The early detection of prostate carcinoma with prostate specific antigen: the Washington University experience

BACKGROUND: It is not yet known whether screening for the detection of early prostate carcinoma will reduce mortality rates. However, data are available to assess intermediate outcomes from screening, including the performance characteristics of the screening tests and shifts in disease stage. METHODS: Approximately 30,000 community volunteers (mean age 60 years; <5% nonwhite) were enrolled in 1 of 3 screening studies. Volunteers were screened with PSA or PSA in combination with digital rectal examination at 6-month intervals, and prostatic biopsy was recommended for those with results suspicious for cancer. Based on a first-time screen, the current study reports screening test results, the proportion of men recommended to undergo biopsy, the proportion who actually underwent biopsy, and the carcinoma detection rates for each study, stratified by initial PSA level. The authors also report the pathologic features of screen-detected carcinomas for a subset of men who underwent radical prostatectomy and for whom complete embedding and microscopic examination of the surgical specimen was performed. RESULTS: Approximately 10% of the volunteers had PSA levels >4.0 ng/mL and 3-10% had digital rectal examination results suspicious for cancer. Overall, 9-20% of volunteers were recommended to undergo biopsy and 8-13% actually underwent the procedure. The positive predictive value for carcinoma detection ranged from 25-33% across studies. In the subset of men for whom surgical specimens were completely embedded, the majority of tumors detected had the clinicopathologic features of significant carcinoma (<10% possibly harmless). CONCLUSIONS: The intermediate outcomes for screening with PSA and/or PSA in combination with digital rectal examination are encouraging. In community volunteers these screening tests demonstrated reasonable positive predictive value and detected carcinomas at an earlier stage. The majority of screen-detected tumors had the pathologic characteristics of medically significant carcinoma.     

Comparison of percent free prostate specific antigen and prostate specific antigen density as methods to enhance prostate specific antigen specificity in early prostate cancer detection in men with normal rectal examination and prostate specific antigen between 4.1 and 10 ng./ml

PURPOSE: We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. MATERIALS AND METHODS: PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. RESULTS: In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. CONCLUSIONS: Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.     

PSATZ (prostate specific antigen adjusted for the transition zone volume)

This brief review discusses the diagnostic ability of prostate specific antigen adjusted for the transition zone volume (PSATZ) for the detection of prostate cancer in patients with intermediate prostate specific antigen (PSA) levels. PSATZ was defined as the quotient of the PSA value and the calculated transition zone volume. In comparison with standard parameters including PSA and prostate specific antigen density, PSATZ could be a useful indicator for the detection of prostate cancer in patients with PSA values between 4.1 and 10.0 ng/ml, especially in those with normal digital rectal examinations. Similar observations consistent with our results have been also reported by other investigators. PSATZ has some disadvantages including volumetry and expensive cost. Further study is necessary to discuss whether PSATZ is superior to other new modalities such as free-to-total PSA ratio with regard to diagnostic cost and efficacy.     

Age specific prostate specific antigen reference ranges: population specific

BACKGROUND: Anastomosis of the left internal thoracic artery to the left anterior descending artery without sternotomy and without cardiopulmonary bypass is a standard approach in minimally invasive coronary artery bypass grafting. To expand the indications for minimally invasive coronary artery bypass grafting from one-vessel disease to two-vessel disease, we began to perform anastomosis of the right gastroepiploic artery (RGEA) to the right coronary artery (RCA). METHODS: From February to November 1996, an RGEA graft was used in 25 of the 100 patients who underwent minimally invasive coronary artery bypass grafting at our clinic. Eleven of the patients had only RCA disease and 14 had both RCA and left anterior descending artery disease. One of the operations was a redo coronary artery bypass grafting. The RGEA was anastomosed to the RCA through a laparotomy incision and the left internal thoracic artery was anastomosed to the left anterior descending artery through a left anterior thoracotomy. In 5 patients, the RGEA was lengthened by venous grafting. RESULTS: All patients underwent angiography after operation; 82.6% of the RGEA grafts and all the left internal thoracic artery grafts were functioning well. In three of the four nonvisualized RGEA grafts, the percentage of proximal stenosis of the RCA seen on postoperative angiography was not critical (40%, 50%, and 50%, respectively), allowing significant competitive flow through the native bypassed RCA. The patency of all the RGEA grafts without competitive flow was 95%, with a 95% confidence interval of 75.1% to 99.9%. CONCLUSIONS: The indications for minimally invasive coronary artery bypass grafting could be extended to primary operations in patients with left anterior descending artery and RCA lesions by using both the left internal thoracic artery and the RGEA.     

