Malignancy of gastric cancer according to DNA ploidy pattern and tumor markers

Microfluorometric analysis of DNA content was performed on samples from 172 gastrectomy specimens of cancer. Histograms of DNA content were classified into three ploidy patterns; type I, II and III. Also, immunocytochemical examination for tumor markers (CEA, AFP and hCG) was performed. Type I was predominant in intramucosal carcinoma. Type III was predominant in differentiated carcinomas, in elevated type of early carcinomas and in gross type 1 and 2 of advanced carcinomas. Prognostic serosal factor exerted a greater influence on the prognosis than ploidy pattern. But in the patient without prognostic serosal factor, type III had a poorer prognosis than the other types because of vessel invasion, lymph node metastasis and liver metastasis. AFP and hCG were highly positive in type III. Furthermore type III cancer producing more than two tumor markers had an extremely poor prognosis. Analysis of ploidy pattern and tumor markers may prove to be a highly useful adjunct in the evaluation of malignancy in gastric cancer.     

A new hypothesis on the natural history of bladder cancer based on the study of tumor DNA levels by flow cytometry

72 bladder tumors were studied for nuclear DNA content with flow cytometry. A bimodal DNA profile was present in 33 of them (45%). The following findings concerning the aneuploid second peak of these 33 tumors are remarkable. Aneuploid peak DNA index distribution is discontinuous: there is no peak below 1.5 nor between 2.3 and 2.7. Aneuploid peak importance (second peak cell percentage versus all tumor cells in the same sample) increases when its DNA index decreases from 2.0 to 1.5 = this percentage is on average 45% for a DNA index of 2.0 and increases to 75% when DNA index decreases to 1.5. Aneuploid peak mitotic activity increases when DNA index decreases from 2.0 to 1.5 = the percentage of S G2 M cells of the aneuploid peak is in the range of 15% for a DNA index of 2.0 and in the range of 22% for a DNA index of 1.5. These findings are in favor of a dynamics in bladder cancer natural history. Tumors are supposed to share the same clonal evolution, in 3 stages. First stage: transformed tumor cell DNA profile is unimodal with a DNA index in the region of 1; second stage: due to chromosomic non-dysjunction during mitosis, a second peak appears with a DNA index of 2. Third stage: DNA index of this aneuploid second peak progressively decreases from 2 to 1.5 as a consequence of non vital chromosomes loss by tumor cells. It is suggested that DNA index as defined by flow cytometry does not have an absolute prognostic value per se, but in combination with tumors mitotic activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The significance of tumor heterogeneity for prediction of DNA ploidy of prostate cancer

OBJECTIVE: In a previous study, we mapped the ploidy heterogeneity of prostate cancer using flow cytometry in 676 tumor samples from 50 radical prostatectomy specimens. Ploidy heterogeneity was common (42% of tumors) and was found in all non-diploid tumors. The volume of non-diploid tumor was estimated and found to predict extra-prostatic extension and seminal vesicle invasion. The aim of this study was to evaluate the impact of tumor heterogeneity on preoperative ploidy assessment. MATERIAL AND METHODS: In 50 men at least six core biopsies were taken before prostatectomy. Sections from biopsies with cancer were Feulgen-stained for image cytometry. After exclusion of biopsies with insufficient material, 123 histograms from 48 men (mean 2.6; range 1-7) remained for analysis. RESULTS: In 32 men, biopsies were diploid. In 16 men, at least one biopsy was non-diploid (14 tetraploid, two aneuploid) and 10 of them also had diploid biopsies. In 34 men (71%), the prostatectomy specimens were correctly predicted as being either diploid (48%) or non-diploid (23%). The sensitivity and specificity of biopsies for predicting non-diploid cancer were 55% and 82%, respectively, and the positive and negative predictive values were 69% and 72%, respectively. The ploidy status of tumors with and without ploidy heterogeneity was correctly predicted in 55% and 82% of cases, respectively (p=0.04). Biopsies underestimated ploidy in 9/20 tumors (45%) with heterogeneous ploidy status. Underestimation mainly occurred when one or two cores were analyzed. CONCLUSIONS: Preoperative prediction of the ploidy status of prostate cancer is hampered by tumor heterogeneity. Analysis of multiple biopsies is important for correct preoperative ploidy estimation.     

