Abstract
Hypocholesterolemia has been observed in patients with cancers of various organs; however the potential role of alterations in serum lipid profile in oral cancer remains controversial. Hence, this study aimed to evaluate the serum lipid profile in oral squamous cell carcinoma (OSCC) and its prognostic significance. Ninety untreated OSCC patients, who reported to the craniofacial unit for treatment between 2011 and 2014, were identified to obtain clinicopathological data and preoperative blood investigations including lipid profile. The fasting blood lipid profile, including total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL), was evaluated using a fully automated biochemistry analyser. Data were analyzed statistically using the Student’s t -test, analysis of variance, and post hoc tests. Statistically significant decreases in serum TC, HDL, and LDL levels were observed in OSCC patients as compared to healthy controls ( P < 0.05). There was no statistically significant difference in mean lipid profile values in terms of stage, grade, or lymph node metastasis. This study identified changes in lipid profiles in OSCC. The results suggest that during the development and progression of OSCC, levels of serum lipids are decreased. A review of the literature confirmed that OSCC patients exhibit aberrant serum lipid patterns.
Oral cancer is the eighth most common cancer in the world. In India, oral cancer is the second most common cancer. Squamous cell carcinoma (SCC) comprises about 90–95% of all oral malignancies, and hence the term ‘oral cancer’ is used in a restricted sense to describe SCC. The mechanism of carcinoma development is complex and comprises proliferation, apoptosis, and differentiation, and the interplay between these intricate processes determines tumour development and progression. Newly proliferating tumour cells need many of the basic components used in physiological processes at well above the normal limits. An example is the lipids that form the major cell membrane components essential for various biological functions, including cell division and the growth of normal and malignant tissues. The increased need for lipids to fulfil the requirements of these new cells would be expected to diminish the existing lipid stores. Also, cancer cells that are not rapidly proliferating require increased amounts of lipids for enhanced signalling and resistance against apoptosis.
Oral cancer may interfere with food intake, therefore it can be intuitively expected that patients with oral cancer will have lower serum levels of lipids because of lowered lipid digestion and absorption. However, the plasma cholesterol concentration is not simply derived from dietary cholesterol intake or endogenous cholesterol. Rather, it also reflects the rate of synthesis of cholesterol-carrying lipoproteins. Therefore, serum lipid levels are less influenced by oral intake, and other factors such as genetic background or hormones, or environmental issues, are also involved in the regulation of plasma cholesterol.
The utility of variations in blood cholesterol levels in the diagnosis and treatment of various diseases has been studied by several researchers. High cholesterol levels in the blood are associated with an increased risk of coronary heart disease, whereas the implications of decreased cholesterol levels remain imprecise. Researchers have reported the association of plasma/serum lipids and lipoproteins with different cancers. Cancer patients often display significantly lower levels of serum total cholesterol (TC). An inverse association between cholesterol and all cancers, such as hematopoietic, bowel, lung, prostate, and head and neck cancers, as well as oesophageal cancers, have been reported in the literature. The ‘preclinical cancer effect’ hypothesis has received considerable attention as an explanation for the observed inverse association. Malignant neoplasms are known to have protean physiological effects, which might include the depression of blood cholesterol. Some investigators have also found a relationship between low serum cholesterol and an increased risk of cancer occurrence and mortality. Alterations in the circulatory cholesterol levels have been found to be associated with the aetiology of breast cancer and colorectal cancer. Breast cancer patients display significantly elevated levels of serum cholesterol, and a few studies have shown high cholesterol levels to be associated with an increased risk of breast cancer and cancer recurrence. However, the literature on the cancer–cholesterol question has remained inconsistent.
Studies have demonstrated that cancer patients often display aberrant lipid profiles. The association of different lipoprotein sub-fractions with cancer risk has also been studied widely. Low levels of serum high density lipoproteins (HDL) have been associated with an increased risk of all cancers. In contrast, other studies have shown an increased risk of cancer associated with high levels of serum HDL. Patients with breast cancer display high levels of HDL in comparison with healthy individuals. Decreased serum low density lipoprotein (LDL) levels have also been shown to be associated with an increased risk of various cancers. However, increased LDL levels have been associated with an increased breast cancer risk. Serum triglycerides (TG) are significantly elevated in all types of cancer, as demonstrated by various studies. Serum lipid levels of cancer patients also fluctuate during chemotherapy, and levels may return to normal after treatment. These observations corroborate the correlation between an abnormal serum lipid profile and disease activity.
Significantly lower levels of serum cholesterol, HDL, LDL, and TG have been noted in the majority of studies on oral cancer. Others have observed no significant differences in serum lipid fractions, or a significant increase in the levels of lipid fractions. This information points to an irregular lipid pattern in oral cancer patients. Although alterations in serum lipid profile patterns have long been associated with malignancies, the role of these alterations remains controversial. There is debate as to whether hypocholesterolemia is a predisposing factor for cancer development, or hypocholesterolemia is in fact the result rather than the cause of cancer.
Some studies have reported alterations in serum lipid profiles in oral precancer and oral cancer, but have included small samples. The present study was performed on a relatively large cohort of OSCC patients, comparable to certain earlier research. This study aimed to compare and correlate the serum lipid profiles of patients with carcinoma of different stages and grades, to compare and correlate serum lipid profiles in nodal metastatic and non-metastatic patients, and to determine the association with tobacco consumption.
Methods
A total of 120 patients ranging in age from 20 to 75 years were included in this hospital-based case–control study. Approval for the study was obtained from the ethics committee of the institute. After obtaining written informed consent from the participating patients, a thorough clinical history was taken, including height and weight (to calculate body mass index) and the type, form, frequency, and duration of tobacco use. The subjects were divided into two groups.