Free-to-total prostate specific antigen ratio as a single test for detection of significant stage T1c prostate cancer

PURPOSE: We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels. MATERIALS AND METHODS: The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77% underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens. RESULTS: Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-toal PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84% of stage T1c cancers were significant and comparable to stage T2 or greater cancers. CONCLUSIONS: Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.     

Do prostate specific antigen and prostate specific antigen density enhance the detection of prostate carcinoma after initial diagnosis of prostatic intraepithelial neoplasia without concurrent carcinoma?

BACKGROUND: Prostatic intraepithelial neoplasia (PIN) is considered to be a precursor of prostate carcinoma in which serum levels of prostate specific antigen (PSA) have been correlated with PIN grades. The aim of this study was to determine whether PSA and prostate specific antigen density (PSAD), obtained at the time of initial diagnosis of PIN without concurrent carcinoma, can be used as predictive factors to discriminate patients with subsequent cancer on repeat biopsy. METHODS: We studied, retrospectively, the records of 93 patients with PIN (low and high grade) without concurrent carcinoma at the time of their first needle biopsy. We assessed the relationship between initial PIN grade, PSA, and PSAD with later detection of carcinoma on repeat biopsy. Patients were divided into 3 subgroups for analysis according to their initial PSA level (0-4, 4.1-10, >10 ng/mL). RESULTS: Carcinoma detection rate on repeat biopsy was 13.3% for patients with low grade PIN and 47.7% for patients with high grade PIN (P < 0.006). High grade PIN was frequently associated with subsequent carcinoma whatever the PSA level (33.3-61.9%). Low grade PIN was associated with subsequent carcinoma in 42.8% of the cases when PSA was greater than 10 ng/mL. When PSA was between 4 and 10 ng/mL, low grade PIN carcinoma was found on repeat biopsies in only 10.7% of the cases (P = 0.05). In none of the PSA subgroups did PSAD enhance later cancer detection. CONCLUSIONS: For patients with high grade PIN, the incidence of subsequent carcinoma is high, whatever the PSA values. For these cases repeat biopsies should be recommended. Patients with low grade PIN and PSA greater than 10 ng/mL should have repeat biopsies because the incidence of subsequent carcinoma is high and comparable to high grade PIN. PSAD did not provide additional information.     

The lack of predictive value of prostate specific antigen density in the detection of prostate cancer in patients with normal rectal examinations and intermediate prostate specific antigen levels

PURPOSE: The management of patients with a normal digital rectal examination and a prostate specific antigen (PSA) level of 4.0 to 10.0 ng./ml. remains controversial. To improve the specificity of cancer detection in this group, PSA density has been recommended with biopsies based on a PSA density of 0.15 or more. To evaluate PSA density as a discriminator of prostate cancer we enrolled patients in a prospective study. MATERIALS AND METHODS: A prospective evaluation was done of 44 consecutive patients with a palpably normal digital rectal examination and a serum PSA level of 4.0 to 10.0 ng./ml. enrolled during a 13-month period. All patients underwent transrectal ultrasound with sextant biopsies regardless of calculated PSA density. RESULTS: Overall, 8 of 44 men (18%) had prostate cancer. There was no significant difference in the mean PSA density between the patients with positive and negative biopsies (mean 0.12 and 0.15, respectively, p = 0.258). Also, there was no significant association between PSA or PSA density and a positive biopsy in multivariate analysis (p = 0.863). Receiver operating characteristic curves for PSA and PSA density failed to demonstrate any superior benefit for PSA density in this patient population. A PSA density of 0.15 was an unreliable indicator of cancer (sensitivity 12.5%, specificity 61.1% and positive predictive value 6.7%). CONCLUSIONS: In our study, PSA density did not discriminate between patients with positive and negative biopsies, and in fact most cancers would not have been detected if a PSA density of 0.15 or more had been used as the sole indication for biopsy. Therefore, we recommend systematic biopsies in these patients independent of calculated PSA density.     

Effects of gonadotropin and testosterone treatments on prostate volume and serum prostate specific antigen levels in male hypogonadism

Various monosialo- and disialo-gangliosides and their derivatives were examined by delayed ion extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF MS) in the reflector mode with alpha-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid used as the matrix. Native gangliosides were generally found to give good spectra in the negative ion mode. 2,5-Dihydroxybenzoic acid was a better matrix for gangliosides than alpha-cyano-4-hydroxycinnamic acid, because this matrix seemed to minimize loss of sialic acid and carbon dioxide of gangliosides. About 1 pmol of ganglioside was able to be detected with this matrix. When "A-series" gangliosides such as GD1a and GalNAc-GD1a gave undesirable extra peaks probably due to loss of sialic acid besides molecule-related ion peaks, the methyl-esterification of the gangliosides at the carboxyl groups of sialic acids was found to be necessary to obtain good DE MALDI-TOF mass spectra in the positive ion mode. In contrast, "B-series" gangliosides such as GD1b, GD2, and GD3 gave rise to major dehydrated molecule-related ion [M-H2O-H]- peaks in the negative ion mode without the pretreatment of methyl-esterification. The DE MALDI-TOF mass spectrometric analysis enabled us to distinguish between GD1a and GD1b, which have the same molecular weight. It was also found that not only a purified sample, but also a mixed sample of various gangliosides was amenable to the identification of them by DE MALDI-TOF MS.     