DNA ploidy and tumor invasion in human gastric cancer. Histopathologic differentiation

The relationship between DNA ploidy and tumor invasion in 254 patients with gastric carcinoma was studied, with particular emphasis on histopathologic features. In the differentiated type of adenocarcinoma, there were aneuploid lesions characterized by a relatively high incidence of lymph node metastasis and hematogenous recurrence, even when the invasion was limited to the submucosa. In the undifferentiated type, aneuploid lesions were rarely seen at the early stage, but the frequency remarkably increased with invasion into the deeper layers. Nodal involvement and disseminating metastasis were evident with serosal invasion. Analyzed by a multivariate Cox model, DNA ploidy significantly correlated with prognosis. Thus, DNA ploidy is a major determinant of survival, and the behavior of an aneuploid carcinoma is apparently controlled by individual histologic type.     

Influence of blood group type on the natural history of superficial bladder cancer

The blood group was correlated with the grade and stage at diagnosis, and with the subsequent clinical course in 494 patients with bladder cancer treated at our institution from 1977 to 1986 who were followed for a mean of 5.5 years (range 2 to 9 years). The distribution of blood groups was similar to that reported for the general population and to that of 100 consecutive patients with urolithiasis used as controls, and the distribution was not different among patients with superficial cancer (stages O and A) than in those with advanced disease (stage B or higher). However, among patients with superficial disease high grade (III or IV) lesions were more frequent in those with blood group O (36 per cent) than in those with other blood groups (13 to 18 per cent) (p less than 0.001). In addition, in patients with superficial cancer of all grades progression to advanced disease was significantly greater among those with blood group O (37 per cent) than in those with other groups (12 to 16 per cent) (p less than 0.05). More importantly, in patients with low grade (I or II) superficial cancer development of advanced disease was significantly more frequent among those with blood group O (24 per cent) than in those with other blood groups (0 to 7 per cent) (p less than 0.004). Our findings suggest that individual genetic factors influence the natural history of superficial bladder cancer. The molecular basis of this phenomenon remains to be elucidated.     

Prognostic value of DNA ploidy of colorectal tumor cells

The analysis of ploidy provides valuable information allowing a more precise diagnosis, a more dependable prognostic and the choice of appropriate therapy. With ploidy analysis one can assess the aggressiveness of a given tumor. Aneuploidy of tumors clearly indicates a significantly lower patient survival index. Ploidy analysis of tissue sections yields a clear overall indication of the proportion of cells exhibiting hyperploidy within the tumor mass. The application of this approach is amenable to diverse types of tumors including colo-rectal neoplasias. Additionally, it provides a correlation with the histological presentation of each tumor. The study includes DNA ploidy analysis of 212 patients with primary adenocarcinoma. Sixty-four of the cases examined had follow-ups of a least 2 years. Eighteen of this group had diploid non-proliferating tumors, of which 2 (11%) subsequently died. Nineteen of the 64 had proliferating diploid tumors, 11 (58%) of whom died within the follow-up periods. Twenty-seven patients had tumors which were clearly aneuploid, 12 (45%) of whom later died. Our study demonstrates the prognostic value of ploidy analysis. The preliminary results indicate that mortality of patients with proliferating tumors is approximately 50% after 2 years. This prognostic is independent of other more classical criteria of tumor staging, namely Dukes' classification, histological differentiation and size of tumor. In the near future, ploidy analysis should be introduced as a standard part of tumor assessment. It clearly provides a valuable prognostic allowing the selection of patients requiring a careful follow-up.     

