Serum lactic dehydrogenase isoenzymes alteration in carcinoma cervix uteri

Serum lactic dehydrogenase isoenzymes alteration in carcinoma cervix uteri

91 In?. J. Gynecol. Obstet., 1988,27: 91-95 International Federation of Gynecology & Obstetrics Serum lactic dehydrogenase carcinoma cervix uteri M...

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In?. J. Gynecol. Obstet., 1988,27: 91-95 International Federation of Gynecology & Obstetrics

Serum lactic dehydrogenase carcinoma cervix uteri M. Kumar,

isoenzymes alteration

in

A. Birdi, Y .N. Gupta and S. Gupta

Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi flndia) (Received May lst, 1987) (Revised and accepted July lOth, 1987)

Abstract

Serum LDH-isoenzyme studies revealed that in carcinoma cervix, the principal activity was confined to LDH-2 and LDH-3 with a significant rise in LDH-2 fraction when compared with the control values (P < 0.001). Radiotherapy caused significant lowering of LDH-2 and LDH-3 (P < 0.001 in each case). There was no relation of LDHisoenqyme distribution in different clinical stages and morphological distribution within the tumor. Further, LDH-2 and LDH-3 were found to be lowered significantly in good and moderate clinical radiation response (CRR) groups (P < 0.001 in each case) but in poor CRR group no significant change in LDH-2 following and LDH-3 was observed radiotherapy. LDH-isoenqyme determination in carcinoma cervix is very helpful in assessing the treatment response following radiotherapy and thus may be an important prognostic parameter. Keywords: LDH isoenzymes; Carcinoma cervix; Clinical radiation response. Introduction

LDH

is

a

conglomeration

of

five

0020-7292/88/$03.50 0 1988 International Federation of Gynecology St Obstetrics

isoenzymes derived from different sources [24]. Several investigators have studied their levels in serum and tried to correlate the distribution pattern with the diagnosis of various diseases. Wroblewski et al. [27] have patterns in LDH-isoenzyme studied myocardial infarction, infective hepatitis and biliary obstruction. Zondag [28] has reported of LDHsignificance the prognostic isoenzymes in cases of seminoma of testes, malignant melanoma and dysgerminoma of ovary. LDH-isoenzyme patterns have been studied in various malignant conditions by workers [1,4,7,9,12,14,25]. many Stinslawsley et al. [18] and Sarvanon et al. [15] have observed the LDH-isoenzyme pattern in breast carcinoma. Recently, LDHisoenzymes pattern has been widely studied in gastrointestinal malignancies [5,10,11,16,22] and ovarian carcinoma [2,3]. Studies have also been carried out in pleural effusion in benign as well as in malignant status [23]. Though serum LDH has been studied in cancer of the cervix, in serum and vaginal aspirates [17], a profile of serum LDHisoenzyme levels in carcinoma of the cervix is lacking. Thus, it is worthwhile to know whether there is LDH-isoenzyme pattern specific for this group to help in early diagnosis and prediction of prognosis in this common type of malignancy. Clinical and Clinical Research

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Table 1.

Mean (A S.E. Vo)LDH isoenzymes in pretreatment group of patients with carcinoma cervix and controls.

Group

LDH-1

LDH-2

LDH-3

Patients (n = 106) Controls (n = 24)

22.89 f 0.69

33.44 f 0.77

32.94 + 0.78

22.28 f 1.65

29.09 f 1.62

NS

< 0.01

P-value (Students’ t-test)

Materials and methods Blood samples were collected from 106 patients with carcinoma of cervix uteri attending the out-patient department of the Radiotherapy University Hospital, Banaras Hindu University, Varanasi, India. Followup data are available in only 88 cases as 18 patients did not complete treatment. For comparison 24 healthy age-matched female controls were selected. Blood samples before and after radiotherapy were collected and allowed to clot at room temperature and serum collected. The separation of isoenzymes was done by electrophoresis [13], and isoenzymes were then visualized by a staining procedure specific to LDH and scanned by densitometer (Carl Zeiss, Jena, Germany). Sugimori and Taki [20] classified the clinical radiation response (CRR) into good, moderate and poor based on gross inspection of the cervix, assessed after a full course of radiotherapy (1) Good CRR - is characterized by flat cervix, obvious epithelization and Table II.