The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer

PURPOSE: We determine the influence of age, prostate volume, total serum prostate specific antigen (PSA) level and histological evidence of acute inflammation in biopsy specimens on the percent free serum PSA level in men without clinically detectable prostate cancer. MATERIALS AND METHODS: We studied 70 men with total PSA levels of 2.6 to 9.9 ng./ml. who had undergone at least 3 sets of prostate biopsies that were negative for cancer as part of our PSA based prostate cancer screening program. Total and free PSA levels were measured using Hybritech immunoassays. Prostate volume and the presence of acute inflammation were determined from the most recent transrectal ultrasonography and prostate needle biopsy. RESULTS: Percent free PSA levels correlated significantly with age (r = 0.48, p = 0.0001) and prostate volume (r = 0.44, p = 0.0002) but not with total PSA (r = 0.04, p = 0.7). The mean percent free PSA did not differ for those with or without acute inflammation. Multivariate regression models demonstrated that age and prostate volume were significant predictors of percent free PSA. CONCLUSIONS: Among men without detectable prostate cancer and a total PSA level between 2.6 and 9.9 ng./ml. percent free serum PSA was higher in older men and in men with a larger prostate gland but was not influenced by total PSA level or the presence of acute inflammation in the prostatic biopsy specimen.     

Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men

PURPOSE: We investigate and define the effects of exogenous testosterone on the normal prostate. MATERIALS AND METHODS: A total of 31 healthy volunteers 21 to 39 years old were randomized to receive either 100, 250 or 500 mg. testosterone via intramuscular injection once a week for 15 weeks. Baseline measurements of serum testosterone, free testosterone and prostate specific antigen (PSA) were taken at week 1. Semen samples were also collected for PSA content and prostate volumes were determined by transrectal ultrasound before testosterone injection. Blood was then drawn every other week before each testosterone injection for the 15 weeks, every other week thereafter until week 28 and again at week 40. After the first 15 weeks semen samples were again collected, and prostate volumes were determined by repeat transrectal ultrasound. RESULTS: Free and total serum testosterone levels increased significantly in the 250 and 500 mg. dose groups. No significant change occurred in the prostate volume or serum PSA levels at any dose of exogenous testosterone. Total semen PSA levels decreased following administration of testosterone but did not reach statistical significance. CONCLUSIONS: Despite significant elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.     

The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia

BACKGROUND: Determining the ratio of free to total prostate specific antigen (f-PSA to t-PSA, calculated as the percentage of f-PSA [f-PSA%]) in serum allow for a clearer distinction between patients with prostate carcinoma (PCa) and patients with benign prostate hyperplasia (BPH) than determining the level of t-PSA alone. To find influencing factors on f-PSA%, the authors investigated prostate volume, TNM classification, and tumor stage. METHODS: The authors measured f-PSA and t-PSA in 36 men with untreated PCa (tumor classification: T1, 2, 3pNO, MO), 44 patients with BPH, and 54 healthy controls. Prostate volume was determined by transrectal ultrasound. RESULTS: The median values of t-PSA and f-PSA% were 7.8 micrograms/L and 10.5% in PCa patients, 4.3 micrograms/L and 20.8% in patients with BPH, and 1.4 micrograms/L and 23.6% in the control group. Patients with PCa had a significantly lower proportion of f-PSA than BPH patients and healthy men. There was no correlation of f-PSA% to TNM stage or tumor grade. In PCa patients a significant positive correlation (correlation coefficient [r] = 0.51, P < 0.001) was found between f-PSA% and prostate volume, whereas there was no significant correlation in BPH patients (r = -0.27, P > 0.05). There was a significant difference in f-PSA% between PCa and BPH patients with prostate volumes smaller than 40 cm3 (9.0% vs. 21.6%, P < 0.01) but not between patients in these 2 groups with prostate volumes exceeding 40 cm3 (15.1% vs. 18.2%, P = 0.11). CONCLUSIONS: Determining the ratio of f-PSA to t-PSA to discriminate between PCa and BPH patients yields significant results only in men with a prostate volume of less than 40 cm3.     