Multifactorial analysis of local recurrences in rectal cancer,including DNA ploidy studies: A predictive model

DNA ploidy studies were performed in 188 patients operated on for rectal cancer. In order to define different risk groups of patients, a stepwise logistic regression was carried out in 138 patients who underwent abdominal curative resections. Thirtyseven variables were analyzed. Although several variables were significant, only three improved the prognostic value: (1) more than three positive lymph nodes (p=0.0007); (2) macroscopic local tumor invasion (p=0.01); and (3) DNA ploidy (p=0.03). Standardized discriminant coefficients were used to obtain a model and format for predicting local recurrences. This is the first time that a predictive model for rectal cancer, using DNA ploidy as a variable, is reported.Based on calculated discriminant values (DV), patients can be divided into three subgroups: (1) low risk for local recurrences (DV<–1.9,n=56)—local recurrences were observed in two patients (3.6%); (2) moderate risk (DV between –1.9 and –0.6,n=55)—local recurrences occurred in nine patients (16.4%); and (3) high risk (DV>–0.6,n=27)—local recurrences occurred in 14 patients (51.8%). This predictive model for local recurrences has much better prognostic value than Dukes' staging (p<0.0001).

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Resumen Se efectuaron estudios de ploidia de DNA en 188 pacientes operados por cáncer rectal. Con el objeto de definir los diferentes grupos de pacientes, se hizo un análisis de regresión en 138 pacientes que recibieron resecciones curativas, mediante el análisis de 37 variables.Aunque diversas variables fueron de significación, sólo tres incrementaron el valor pronóstico: 1) más de tres ganglios linfáticos positivos (p=0.0007); 2) invasión tumoral local macroscópica (p=0.01); y 3) ploidia de DNA (p=0.03). Se utilizaron coeficientes estandarizados de discriminación con el fin de obtener un modelo y un formato para la predicción de recurrencias locales. Esta es la primera vez que se reporta un modelo de prediccción para el cáncer rectal utilizando la ploidia de DNA.Con base en los valores de discriminación calculados (VD), los pacientes pueden dividirse en tres subgrupos: 1) de bajo riesgo de recurrencia local (VD<–1.9, n=56)—se observaron recurrencias locales en dos pacientes (3.6%); 2) de riesgo moderado (VD entre –1.9 y –0.6, n=55) —se presentó recurrencia local en nueve pacientes (16.4%); y 3) de alto riesgo (VD >–0.6, n=27) —se presentó recurrencia local en 14 pacientes (51.8%). Este modelo de predicción de recurrencia local exhibe un valor de pronóstico mucho mejor que el de la estadificación de Dukes (p<0.0001).

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Résumé La ploïdie de l'ADN a été étudiée chez 188 patients opérés d'un cancer du rectum. Par une régression logistique pas-à-pas chez 138 patients ayant eu une résection à visée curative, 37 variables ont été analysées dans le but de définir des groupes à risque. Bien que plusieurs de ces variables aient une valeur significative, trois seulement d'entre elles ont une valeur pronostique: 1) plus de trois ganglions lymphatiques envahis (p= 0.0007); 2) envahissement (macroscopique) local (p=0.01), et 3) la ploïdie de l'ADN (p=0.03). Des coefficients discriminants standardisés ont été utilisés afin d'obtenir un modèle pour prédire les récidives locales. C'est la première fois qu'un modèle prédictif pour cancer rectal est rapporté en tenant compte de la ploïdie de l'ADN. Se basant sur les valeurs discriminantes (VD), on peut diviser les patients en trois groupes: 1) patients à petit risque de récidive locale (VD<–1.9, n=56): des récidives locales ont été observées chez deux patients (3.6%); 2) patients à risque modéré de récidive locale (VD entre –1.9 et –0.6, n=55), les récidives locales ont été observées chez neuf patients (16.4%) et 3) patients à haut risque de récidive locale (VD>–0.6, n=27): des récidives locales ont été constatées chez 14 patients (51.8%). Ce modèle prédictif pour les récidives locale a une valeur pronostique bien meilleure que le stade de Dukes (p<0.0001).

