12 0.75 0.25 0.25 2 33
35 3 24 10.5 30 9 12.25 45.5 41.25 30 22.5 6 30 9 3.75 5 36 90 136
23 8%
+ + + + + + + + + +
+ + + + + + +
I D I I I I D D D D I I I D I I M D D
D B D B D A D D B D A A A D B B C C D
T3 T2 T3 T2 T3 T2 T3 T3 T3 T2 T3 T2 T3 T2 T2 T2 T2 T2 T3
15 2.2 12.5 3 30 10 10 5 7 1.5 7.5 1.3 20 5 0.7 2.2 24
Follow-Up
Months
NS Alive Alive Alive Alive Alive Alive Alive Alive Alive DnRT DnRT DnRT DnRT DnRT DRT DRT DRT DRT
Lost 156 156 108 96 96 96 96 60 60 84 30 24 24 12 72 48 48 12
Abbreviations: D, diffuse type with signet ring cells; I, intestinal type; M, m i x e d type; DnRT, de a t h n o n r e l a t e d to the tumor; DRT, d eath related to the tumor; NS, n o t stated. *Lauren's classification. ~'Growth p a t t e r n of AGC a c c o r d i n g to Mori's classification.
A
AGCIEGC
B
:l.O0-
LYNPHNODES ~..00
-
i
n
n n
/ >.
0.75
8 &
0.50 -
> ~n
0.25
-
0.00
-
I
-
t
I
0.75
II
_
_
1
~
-
t~ 1313
'L
13 13
fl 0.50 -
1
>
0.25
-
0.00
-
12
Survival in months
3L 46 66 7~ o~ ol ~B 1~o ~2 N4 Survival in months
LYMPHANGITZ5
C
2 '~
D
AGC
1.00
-
1.00- ~
0,75
-
0.75 -
n
I
1
m
In
I
I1
IN
11
0.50
-
0.25
-
0.00
-
0.50
-
0.25
-
0.00
-
>
Z
2~ 3L 40 66 72 o~ o~ I~0 I~0 112 N4 Survival in months
Survival in m0ntns
FIGURE 4. Kaplan-Meier survival curves. (A) Group 0: with a ratio of fAGC/EGC < 10%. (B) Group 1: with a ratio of fAGC/EGC -> 10%. (C) Group 0: lymph n o d e negative; group 1: lymph node positive. (C) Group 0: lymphangitis carcinomatosa negative; group 1: lymphangitis carcinomatosa positive. (D) Group 0: fAGC area < 2 cm2; group 1: fAGC area _> 2 c m 2.
818
ECG WITH FOCAL ADVANCED CANCER (Osterheld et al)
TABLE 2. DNA Ploidy Values in the EGC and fAGC Components (19 Cases) Patients
EGC
HS81-26955 HS82-30913
Diploid Diploid, tetraploid peak 10%
HS83-16396 HS84-6284 HS85-11162 HS85-963 HS86-18411 HS87-10752 HS87-17781 HS87-29686 HS87-31943 HS87-33706 HS87-34860 HS88-708 HS88-17339 HS91-20782 HS91-27242 HS92-20673 IIS92-12630
Diploid Diploid Diploid Diploid, tetraploid, peak 38% Diploid Diploid Diploid Diploid Diploid, tetraploid peak 12.6% Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid
REFERENCES
fAGC * Diploid, tetraploid peak 7% Diploid Diploid Diploid Diploid t Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid Diploid * Diploid Diploid
*Insufficient material for cytometry. tIsolated cells escaped detection by cytometry.
management impose the need for more detailed gross and histological examination of gastrectomy specimens according to the protocol discussed in this article. In conclusion, our study (1) defines a variant of early gastric carcinoma characterized by a superficial growth pattern with focal invasion of the muscularis propria, regardless of extent or pattern of infiltrative growth and displaying better prognosis than AGC; and (2) confirms the importance ofDNA ploidy assessment in gastric carcinoma as an independent predictor of prognosis.
Acknowledgments. T h e authors thank P r o f ET. Bosman for critical review of the manuscript, S. Burki a n d J . Maillardet for photography, and G. Van Melle for statistical assistance.
819
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