A long follow-up on prostate specific antigen density and prostate biopsy

OBJECTIVE: To determine prostate specific antigen density (PSAD) in a risk population without evidence of prostatic cancer, and to assess the long-term usefulness of PSAD as a parameter for determining the need for a prostatic biopsy in patients with a normal digital rectal examination (DRE) and transrectal ultrasound (TRUS). METHODS: The records of 582 patients referred to the clinic between February, 1992 and February, 1994 were studied retrospectively. All these patients with lower urinary tract symptoms (LUTS) were evaluated based on the following parameters: digital rectal examination, serum PSA levels, prostate volume measured using transrectal ultrasound and PSAD. Prostatic biopsy was performed on 431 patients who had a serum PSA level greater than 4.0 ng/mL. A total of 299 patients (69.3%) had PSA levels between 4.0 and 10.0 ng/mL and represented the target population. The study had two parts, in the first one cancer was diagnosed just by one biopsy and in part II, the patients with negative biopsy in part I were followed for a two-year period and required 2 or 3 biopsies for diagnosis. Of the total of patients who had a negative prostate biopsy in part I of the study, 269 were followed for a period of two years with repeated prostate biopsies. RESULTS: Overall prostate cancer was detected in 22/299 (13.9%) patients, 6/105 (5.7%) with PSAD up to 0.15 and 16/194 (8.2%) with PSAD over 0.15 (p = 0.569). CONCLUSION: PSAD is a useful indicator in decreasing the number of negative biopsies in patients with benign prostatic hyperplasia. However, in a long-term follow-up the PSAD (cutoff level 0.15) was unable to predict which patients had a positive biopsy. According to our results, 5.6% of patients with prostate cancer will be missed using the PSAD criteria.     

Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation

Immunization of mice with gp96/grp94 heat shock proteins (HSPs) elicits tumor-specific cellular immunity to the tumors from which gp96 is isolated. However, the cDNA sequence of gp96 is identical among tumors and normal tissues. This raises the question regarding the structural basis of the specific immunogenicity of gp96. As HSPs bind a wide array of molecules including peptides, we have proposed that gp96 may not be immunogenic per se, but may chaperone antigenic peptides. Furthermore, gp96 is localized predominantly in the lumen of the endoplasmic reticulum (ER) suggesting that it may act as a peptide acceptor and as accessory to peptide loading of MHC class I molecules. We demonstrate here that gp96 molecules contain ATP-binding cassettes, bind ATP and possess an Mg(2+)-dependent ATPase activity. Gp96 preparations are also observed to contain tightly bound peptides, which can be eluted by acid extraction. These properties of gp96 are consistent with its proposed roles in chaperoning antigenic peptides and in facilitating MHC class I--peptide assembly in the ER lumen. We present a model to explain how interaction of gp96 with MHC class I may result in transfer of peptides to the latter.     

The importance of human glandular kallikrein and its correlation with different prostate specific antigen serum forms in the detection of prostate carcinoma

BACKGROUND: Human glandular kallikrein (hK2), the prostate specific antigen (PSA) close homologue, possesses approximately 80% structure identity with PSA. The identification of PSA was an important step in the detection of prostate carcinoma (PCa). Thus, hK2 measurement in the serum has the potential to become another important diagnostic test for PCa. In the current study, the authors measured the serum concentrations of the hK2 with "in-house" immunofluorometric assays in different patient groups. The correlation between serum hK2 and different PSA forms was investigated. METHODS: The prospectively collected serum samples were obtained preoperatively on admission from 311 consecutive male patients. Sixteen patients did not fulfill inclusion criteria; the remaining patients were divided into four groups (Groups I-III confirmed histologically): Group I: patients with PCa (n = 56); Group II: patients with benign prostatic hyperplasia (BPH) (n = 163); Group III: patients with BPH with a chronic in-dwelling catheter (BPH cat) (n = 44); and Group IV-control group (n = 32). The patients in Group IV had urolithiasis, varicocele, or kidney or bladder tumors). An experimental immunofluorometric assay with an analytic sensitivity of 0.01 ng/mL and a functional sensitivity of 0.05 ng/mL was used to determine serum hK2 concentrations. Total PSA, free PSA, and PSA complexed to alpha-1-antichymotrypsin (PSA-ACT) also were measured. hK2 concentrations equal to or above the functional sensitivity limit were correlated with each of these PSA serum forms. Free to total PSA, hK2 to total PSA, and hK2 to free PSA ratios were calculated and compared in different patient groups. RESULTS: The hK2 concentrations were equal to or above the functional sensitivity limit in 179 of 311 samples (57.6%). In these samples, hK2 correlated best with free PSA (correlation coefficient [r] = 0.79) and correlated well with total PSA (r = 0.72) and PSA-ACT (r = 0.74). Similar correlations also could be observed when each clinical group was analyzed separately. The median proportion of hK2 in relation to total PSA was 2.1%, 1.8%, and 1.4%, respectively, for PCa, BPH, and BPH cat patients. Both the free to total PSA ratio and the hK2 to free PSA ratio discriminated well between PCa and BPH patients. Within the range of total PSA of 4-10 ng/mL (PCa [n = 11] and BPH [n = 41]) the hK2 to free PSA ratio had a specificity of 63.4% and 90.9% sensitivity (area under the receiver operating characteristic [ROC] curve = 0.85) whereas the free to total PSA ratio had a 34.1% specificity at the same sensitivity level (area under ROC curve = 0.74). CONCLUSIONS: The hK2 serum level correlates well with all PSA serum forms in all clearly defined clinical groups. The preliminary finding that the hK2 to free PSA ratio appeared to improve the detection of PCa compared with the free to total PSA ratio in patients with total PSA within a 4-10 ng/mL range is of clinical interest. Combining human serine proteases in the multivariate regression analysis will be a tool to improve cancer detection. Further investigations with more sensitive hK2 assays and in larger patient populations are needed to confirm this finding.     

