Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence

doi:10.1016/S0039-6060(96)80138-3

Surgery

Volume 119, Issue 4, April 1996, Pages 397-402

https://doi.org/10.1016/S0039-6060(96)80138-3 Get rights and content

Background. Even after curative resection of an early gastric cancer, some patients die of a recurrence. It is our view that patients with early gastric cancer who died of their disease had occult micrometastases in perigastric lymph nodes at the time of the original diagnosis. In an attempt to identify these micrometastases, lymph nodes dissected from early gastric cancer lesions were stained after operation with a monoclonal antibody against cytokeratin, an essential constituent of the cytokeleton of epithelial cells.

Methods. The 420 dissected lymph nodes from 34 patients with node-negative early gastric cancer who died of a recurrence were examined for the presence of tumor cells. We used immunocytochemical techniques and an antiserum to epithelial membrane antigen. The monoclonal antibody CAM 5.2 recognizes cytokeratin polypeptides (human cytokeratin numbers 8 and 18) commonly present in epithelial cells. Clinicopathologic characteristics and prognosis were determined for patients with cytokeratin-positive cells in the lymph nodes.

Results. Of 420 lymph nodes, 15 (3.6%) nodes and 23.5% (8 of 34) of the patients presented with cytokeratin-positive cells at the time of primary operation. The presence of cytokeratin positivity was not related to various clinicopathologic factors. The histologic stage of eight cytokeratin-positive cases was upstaged by the group of cytokeratin-positive lymph nodes from stage I to three of stage II, four of stage III, and one of stage IV, hematogenous recurrences were common, and the prognosis was poorer.

Conclusions. Immunohistochemical techniques aid in identifying micrometastatic disease in lymph nodes missed in routine hematoxylin-eosin staining. Cytokeratin staining of the dissected lymph nodes is recommended to precisely determine tumor stage and prognosis for patients with early gastric cancer.

References (24)

MollR et al.
The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells
Cell
(1982)
LindemannF et al.
Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients
Lancet
(1992)
MaeharaY et al.
Cytokeratin staining reveals micrometastasis in lymph nodes of early gastric cancer
Surgery
(1995)
MaeharaY et al.
Predictors of lymph node metastasis in early gastric cancer
Br J Surg
(1992)
OkamuraT et al.
Lymphadenectomy for cure in patients with early gastric cancer and lymph node metastasis
Am J Surg
(1988)
BabaH et al.
Effect of lymph node dissection on the prognosis in patients with node-negative early gastric cancer
Surgery
(1995)
MaeharaY et al.
Prophylactic lymph node dissection in patients with advanced gastric cancer promotes increased survival time
Cancer
(1992)
MaeharaY et al.
Early carcinoma of the stomach
Surg Gynecol Obstet
(1993)
MaeharaY et al.
Gastric cancer in patients over 70 years of age
Br J Surg
(1995)
KorenagaD et al.
DNA ploidy is closely linked to tumor invasion, lymph node metastasis, and prognosis in clinical gastric cancer
Cancer
(1988)

OiwaH et al.

Growth pattern and p53 overexpression in patients with early gastric cancer

Cancer

(1995)

CutaitR et al.

Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins

Dis Colon Rectum

(1991)