     

Studies on DNA content in ploidy patterns of esophageal cancer

The present study was undertaken to evaluate the nuclear DNA content of esophageal cancer cells consequent on the process of growth and progression of the cancer. In experimental animal studies, 47 esophageal cancers were induced in male Wistar rats by oral administration of N-amyl-N-methylnitrosamine (AMN) and were analysed in the study of ploidy patterns. The study was also carried out to determine the DNA content in the ploidy patterns in man. Primary tumors associated 421 metastatic lymph nodes in the 62 patients with thoracic esophageal cancer were subjected for the study of ploidy patterns. The nuclear DNA content was determined by means of flow cytometry. In the study of the experimentally-induced esophageal cancer in rats, aneuploidy was found in 18% at a depth of submucosa, 30% at proprial muscle, 59% at adventitia, and in 50% at a depth of neighboring structures, respectively. Clinically in man, the incidence of DNA diploidy and aneuploidy in the 62 primary cancers was 56% and 44%, respectively. In the 421 metastatic lymph nodes, diploid was found in 73% and aneuploid in 11%, while the combination of diploid and aneuploid was observed in 16%. Difference in the DNA index (DI) between the primary cancers and metastatic lymph nodes was found in 29 cases (46.8%), and the difference increased with progression of the cancer. Two hundred and ninety seven metastatic lymph nodes of 29 cases were subdivided into 4 groups based on the extent of the cancerous nests, and the DI value was found to be increased in proportion to the extension. With the results, the DI value of esophageal cancer appeared to be changed dependently by the variation of cell populations in the cancer or in the DNA content of the cancer cells.     

Correlation between DNA ploidy patterns and tumor progression, prognosis, and tumor infiltrating lymphocytes in human esophageal cancer

Cytophotometric DNA analyses were performed on 35 primary esophageal cancer. Histograms of DNA measurement were classified into three patterns (diploid pattern, aneuploid pattern and mosaic pattern) and were compared with histological findings, prognosis, and degree of lymphocytes infiltration around the tumor. Survival rate was worse in patients with mosaic pattern than the others, and 4-year survival rates of each patterns were 66.7% (diploid), 53.6% (aneuploid) and 25.4% (mosaic). Diploid cell line was observed frequently in the superficial cancers, and as the cancers infiltrated more deeply, mosaic cell line increased. Mosaic cell line appeared more frequently in well differentiated squamous cell carcinomas. In patients with mosaic pattern, there was high frequency of lymphnode metastasis and vascular invasion, as compared with diploid pattern. The rate of vascular invasion tended to increase in the following order; diploid, aneuploid and mosaic types. Furthermore in the diploid tumors, the degree of lymphocyte infiltration around tumor tended to increase. These findings suggest that the change of DNA content may occur frequently during tumor progression and may be affected by tumor infiltrating lymphocytes. So the DNA ploid pattern will be also to be one of the conjecturable factors of the prognosis of esophageal cancer.     

胃癌与端粒酶活性表达及DNA倍体关系的研究

目的　揭示胃癌与端粒酶活性及DNA倍体的关系。方法　检测 30例胃癌标本 ,同时取无瘤残端作为对照。端粒酶检测采用端粒重复扩增 酶联免疫吸附法 (TRAP ELISA法 )。DNA倍体的测定采用流式细胞术 ,一步法检测DNA含量。结果　肿瘤瘤体端粒酶阳性率 83 3% (2 5 / 30 ) ,无瘤残端端粒酶阳性率 3 3%(1/ 30 ) (P <0 .0 5 ) ;端粒酶阳性瘤体平均直径 6 5cm ,阴性瘤体平均直径 3 6cm(P <0 .0 5 ) ;端粒酶阳性肿瘤淋巴转移率 5 3 3% (16 / 30 ) ,阴性者无淋巴转移 (0 / 5 ) (P <0 .0 5 ) ;端粒酶阳性肿瘤中异倍体肿瘤占 5 6 0 % (14/2 5 ) ,而端粒酶阴性者无异倍体出现 (P <0 .0 5 )。结论　胃癌端粒酶活性升高 ,端粒酶阳性肿瘤瘤体大 ,淋巴转移率高 ,且异倍体发生率高 ,预后差。提示端粒酶的激活与胃癌的发生发展有密切关系。     