Influence of age on serum prostate specific antigen concentration

322 men who had not prostatic diseases were selected at random for defining the characteristics of serum prostate specific antigen (PSA) in order to use PSA more appropriately in detecting clinically significant prostate cancer. The serum PSA concentration is correlated with patient age (r = 0.301; P < 0.0001), PSA is increased with age. The recommended upper limits (mean +2 standard deviations) for serum PSA for men aged 20-49 years was 2.71 ng/ml; for 50-59 years, 5.01ng/ml; for 60-69 years, 6.05 ng/ml; and for greater than or equal to 70 years, 7.92 ng/ml. Our findings led to proposals for using age-specific PSA reference range instead of a single reference range for men of all age groups. These age-specific reference ranges have the potential to increase the specificity of using PSA for detecting prostate cancer.     

The clinical value of prostate-specific antigen velocity as a method for prostate cancer detection

The usefulness and problems associated with measuring of prostate-specific antigen (PSA) velocity (PSAV) for detecting prostate cancer are reviewed. PSA is not a cancer-specific serum marker, and various physiologic and benign pathologic processes influence serum PSA concentrations. Thus, it is important to distinguish between the elevation of serum PSA caused by cancerous tissue and biological variations. Smith suggested that a PSAV cutoff point of 0.75 and 0.4 ng/ml/year or more maximized the sensitivity and specificity of predicting cancer in those with normal PSA levels and elevated PSA levels (greater than 4.0 ng/ml), respectively. We also demonstrated that PSAV is significantly higher in moderately to poorly differentiated cancer than that in well differentiated cancer.     

Tumor recurrence following resection for early gastric carcinoma and its implications for a policy of limited resection

Some patients suffer postoperative recurrence after curative resection of early gastric carcinoma. This study reviewed consecutive patients with a single primary lesion and analyzed the relation between the pathologic findings and recurrence of early gastric carcinomas for determining indications for limited surgery. Among the 1585 consecutive patients with a solitary primary lesion of an early gastric carcinoma who had undergone curative surgery between 1963 and 1989 at one general hospital, pathologic findings relating to recurrence were analyzed according to Japan's General Rules for Gastric Cancer Study in Surgery and Pathology. Of these carcinomas, mucosal carcinomas comprised 701 (44.2%) and submucosal ones 884 (55.8%). The total recurrence rate in this series was 1.0%. Submucosal carcinomas (1.6%) were significantly (p < 0.02) more recurrent than mucosal ones (0.29%). Of the 16 patients with recurrence, 10 (62.5%) died within 5 years after surgery, frequently because of blood-borne metastasis. Macroscopically elevated components, the degree of histologic differentiation, and lymph node metastasis significantly contributed to the postoperative recurrence. After detailed analysis of submucosal carcinomas, it is strongly suspected that carcinomas with a macroscopically elevated component were significantly associated with nodal involvement and microvessel invasion, and that these abnormalities lead to recurrence. Among the early gastric carcinomas, differentiated submucosal carcinomas with a macroscopically elevated component, lymph node metastasis, or both have the most potential of recurrence after surgery. Mucosal carcinomas must be restricted to limited surgery, but, blood-borne metastasis should be carefully avoided.