LDH4

LDH-5

8.96 f 1.18

1.91 f 0.55

32.07 f O.%

14.86 + 2.73

1.93 f 0.82

NS

< 0.05

NS

apparent reduction of the tumour size and/or parametrial induration. (2) Poor CRR - characterized with bleeding erosions, dirty crater formation in cervix or no sign of reduction of tumour size. (3) Moderate CRR - It is in between these two groups. Cytologically it corresponds either with good or poor response as there are no well-defined cytological criteria for moderate response. Results The value of LDH-isoenzyme in carcinoma cervix in comparison to controls are shown in Table I. It is clear that LDH-2 had a maximum mean value of 33.44 2 0.77 in the 106 pretreatment cases. This value was significantly more in comparison to the control population (29.00 + 1.62, P < O.Ol), while LDH4 was significantly more in the control group (14.86 f 2.73) as compared to the pretreatment group value (8.96 + 1.18, P < 0.05). LDH-1, LDH-3 and LDH-5 remain unchanged statistically. Radiotherapy caused a significant lowering of LDH-2 and LDH-3, 30.39 + 0.82 and 28.93 & 0.78, respectively

Comparison of pre- and post-treatment (mean + S.E. V’o)LDH isoenzymes (n = 88).

Group

LDH-1

LDH-2

LDH-3

LDH-4

LDHJ

Pre-treatment Post-treatment Mean difference

22.79 + 0.73 31.09 + 0.81 8.29 f 1.02

34.49 f 0.80 30.39 f 0.82 4.10 + 0.79

32.79 f 0.88 28.93 + 0.78 3.86 f 0.81

8.84 f 0.95 8.45 + 0.96 0.39 f 0.63

1.48 f 0.57 0.90 + 0.33 0.58 f 0.39

P-value (Students’ t-test)

< 0.091

< 0.001

< 0.001

NS

NS

Int J Gynecol Obstet 27

LDH-isoenzyme alteration Comparison of pre- and post-treatment Table III. response groups (n represent number of observations).

values

of LDH isoenzyme

(mean

f. S.E.

o/o) in different

clinical

radiation

LDH-1

LDH-2

LDH-3

LDH-4

LDH-5

Pretreatment Post-treatment Mean difference P-value

22.43 + 0.84 32.29 f 0.92 9.86 -e 1.24 < 0.001

34.37 f 1.09 29.92 f 1.00 4.45 f 0.95 < 0.001

33.04 f 1.17 28.35 + 1.11 4.60 2 1.02 < 0.001

8.20 -e 1.28 7.02 r 1.09 1.18 f 0.65 NS

2.17 + 0.91 1.37 * 0.55 0.80 f 0.61 NS

Moderate (n = 28)

Pretreatment Post-treatment Mean difference P-value

22.21 f 1.35 31.57 + 1.46 9.36 f 1.85 < 0.001

34.28 + 1.40 28.86 2 1.28 5.42 ~?r 1.11 < 0.001

32.57 f 1.43 28.53 -t 1.33 4.04 + 1.51 < 0.001

10.25 f 1.53 11.21 f 1.58 0.96 k 1.29 NS

None 0.36 2 0.35 0.36 2 0.35 NS

Poor (n = 9)

Pretreatment Post-treatment Mean difference P-value

26.89 f 2.36 22.22 + 2.29 4.67 + 1.83 < 0.01

32.89 2 1.40 37.22 + 2.83 4.33 + 2.82 NS

33.32 2 3.18 32.33 f. 3.33 1.11 f 2.21 NS

8.67 + 4.98 7.55 f 4.17 1.12 + 0.84 NS

1.66 * 1.66 1.11 f 1.05 0.55 f 0.8 NS

Group

Good

(n = 51)