60例直肠癌标本细胞DNA含量变化分析

目的研究细胞DNA倍体定量分析在直肠癌诊断中的作用和意义。方法用全自动细胞DNA倍体分析仪对结直肠肿瘤细胞、癌旁组织、正常组织进行DNA倍体分析,比较肿瘤组织DNA细胞倍体与临床病理特征的相关性,以及与常规细胞学、病理组织学、分析相互诊断的吻合率。结果肿瘤组织的异倍体率显著大于癌旁组织,癌旁组织的异倍体率显著高于正常组织。直肠肿瘤细胞、癌旁组织、正常组织异倍体率有明显的差异。结论结直肠癌肿瘤组织的恶性度与染色体异倍体之间有显著的相关性,病理组织学、DNA细胞倍体分析诊断相互吻合,细胞DNA倍体定量分析在直肠癌诊断中具有一定的作用。     

尿脱落细胞DNA倍体分析联合细胞免疫组化方法在膀胱肿瘤二次电切中的应用

目的 探讨尿脱落细胞DNA倍体分析联合细胞免疫组化方法在膀胱肿瘤二次电切中的应用效果。方法 选取上海市静安区市北医院2017年3月至2020年9月收治的48例尿路上皮癌行二次电切的患者纳入观察组,另选取53例血尿患者纳入对照组,两组均接受尿脱落细胞DNA倍体分析和细胞免疫组化检查。结果 观察组的DNA倍体分析异常的阳性率为18.75%（9/48）,高于对照组[1.89%（1/53）](P<0.01)。观察组尿脱落细胞免疫组化检查异常的阳性率为16.67%（8/48）,高于对照组[1.89%（1/53）](P<0.05);术后观察组DNA倍体分析异常诊断膀胱癌的确诊率为75.00%(9/12),而尿脱落细胞免疫组化检查确诊阳性率为66.67%(8/12),两者均高于对照组(均为0)(均P<0.01)。结论 尿脱落细胞DNA倍体分析联合细胞免疫组化方法的检查结果可为膀胱肿瘤二次电切提供手术依据。     

The natural history of prostate cancer

Predicting the long-term outcome of patients who choose watchful waiting as initial therapy for prostate cancer is difficult. The wide variation in disease progression, the impact of competing medical hazards, and the potential impact of early hormonal therapy that is characteristic of contemporary patients all conspire to compromise survival estimates dating from the pre-PSA era. The survival analysis figure developed by Albertsen et al (Fig. 1) estimates a 15-year survival rate based on patient age and Gleason score at diagnosis from patients diagnosed in the pre-PSA era. Although no effort was made to adjustfor competing medical hazards, patients and clinicians can adjust a patient's chronological age to match his "physiological" age. The advent of widespread PSA testing appears to have advanced the date of diagnosis by approximately 5 years and the onset of secondary treatment by at least as many years. Therefore, the figure describing the natural history of prostate cancer most likely underestimates rather than overestimates survival among men with newly diagnosed, localized prostate cancer who select watchful waiting as their treatment choice. As contemporary databases of men with localized prostate cancer mature, more data on the natural history of this disease will become available. Only time will tell how the use of PSA has altered the precision of historic case-series data.     

DNA ploidy status in the diagnosis and prognosis of cancer.

DNA ploidy status of tumour cells is becoming a part of patient's record, because it brings an objective assessment of diagnostic and prognostic significance. DNA ploidy status in diagnosis--DNA ploidy status of some tumour types can be used as an adjunct to cytologic or histologic examination and provide an additional diagnostic information. For example, small cell lung carcinoma cells may be difficult to differentiate from cells of other benign neuroendocrine tumours. By computing the DNA malignancy grade, as defined by Bocking A. et al., it was possible to distinguish levels of malignancy among neuroendocrine tumours. Thus we were able to demonstrate that typical carcinoids may be differentiated from small cell carcinomas and atypical carcinoids. DNA ploidy status in prognosis--A large number of studies strongly support a correlation between DNA ploidy patterns and clinical course of malignant tumours. However, the prognostic value of DNA ploidy status has to be evaluated in relation to conventional clinico-pathologic characteristics, by multivariate analysis in order to demonstrate its independent contribution. For example, we demonstrated, in a prospective study of 211 colorectal adenocarcinomas, that ploidy status was an independent predictor of prognosis only in the early stages of the disease (Dukes' A, B, C), but not when advanced stages-(Dukes' D) were considered. In conclusion, DNA ploidy status may be used as an important objective parameter either in diagnosis or in prognosis, complementary to the traditional clinico-pathological characteristics.     

