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Annals of Surgical Oncology 9:13-19 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Occurrence and Prognostic Implications of Micrometastases in Lymph Nodes From Patients With Submucosal Gastric Carcinoma

Hong-Jo Choi, MD, Yun-Ki Kim, MD, Young-Hoon Kim, MD, Sang-Soon Kim, MD and Sook-Hee Hong, MD

From the Departments of Surgery (H-JC, Y-KK, Y-HK, S-SK) and Pathology (S-HH), Dong-A University College of Medicine, Pusan, South Korea.

Correspondence: Address correspondence and reprint request to: Hong-Jo Choi, MD, Department of Surgery, Dong-A University College of Medicine, 3-1 Dongdaeshin-Dong, Seo-Gu, Pusan 602-715, South Korea; Fax: 82-51-247-9316; E-mail: colonch{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The aims of this study were to assess the incidence of micrometastases of lymph nodes in patients with early gastric cancer invading the submucosal layer and to investigate the correlation between nodal micrometastases and malignancy potential to determine whether micrometastases of lymph nodes have prognostic significance, by use of an anticytokeratin immunohistochemical technique.

Methods: A total of 2272 lymph nodes taken from 88 patients (25.8 per case) were assessed by immunohistochemical technique by use of monoclonal anti-human cytokeratin 8 antibodies. Clinicopathologic parameters and prognosis were compared between patients with and without micrometastases.

Results: The incidence of nodal involvement by tumor cells in 88 patients with submucosal gastric cancer increased from 19.3% (17 patients) by hematoxylin-eosin (H&E) staining to 31.8% (28 patients) by cytokeratin immunostaining. The rate of positive node in this study increased from 1.0% (23 of 2272 nodes) by H&E staining to 2.5% (57 of 2272 nodes) by immunostaining (P = .0002). No correlation was observed between the incidence of lymph node micrometastases and various clinicopathologic parameters, including tumor site and size, histological differentiation, Lauren classification, gross tumor type, vascular and lymphatic invasion, and perineural invasion. There was no difference in disease-free survival, estimated by the Kaplan-Meier life-table method, between the micrometastasis-negative and -positive groups (95% and 92.9%, respectively). Multivariate analyses showed that tumor size and diffuse subtype by the Lauren classification were significant factors for survival time (P = .0042 and .014, respectively).

Conclusions: Immunohistochemical staining with an anticytokeratin antibody seems to be of little prognostic value in patients with submucosal gastric carcinoma. Thus, this immunostaining technique does not offer a significant benefit of different strategies for additional therapy or follow-up over conventional pathologic staging with H&E staining.

Key Words: Submucosal gastric carcinoma • Lymph node micrometastases • Cytokeratin immunohistochemistry • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
When the submucosal layer is invaded by tumor cells in early gastric carcinoma, the incidence of lymph node metastasis increases,1,2 and identification of lymph node metastasis is one of the most important factors for predicting the likelihood of long-term survival.3–5 Hematoxylin-eosin (H&E) staining has been in wide use for pathologic diagnosis in a respective section of lymph nodes; however, this conventional histopathologic examination may underestimate lymph node micrometastases represented by single cells or small clusters of tumor cells. Cytokeratin proteins serve as reliable markers for the epithelial origin of cells because they are essential constituents of the cytoskeleton of both normal and malignant epithelial cells in lymph nodes.6,7 Immunohistochemical methods with anticytokeratin antibodies have recently been shown to be capable of detecting occult tumor cells within lymph nodes considered free of metastases by routine H&E staining in patients with breast cancer8,9 and colorectal cancer.10–14 If this phenomenon is associated with tumor aggressiveness in gastric carcinoma, it may imply upstaging and may enable some groups of patients to be offered a more rational approach to planning adjuvant therapy.