(P < 0.001 in each case) while LDH-1 was significantly increased (31.09 f 0.87, P < 0.001) (Table II). There is no constant pattern of LDH-isoenzyme distribution in successive clinical stages. The distribution pattern of LDH was found to be unrelated to different types of squamous cell carcinoma. When the cases of carcinoma cervix were assessed in terms of clinical radiation response (CRR), it was observed that LDH-1 was constantly raised following therapy in all three CRR groups while LDH-2 and LDH-3 were lowered significantly (4.45 + 0.95 and 4.69 + 1.02, P < 0.001) in both good and moderate radiation response groups as a result of radiotherapy while in the poor CRR group the values did not alter statistically (Table III). Discussion

LDH-isoenzymes are of the metabolic chain of anaerobic glycolysis and are a constituent part of all tissue. Electrophoretically, LDH-1 and LDH-2 indicate aerobically active isoenzymes and LDH4 and LDH-5 anaerobically active isoenzymes. A transformed cell derives energy from anaerobic glycolysis [8]. The present study shows that in carcinoma of

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cervix uteri, the principal LDH isoenzyme activity is mainly confined to LDH-2 and LDH-3 with a significant increase in LDH-2 as compared to control. This is in agreement with other workers [21,25]. Several workers believe that elevated LDH2, LDH4 and LDH-5 are indicative of presence of malignant cells irrespective of the tissue of origin [4,9,14]. Others have suggested that LDH isoenzyme activity in malignancy is confined to LDH-2, LDH-3 and LDH4 with a significant increase in LDH-3 [7,26] while Anantharayanan et al. [l] have shown increase in LDH-1 and LDH-2 in early cases of malignancy. Vergnon et al. [23] showed both types of pattern in LDH-isoenzyme studies of malignant pleural effusion in 35 cases; 21 of them had high LDH-5 while there was low LDH-5 in 14 cases including 5 cases of small cell carcinoma lung and 3 cases of lymphoma. This indicates that the isoenzyme pattern in carcinoma of the cervix differs from other malignancies by having a low LDH-5 profile associated with a significant increase in LDH2 and LDH-3 in comparison to control. This raises the question of parenteral cell origin of these malignancies. It is possible that sole of malignant tissue should not be sufficient to increase the LDH-5 fraction and is not the Clinical and Clinical Research

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sole determinant of isoenzyme pattern in different malignancies. Alternatively, it is also probable that there is not sufficient leakage of LDH-5 isoenzyme from malignant cells directly into the serum. Comparison between the LDH-isoenzyme value of serum and tissue may prove a valuable tool in the diagnosis and a good prognostic indicator; the test requires a small volume of sample, is technically easy and fast to perform [23]. In the present study there is no relation of LDH isoenzyme distribution pattern with the clinical progression and degree of differentiation within the squamous cell carcinoma of the cervix. Following radiotherapy, the LDH-pattern in different clinical radiation response groups shows a significant lowering of LDH-2 and LDH-3 in good and moderate CRR group but remains unchanged in the poor CRR group. Thus, higher post-treatment values of LDH-2 and LDH-3 are an indicator of poor clincial radiation response. It is clear from the present study that LDH-isoenzyme studies are very useful in evaluating prognosis after treatment patients with carcinoma cervix. in Starkweather et al. [19] also observed the prognostic value of LDH distribution in lung carcinoma. References Ananthanarayanan PH and Ramkrishnan S: Serum lactate dehydrogenase isoenzymes in early malignancy. Indian J Med Res 68: 459,1978. Awis GM: Carcinoma of ovary and serum lactic dehydrogenase Levels. Surg Gynaecol Obstet 146: 893, 1978. Awis GM: Serum lactic dehydrogenase levels in diagnosis and treatment of carcinoma of the ovary. Am J Obstet GynaecolI16: 1053,1973. Bar U, Schmidt E and Schmidt FW: Enzyme-muster und Isozyme menschlicher Tumoren. Klin Wochenschr 41: 977,1%3. Carda-Abella P, Perez-Cuadrado S and Mate-Jimenez J: LDH-isoenzyme patterns in human gastric mucosa with precancerous changes. Cancer 42: 490,1978. Carda-Abella P, Perez-Cuadrado S, Lara-Baruque S, Gil grande L and Nunez-Puertas A: LDH isoenzyme pattern in tumors, polyps and uninvolved mucosa of human cancerous colon. Cancer 42: 490, 1978.