DNA ploidy and the prognosis of stage pT1 bladder cancer

The histopathological grade, proportion of "S"-phase nuclei and DNA ploidy values were linked and of prognostic significance in a retrospective series of stage pT1 bladder cancers. Nuclei were extracted from paraffin sections of 75 biopsies (56 patients). DNA ploidy and the proportion of "S"-phase nuclei were measured using flow cytometry. Progressive disease (pT2 or greater) developed within 3 years in 35% (6/17) of patients with poorly differentiated tumours, 35% (8/23) with aneuploid tumours and 35% (7/20) of those with a high proportion of "S"-phase nuclei. Of 8 tumours with all 3 features, progressive disease developed in 6 cases (75%). Of 9 patients who developed progressive disease, 8 (89%) had aneuploid tumours. Progressive disease did not develop in 11 patients with well differentiated tumours, compared with 4% (1/24) in diploid/tetraploid tumours and 7% (2/27) in those with a low/medium percentage of "S"-phase nuclei. In contrast to muscle-invasive disease, recurrent superficial tumours developed with a high incidence in all groups. Only 6/56 patients (11%) remained alive and disease-free for 3 years. It is concluded that these 3 features are of similar prognostic significance and accuracy in identifying patients requiring more aggressive therapy.     

The natural history of breast cancer

The natural history of breast cancer has not been fully elucidated, but physicians are making progress in the treatment of patients with this disease. Randomized, controlled trials indicate that screening, adjuvant systemic therapy, and adjuvant radiotherapy can reduce the risk for death caused by breast cancer. More importantly, national statistics show that breast cancer death rates are now decreasing (after remaining stagnant for nearly 40 years), but additional investigation into the natural history of breast cancer is clearly warranted. The randomized controlled trials on screening and local therapy, in particular, provide important insights into the natural history of the disease. Thus, the results of these trials should serve as a basis for additional investigation. Ultimately, a better understanding of the natural history of breast cancer may translate into improved treatments and better outcomes.     

Influence of phlebographic abnormalities on the natural history of venous ulceration

Eighty-five limbs in 73 patients with a healed venous ulcer were assessed by ascending and descending phlebography, foot volume plethysmography and transcutaneous oxygen measurements. Forty-four limbs had post-thrombotic changes on ascending phlebography. In 24 (28 per cent) these extended into the femoral vein, while in 20 (24 per cent) only the calf veins were involved. In the 41 limbs (48 per cent) with normal deep veins on ascending phlebography, 11 had evidence of localized incompetence of the calf communicating veins, 14 had either long saphenous incompetence, deep vein reflux to the level of the knee or below, or both of these abnormalities, and 16 limbs had no phlebographic abnormalities. However all limbs had a decreased half volume refilling time on foot volume plethysmography. Limbs with post-thrombotic changes extending into the femoral vein were associated with a significantly longer history of ulceration and more ulcer recurrences than limbs with calf vein damage (P less than 0.05 for each) and limbs with normal deep veins (P less than 0.01 for each). However, these limbs did not have lower transcutaneous oxygen ratios or longer times to achieve ulcer healing. Ascending phlebography identified a group of limbs with extensive post-thrombotic changes in which there was a higher incidence of ulcer breakdown, but this was not associated with a delay in ulcer healing.     

直肠癌直肠系膜播散的临床病理观察

目的探讨直肠癌根治术直肠系膜的合理切除范围。方法采用连续病理切片方法观察40例直肠癌的手术标本。结果40例直肠癌中发现直肠系膜有癌播散6例(15%),播散方式有肿瘤直接浸润、在系膜中形成孤立癌灶、血管和(或)淋巴管的转移。播散范围均在肿瘤下缘4cm之内。直肠癌直肠系膜播散与肿瘤分型、分化程度、肠壁浸润深度相关,与肿瘤大小及癌胚抗原(CEA)水平无相关。结论直肠癌根治术中直肠系膜的远端切缘应超过肿瘤下缘4cm。