The aims of this study were to evaluate the incidence of lymph node micrometastases and to confirm whether increased detection of occult tumor cells in lymph nodes correlates with clinical behavior in a group of patients with early gastric carcinoma invading the submucosal layer, thus determining whether immunohistochemical evaluation of lymph node micrometastases could help in distinguishing between patients with high and low malignancy potential.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Pathologic Review
The study population was composed of 88 patients (56 men and 32 women) with submucosal gastric carcinoma who underwent gastrectomy with D2 lymph node dissection under the care of the Department of Surgery, Dong-A University Hospital, from 1991 to 1995. No patient received postoperative adjuvant chemotherapy. In this study, patients with another primary cancer, those who died in the postoperative period (within 30 days after surgery) or who died of a cause other than gastric carcinoma, and those who were lost to follow-up have been excluded. The mean age was 59 years (range, 37–79) at the time of diagnosis. Radical total gastrectomy was performed in 10 patients (11.4%) and radical subtotal gastrectomy in 78 patients (88.6%). The median follow-up was 87 months (range, 60–114) for surviving patients.

Original pathologic reports and histological sections from all 88 surgical specimens were reviewed by an experienced pathologist (S.-H.H.). The tumors and their regional lymph nodes, fixed in formalin and embedded in paraffin, were examined conventionally with H&E staining, and then further sections of the same tissue blocks were examined by immunohistochemical techniques. As many perigastric lymph nodes as possible were collected by means of careful manual palpation.

Immunohistochemistry and Analysis
A single 4-µm section of each lymph node was obtained for immunohistochemical staining of anticytokeratin antibody. Immunostaining was performed with the standard streptavidin-biotin method.15 In brief, sections were dewaxed in xylene, rehydrated in graded alcohol series, and incubated with 3% hydrogen peroxide for 10 minutes to block endogenous peroxidase activity. Subsequently, sections were washed in phosphate-buffered saline, and normal nonimmune serum was applied for 20 minutes to minimize nonspecific antibody binding. A primary monoclonal anti-human cytokeratin-8 (Dako, Carpinteria, CA) was reacted with tissue specimens at room temperature for 1 hour. Sections were subsequently washed with phosphate-buffered saline for 10 minutes, and the second biotinylated polyvalent antibody, Histostain-Plus (Zymed Lab Inc., South San Francisco, CA) was applied for 10 minutes, followed by the application of peroxidase-labeled streptavidin. The reaction products were visualized with aminoethyl carbazole as the chromogen, and sections were counterstained with Mayer’s hematoxylin. Positive controls consisted of lymph nodes from stage IIIB patients and a slide from each block stained by exclusion of the primary antibody for negative control.

First, the H&E stained slides were assessed by a pathologist (S.-H.H.) for the presence of metastasis in the lymph node at x100 magnification. Slides immunostained for cytokeratin were then re-examined, and the results were compared with those obtained from the H&E slides. Any tumor cells, single or in groups, detected by cytokeratin immunohistochemistry were considered to be positive micrometastases in the lymph node. The reviewing pathologist was unaware of corresponding clinical data and outcome.

Statistical Analysis
Data were entered into a spreadsheet program and subsequently imported into a statistical program (GraphPad PrismTM, Version 3.0; GraphPad Software Inc., San Diego, CA). To assess the association of micrometastases with clinical and pathologic variables, unpaired t-tests, two-sided Fisher’s exact tests, and {chi}2 test were performed. A P value of <.05 was considered statistically significant. Disease-free survival curves were calculated with the Kaplan-Meier method and analyzed by the log-rank test.16 To assess the relative prognostic value of patient characteristics associated with survival, multivariate analyses with the PHREG program in SASTM (SAS Institute, Cary, NC) were applied to fit a Cox proportional hazard regression model.17 After initial screening by univariate analysis, variables were entered into the model by use of a forward stepwise selection procedure.17


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The number of lymph nodes examined in each patient is shown in Fig. 1. A total of 2272 (median, 25; range, 12–47) lymph nodes were dissected from 88 patients who underwent surgical resection. The micrometastatic foci identified by the immunohistochemical staining typically had the morphological appearance of epithelial cells. They were composed of a single cell or cell clusters within the capsule of the lymph node either in the sinus or in the lymphatic vessels (Fig. 2). Routine examination by H&E staining confirmed metastasis in 21 lymph nodes from 15 patients. All of these nodes were also cytokeratin positive, and these were categorized to be micrometastasis positive. Micrometastases were also detected in additional 7 H&E staining-negative nodes from 6 of these 15 patients. Cytokeratin immunostaining was also positive in other 29 lymph nodes from 13 patients in whom no nodal metastasis was identified by the H&E staining. The rate of positive node varied considerably from 1 of 32 (3.1%) to 6 of 14 (42.9%). As a result, micrometastases were confirmed in 57 nodes from 28 patients (31.8%). As shown in Fig. 3, the number of patients with lymph node involvement increased from 15 (17%) by H&E staining to 28 (31.8%) by cytokeratin immunostaining (P = .053), and as shown in Fig. 4, the incidence of lymph node involvement in relation to the total number of lymph nodes collected increased from .9% (21 of 2272 lymph nodes) by H&E staining to 2.5% (57 of 2272 lymph nodes) by cytokeratin immunostaining (P < .0001).