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Gastric cancer (GC) is a tumour entity with highly variant outcomes. Lymph node metastasis is a prognostically adverse biomarker. We hypothesised that GC primary tissue contains information that is predictive of lymph node status and patient prognosis and that this information can be extracted using deep learning (DL).
Using three patient cohorts comprising 1146 patients, we trained and validated a DL system to predict lymph node status directly from haematoxylin and eosin–stained GC tissue sections. We investigated the concordance between the DL-based prediction from the primary tumour slides (aiN score) and the histopathological lymph node status (pN). Furthermore, we assessed the prognostic value of the aiN score alone and when combined with the pN status.
The aiN score predicted the pN status reaching area under the receiver operating characteristic curves of 0.71 in the training cohort and 0.69 and 0.65 in the two test cohorts. In a multivariate Cox analysis, the aiN score was an independent predictor of patient survival with hazard ratios of 1.5 in the training cohort and of 1.3 and 2.2 in the two test cohorts. A combination of the aiN score and the pN status prognostically stratified patients by survival with p-values <0.05 in logrank tests.
GC primary tumour tissue contains additional prognostic information that is accessible using the aiN score. In combination with the pN status, this can be used for personalised management of GC patients after prospective validation.
Lymph node micrometastasis of poorly differentiated node-negative gastric cancer risks a worse-than-expected survival outcome under standard management algorithm
2022, European Journal of Surgical Oncology
Investigation of lymph node micrometastasis (mN) of gastric cancer has been focused on either T1 disease or T1-4N0 disease. Yet, it is unclear whether standard management algorithm toward poorly differentiated gastric cancer (PDGC) is more vulnerable to existence of mN, given its inherently biological aggressiveness, as compared with other histological types.
A surgical series (n = 3456) of gastric cancer categorized by histological differentiation was enrolled to analyze survival stratification. Of them, a cohort of T1-T4 N0 PDGC (n = 100) were subjected to cytokeratin immunohistochemistry, a surrogate of mN.
Cancer-specific survival by AJCC8 staging system could be nicely differentiated in both well-/moderately differentiated and signet ring cell types, while those between stage IA versus IB (p = 0.105), and stage IB versus IIA (p = 0.141) in PDGC could not. Thirteen (13%) out of 100 node-negative PDGC cases exhibited mN, with 5, 2, 5 and 1 cases occurring in T1, T2, T3, and T4 stage, respectively, without identifiable contributing factors. Prognostic performance of AJCC8 working upon PDGC became more discriminative by incorporating mN, as hazard ratio of stage IIIC referenced to stage IA increased from 43 to 78.
Defective discriminative survival of PDGC by standard staging algorithm prompted us to survey mN occurring in T1-T4N0 PDGC. The prognostic performance of AJCC8 working upon PDGC was enhanced by incorporating mN. As so, we recommend documentation of mN exclusively on node-negative PDGC that helps unveil stage migration phenomenon and switch to appropriate adjuvant therapy in need.
Detection and prognostic significance of isolated tumor cells and micrometastases in pelvic lymph nodes of patients with early ovarian clear cell carcinoma
2021, Journal of the Formosan Medical Association
Ovarian clear cell carcinoma (OCCC) accounts for approximately 18% of all epithelial ovarian malignancies in Taiwan and portends a poor prognosis. Here, we sought to investigate whether immunohistochemistry with an anti-pan-cytokeratin antibody cocktail (AE1/AE3) can be used as an adjunct to hematoxylin and eosin (H&E) staining for improving the detection of isolated tumor cells (ITCs) and micrometastasis to pelvic lymph nodes (LNs). We also assessed whether these lesions may predict disease recurrence.
Pelvic lymphadenectomy specimens were obtained from 197 patients with stage 1 OCCC who had undergone surgery between 2000 and 2018 from Linkou and Kaohsiung Chang Gung Memorial Hospital. Immunohistochemical staining with AE1/AE3 was applied to a total of 1186 slides. Clusters of metastatic tumor cells, detected immunohistochemically, were classified as ITCs (clusters with diameters of ≤0.2 mm) or micrometastases (tumor cell clusters of >0.2 but ≤2.0 mm). We also assessed the diameter of metastases in patients with positive lymph nodes (stage IIIA1, n = 3, 7 positive nodes).
Clusters with a positive AE1/AE3 staining were identified in five (2.53%) of the 197 patients (ITCs, n = 3; micrometastasis, n = 2). Four patients had no evidence of disease recurrence but a patient recurred at follow-up. Metastatic foci of patients with stage IIIA1 disease were all >2.0 mm in size.
Immunohistochemical staining with AE1/AE3 can identify micrometastasis or ITCs in LNs missed on routine H&E staining. The role of micrometastasis in predicting recurrent OCCC and implementing on treatment strategies requires further investigation.
A better prognostic stratification for the 8th edition of the AJCC staging system of gastric cancer by incorporating pT4aN0M0 into stage IIIA
2019, Surgical Oncology
Citation Excerpt :