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Darnle SR and Talavdekar RV: Studies of isoenzymes in relation to cancer: Lactic dehydrogenase &enzyme composition of sera and effusion in benign and malignant conditions. Indian J Cancer II: 410,1974. 8 Fleisher M, Wasserstrom WR, Schold SL, Swartz MK and Posner JB: Lactic dehydrogenase isoenzyme in cerebrosphral fluid of patients with systemic cancer. Cancer 47: 2654.1981. 9 Goldman RD, Kaplan NO and Hall TC: Lactate dehydrogenase in human tissues. Cancer Res 24: 389, 1964. 10 Langvad E: LDH isoenzyme pattern in tumor bearing colon. Int J Cancer 3: 27, 1968. 11 Marshall MJ, Neal FE. and Goldberg DM: Effect of radiotherapy upon enzymes of glycolytic and related pathways in human uterine Cancer. Br. J. Cancer 39: 90, 1979. 12 Messey WH, Daniel DL, Fletcher WS and Wood DC: Lactic dehydrogenase isoenzyme alterations in malignant disease of the liver. Am J Surg 122: 209.1971. 13 Nerenberg ST and Pogojeff G: Laboratory diagnosis of specific organ disease by means of combined serum isoenzyme pattern, Am J Clin Path01 51: 429,1969. 14 Richterich A and Burger A: Lactic dehydrogenase in human cells and malignant effusions. Enzyme Biol Clin 3: 65,1%3. 15 Sarvanon CS, Balasubramaniam MK, Gopalkrishnan V, Govindarajulu P and Rao RN: Biochemical studies in breast carcinoma. Indian J Cancer 14: 38,1977. 16 Sarvanon CS. Govindarajulu P and Rao RN: Lactate dehydrogenase and its isoenzymes in gastric cancer. Indian J Cancer 16: 42,1979. 17 Saxena S, Pendse V, Kanas, Goyal A, Gupta RC and Singh PP: Serum LDH in gynaecologic cancer. J Obstet Gynaecol India34: 717,1984. 18 Stainslawsley M and Vaisillier F: Distribution of LDH isoenzymes in mastitis, fibroadenoma and carcinoma of the human mammacy gland. Eur J Cancer 1: 22 1, 1965. 19 Starkweather WH and Schock HK: Some observation on the lactate dehydrogenase in human neoplastic tissue. Biochem Biophys Acta 62: 440,1%2. 20 Sugimori H and Taki I: Radiosensitivity test for cervical cancer. Acta Cyto116: 331. 1972. 21 Talageri VR, Nadkarni JS and Gollerkeri MP: Evaluation of plasma lactate dehydrogenase isoenzymes in cancer patients. Indian J Cancer 14: 42, 1977. 22 Tayler R, Cumberland VH and Piper DW: LDH isoenzyme patterns in uninvolved mucosa of patients with colorectal carcinoma. Gut 18: 45, 1977. 23 Vergnon JM, Guidollet J, Gateau 0, Ripoll JP, Louisot P and Brune J: Lactic dehydrogenase isoenzyme electrophoretic pattern in the diagnosis of pleural effusion. Cancer 54(3): 507.1984. 24 Vessel ES and Bearn AG: Localisation of lactic dehydrogenase activity in serum fractions. Proc Sot Exp Bio Med 94: 96,1957. 25 Weime RJ, Von Hove WZ and Vanden S: The influence

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of cytostatic treatment in serum LDH patterns of patients with bronchial carcinoma and its relation to tumor regression. ME Ann NY Acad Sci 151: 213,1%8. Wright EG, Cawley LP and Eberhardt I: Clinical application and interpretation of the serum lactic dehydrogenase zymogram. Am I Clin Path01 45: 737, 1966. Wroblewski F and Gregory KF: Lactic dehydrogenase isoenzymes and their distribution in normal tissue and plasma and in disease states. Ann NY Acad Sci 94: 912, 1961.

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Zondag HA: In ‘Enzymes in clinical chemistry (ed R Ruyssen, L. Vandendriessche), p. 124. Elsevier, Amsterdam 1%5.

Address for reprints: Moban Komar, MD 56 S&et Nagar VPr8nasi 2210%

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