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  		FIG. 1. Number of lymph nodes investigated in each patient. A total of 2272 lymph nodes were examined after immunostaining, ranging from 12 to 47 nodes from each patient (median, 25).

 


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  		FIG. 2. Immunohistochemical staining for cytokeratin in perigastric lymph nodes. Dark-staining cytokeratin-positive micrometastatic foci appeared as single cells (A) or clusters of tumor cells (B) within the capsule of the lymph node (original magnification, x200).

 


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  		FIG. 3. Number of patients for positive tumor cells in lymph nodes in each staining. HE, hematoxylin-eosin; CK, cytokeratin.

 


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  		FIG. 4. Number of lymph nodes for positive tumor cells in each staining. The incidence of lymph node involvement in relation to the total number of dissected nodes was significantly higher in cytokeratin immunostaining than that in hematoxylin-eosin staining (P < .0001). HE, hematoxylin-eosin; CK, cytokeratin.

 
Clinical and pathologic factors were compared between 28 patients with lymph node micrometastases and 60 patients without micrometastases (Table 1). The mean age was 59 years in both groups of patients. The presence of micrometastases was not related to sex (P = .64) or tumor size (P = .06). The histological differentiation of the primary tumor did not differ significantly between patients with and those without micrometastases (P = .07) or the Lauren classification (P = .37). No other pathologic parameter of the primary tumor, including gross type, blood vessel and lymphatic vessel invasion, and perineural invasion, showed any significant differences between groups.


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  		TABLE 1. Correlation between clinicopathologic variables and micrometastases
 
The 5-year disease-free survival rate for the 88 patients with submucosal gastric carcinoma was 94.3%, and 5 patients showed postoperative recurrences (all with lymph node metastasis and peritoneal seeding). One of these five patients had already been diagnosed with lymph node metastasis by H&E staining after the operation. Another patient was found to have micrometastases in lymph nodes by cytokeratin immunostaining. There were 2 (7.1%) of 28 cancer-related recurrences in patients with and 3 (5%) of 60 recurrences in patients without nodal micrometastases (Fig. 5). According to the log-rank test, this difference in survival was not statistically significant (P = .6836). Ten variables were entered into a multivariate analysis for disease-free survival by using the Cox proportional hazard model. As shown in Table 2, the forward stepwise regressions revealed a prognostic significance in tumor size (P = .0042) and a diffuse subtype by the Lauren classification (P = .014).



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  		FIG. 5. Disease-free survival in 88 patients with submucosal gastric carcinoma. No survival difference (P = .6836) was observed between groups with micrometastases (dotted line) and without (solid line). CK, cytokeratin.

 

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  		TABLE 2. Summary statistics for the stepwise Cox proportional hazard model
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The presence of nodal metastases is a sign of local tumor extension and tumor cell dissemination associated with worse prognosis in patients with gastric carcinoma.18–21 In addition, the presence of nodal metastases is of particular significance in early gastric carcinoma, and the overall survival rate has been reported to be decreased significantly in patients in whom lymph node metastasis is present, compared with those without nodal involvement.1,18,22

The term "micrometastasis" was originally defined as a metastatic lesion of breast carcinoma measuring <2 mm.23 As the word connotes, micrometastasis retained a morphological implication and referred to a small focus of metastatic tumor often not identified because of the way in which lymph nodes were sampled.24 Routine histopathologic findings by H&E staining are inefficient at recognizing the micrometastases in the lymph nodes, as determined by immunohistochemical or molecular techniques. A reverse transcriptase–polymerase chain reaction technique has been suggested to be supersensitive in detecting micrometastasis in lymph nodes.25 Hayashi et al.26 used a mutant allele–specific amplification technique, which can detect, at the level of an individual cell, micrometastases to lymph nodes that have been diagnosed histologically as metastasis negative. However, false-positive results are allegedly common, and positive results yielded by the polymerase chain reaction may simply indicate the presence of tumor DNA; they do not necessarily mean that cancer cells are present.27 As well as being simple and rapid, immunohistochemical staining with anticytokeratin antibody is, in this sense, more sensitive and specific than molecular methods.