The 3-year recurrence-free survival rate of the patients considered to be positive for cancer cells exposed to the serosa of the primary gastric tumor by their method (41.7%) was significantly (log rank P = 0.0002) worse than that of the patients with negative results (81.0%). Several investigators reported that a conventional pN0 diagnosis after radical surgery for gastric cancer was not a guarantee against recurrence because of lymph node micrometastasis [25–27]. A study from Korea indicated that lymph node micrometastasis is clinically significant as a risk factor for recurrent gastric cancer, where 62.2% of the cases had lymph node micrometastasis in 164 cases diagnosed with pT4aN0M0 by immunohistochemical staining with an anti-cytokeratin antibody.
The aim of this study was to analyze the prognosis of gastric cancer patients categorized as pT4aN0M0, pT1N3aM0/pT2N2M0/pT3N1M0 of stage IIB and stage IIIA and to compare the optimistic prognostic stratification between the AJCC 8th edition staging system and the AJCC modified 8th (m8th) edition staging system by incorporating pT4aN0M0 into stage IIIA.
A total of 1770 patients who underwent gastrectomy were enrolled in this study. The homogeneity, the discriminatory ability, the monotonicity of the gradient assessments, and the discriminatory ability of the AJCC 8th and m8th edition staging systems were compared by using the likelihood ratio χ2 test, a linear trend χ2 test, the Akaike information criteria (AIC) and Bayesian information criterion (BIC) calculations, respectively.
For patients staged IIB, the 5-year survival rate of the patients categorized as pT4aN0M0 were significantly worse than that of the patients categorized as pT1N3aM0/pT2N2M0/pT3N1M0 (59.9% vs. 72.4%, P = 0.036). By contrast, the prognoses of the patients between the pT4aN0M0 category and those staged IIIA were analogous (59.9% vs. 61.5%, P = 0.693). Compared with the 8th edition system, the modified 8th edition staging system had a better homogeneity (higher likelihood ratio χ [2] score, 441.17 vs. 436.24), discriminatory ability, monotonicity of gradients (higher linear trend χ2 score, 436.78 vs. 416.15) and smaller AIC (10364.98 vs. 10369.91) and BIC values (10447.13 vs. 10452.06).
The prognosis of pT4aN0M0 was poorer than those of pT1N3aM0, pT2N2M0, and pT3N1M0, which were staged IIB. There is a better prognostic stratification for the AJCC 8th edition staging system of gastric cancer by incorporating pT4aN0M0 into stage IIIA.
Practical intraoperative pathologic evaluation of sentinel lymph nodes during sentinel node navigation surgery in gastric cancer patients - Proposal of the pathologic protocol for the upcoming SENORITA trial
2016, Surgical Oncology
Citation Excerpt :
Most studies regarding the clinical significance of occult metastasis in gastric cancer patients are retrospective studies of cases of conventional gastrectomy and lymph node dissection, and the oncologic outcome is controversial [32]. Since the potential candidates for SNNS in the forthcoming phase III clinical trial would be patients with cT1N0 gastric cancer, studies that exclusively included patients with EGC were reviewed here to investigate the prognostic significance of occult metastasis in patients diagnosed with EGC without histologic lymph node metastasis by conventional HE staining (Table 2) [33–38]. The incidence of occult metastasis in these studies ranged 10.0–24.6% by additional IHC, which indicates that even in patients with EGC, the occult metastasis rate reached 10% or more.
Over the last decade, as the number of patients with early gastric cancer increased and the subsequent survival rate improved, there has been a consistent effort to verify the applicability of the sentinel node concept in gastric cancer in a bid to improve postoperative quality of life in these patients. During sentinel node navigation surgery in gastric cancer patients, intraoperative pathologic examination of the retrieved sentinel nodes plays a critical role in determining the extent of surgery, but the optimal method is still under debate. Currently, a multicenter, phase III clinical trial is underway to compare laparoscopic sentinel basin dissection with stomach preserving surgery and standard laparoscopic gastrectomy in terms of oncologic outcomes in patients with clinical stage T1N0 gastric cancer. Herein, the currently available intraoperative pathologic techniques are reviewed and their clinical significance and applicability are appraised based on the published literature. The proper pathologic examination of the sentinel lymph nodes in an upcoming clinical trial (SENORITA trial) is also proposed here based on this review.
TUMOR MARKERS EXPRESSION LEVELS IN GASTRIC CANCER PATIENT’S PERIPHERAL BLOOD BY RT-PCR ASSESSMENT
2023, Arquivos Brasileiros de Cirurgia Digestiva

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¹: Supported by grant-in-aid for scientific research (C) (06671286) from the Ministry of Education, Science and Culture in Japan.

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Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence1

Cell

Lancet

Surgery

Br J Surg

Am J Surg

Surgery

Cancer

Early carcinoma of the stomach

Surg Gynecol Obstet

Gastric cancer in patients over 70 years of age

Br J Surg

DNA ploidy is closely linked to tumor invasion, lymph node metastasis, and prognosis in clinical gastric cancer

Cancer

Growth pattern and p53 overexpression in patients with early gastric cancer

Cancer

Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins

Dis Colon Rectum