As well as micrometastases from breast carcinoma,8,9 colorectal carcinoma,10–14 and malignant melanoma,28 those from gastric carcinoma have previously been detected immunohistochemically on formalin-fixed, paraffin-embedded tissue sections by using antibodies to cytokeratin.29,30 Investigations with anticytokeratin antibodies revealed an incidence of micrometastases of 3.3% of lymph nodes collected and of 34% of cases in submucosal gastric cancer and 3.6% and 23.5% of nodes and cases in early gastric cancer who died of recurrence, respectively.29,30 In this immunohistochemical study, as many as 2.5% (57 of 2272) of lymph nodes and 31.8% of patients with submucosal gastric carcinoma showed micrometastases in the regional nodes, thus confirming that this is a common phenomenon in gastric carcinoma.

Only a few studies have been performed to evaluate the prognostic significance of lymph node micrometastases in submucosal gastric carcinoma. Cai et al.29 found that the presence of cytokeratin-positive cells in lymph nodes from submucosal gastric carcinoma patients correlated with a significantly worse prognosis and that cytokeratin immunohistochemistry may make it possible to identify patients with a higher risk of recurrence after removal of a submucosal gastric carcinoma. They also showed that a high incidence of nodal micrometastases was found in submucosal cancer of a larger sized (>2 cm), macroscopically depressed type and in positive lymphatic invasion.29 Maehara et al.30 reported that the survival time of the cytokeratin-positive group was significantly shorter than that of the cytokeratin-negative group in patients with early gastric cancer who died of recurrence, although the presence of cytokeratin positivity was not related to various clinicopathologic factors. In this study, however, patients with lymph node micrometastases found in their resected specimen did not show a worse prognosis than patients in whom such findings were not identified. Moreover, no relationship was seen with age, sex, gross tumor type, or blood vessel invasion, although a weak association was found between micrometastases and tumor size (P = .06), histological differentiation (P = .07), and lymphatic vessel invasion (P = .07). It is speculated that these micrometastases may represent tumor cells that have gained access to the lymphatics and that they may be viewed as an early event in the progression to a frank metastatic disease. However, they are destined to be destroyed by host immune mechanisms before implantation and growth can occur, as suggested by Jeffers et al.11 in colorectal carcinoma. The lack of a correlation between nodal micrometastases and recognized prognostic indicators or survival might also suggest that they may not represent true metastases. Rather, the critical factor may be responsible for these micrometastatic tumor cells’ implanting and growing in the new environment,31 an event that may require a larger number of tumor cells.

To determine factors affecting the survival of patients with submucosal gastric carcinoma, 10 variables (age, sex, tumor size, lymph node micrometastases, histological differentiation, Lauren classification, gross tumor type, blood vessel invasion, lymphatic vessel invasion, and perineural invasion) were analyzed with the Cox proportional hazard regression model. Only the increasing size of the tumor and the diffuse type of the Lauren classification proved to be independent factors for predicting postoperative survival, with risk ratios of 1.496 and 15.690, respectively.

In conclusion, our retrospective data show that the immunohistochemical technique with the anticytokeratin antibody aids in identifying micrometastases in lymph nodes missed in routine H&E staining in submucosal gastric carcinoma. However, it does not reflect a strong indicator of overt metastatic disease or poor prognosis. Thus, it is concluded that immunohistochemical detection of lymph node micrometastases does not offer a significant benefit over conventional pathologic staging with H&E staining in stratifying patients for planning appropriate adjuvant therapy and for prognostic grouping in diverse clinical settings. More definite clinical significance of lymph node micrometastases awaits further extensive prospective studies.


   Footnotes
 
Presented at the Fourth International Gastric Cancer Congress, New York, New York, April 29–May 2, 2001.

Received for publication May 17, 2001. Accepted for publication September 10, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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