Group I consisted of 90 untreated OSCC patients, reporting to the craniofacial unit of the institution for treatment (excision of the lesion along with neck dissection) during the years 2011–2014. The patients were diagnosed with OSCC based on clinical and histopathological examinations. Staging was done according to the Union for International Cancer Control (UICC) classification. Along with the complete blood investigation performed routinely prior to surgery, the patient’s preoperative fasting blood lipid profile was also evaluated. The subjects in the OSCC group were further classified into tobacco users (TU) and non-tobacco users (NTU). Differences in lipid profiles for the various types of tobacco use, i.e. smokeless tobacco, smoking tobacco, and a combination of both forms, were also analyzed.
Group II included 30 age- and sex-matched healthy individuals attending the institution for a routine dental check-up and treatment, without any history of tobacco abuse or oral lesions. These subjects were selected randomly amongst the people who visited the same hospital during the same time period. All of the selected control subjects had a similar socioeconomic background and similar quality of diet to the cancer cases.
Exclusion criteria
Patients who were obese, had any form of cardiac, renal, or liver disorder, uncontrolled diabetes, hypertension, or thyroid disorders, those who were pregnant, patients with a family history of hyperlipidemia, those receiving lipid-lowering drugs, patients on chemotherapy or radiotherapy, and those with malignancies elsewhere in the body were excluded from the study.
Analysis of the lipid profile
A 5-ml blood sample obtained in a fasting state was collected under sterile conditions in a plain vacutainer and allowed to clot for 1 h. The vacutainer was centrifuged at 3000 rpm for 5 min. Serum was then analyzed for the lipid profile including total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides (TG). A fully automated biochemistry analyser (EM 360; Erba Diagnostics Mannheim GmbH, Mannheim, Germany), based on the principle of photometry, was used to perform the lipid analysis.
Statistical methods
Mean, standard deviation, and standard error range values were recorded for all of the variables in the study and subjected to statistical analysis; P -values were obtained. The data were analyzed using SPSS version 11 software (SPSS Inc., Chicago, IL, USA). The Student’s t -test, analysis of variance (ANOVA), and post hoc Tukey honestly significant difference (HSD) test were used. A P -value of <0.05 was considered significant.
Results
In the present study, out of 120 subjects included, 88 (73%) were male and 32 (27%) were female; their mean age was 50.6 years.
The OSCC group comprised 74 (82%) males and 16 (18%) females, with an age range of 20–75 years and mean age of 48.6 years. Fifty-seven percent of OSCC patients were aged ≤45 years. Out of the 90 OSCC patients, 63% had a malignancy of the buccal mucosa, 18% of the tongue, and 19% of the gingiva. The tumour was limited to a single site in 68% of the cases and extended to involve adjacent sites in 32% of cases. The malignancy was stage I in 14%, stage II in 31%, stage III in 47%, and stage IV in 8%. Most cases were stage III (47%). Forty-one patients had early disease (stage I and II) and 49 had advanced disease (stage III and IV). Seventy-seven percent of cases showed an exophytic growth pattern and 23% showed endophytic growth. Sixty-three patients had well-differentiated OSCC, 25 had moderately differentiated OSCC, and two had poorly differentiated OSCC; 70% of tumours were well-differentiated and 30% were moderately to poorly differentiated. Sixty percent of tumours had lymph node involvement and 40% of the cases showed nodal metastasis. Table 1 presents the clinicopathological details of the OSCC patients.
| Parameters | Category | No. of cases | % of cases |
|---|---|---|---|
| Sex | Male | 74 | 82% |
| Female | 16 | 18% | |
| Age | ≤45 years | 51 | 57% |
| >45 years | 39 | 43% | |
| Tobacco habit | No habit | 10 | 11% |
| Tobacco chewer | 55 | 61% | |
| Tobacco smoker | 9 | 10% | |
| Combination of tobacco habits | 16 | 18% | |
| Tumour location | Buccal mucosa | 57 | 63% |
| Tongue | 16 | 18% | |
| Gingiva | 17 | 19% | |
| Tumour extension | Single site | 61 | 68% |
| Multiple sites | 29 | 32% | |
| Tumour type | Exophytic | 69 | 77% |
| Endophytic | 21 | 23% | |
| Tumour size | 1 + 2 (<4 cm) | 63 | 70% |
| 3 + 4 (>4 cm) | 27 | 30% | |
| Tumour stage | I | 13 | 14% |
| II | 28 | 31% | |
| III | 42 | 47% | |
| IV | 7 | 8% | |
| Tumour stage | Early | 41 | 46% |
| Advanced | 49 | 54% | |
| Broder’s grade | Well-differentiated | 63 | 70% |
| Moderately to poorly differentiated | 27 | 30% | |
| Lymph node metastasis | Positive | 36 | 40% |
| Negative | 54 | 60% | |
Serum lipid profile in the OSCC and control groups
The mean serum lipid profile values in the OSCC and control groups are given in Table 2 . The OSCC and healthy control groups differed significantly in TC, HDL, and LDL levels, but not in TG levels. Significant decreases in serum TC, HDL, and LDL levels were observed in OSCC patients as compared to healthy controls ( P < 0.05). The mean TG value was lower in OSCC patients as compared to control subjects, but this reduction was not statistically significant ( P = 0.128).
| Group | Mean ± SD values of lipids (mg/dl) a | |||
|---|---|---|---|---|
| TC | HDL | LDL | TG | |
| OSCC ( n = 90) | 178.27 ± 29.58 | 42.81 ± 10.88 | 106.46 ± 23.07 | 128.80 ± 51.88 |
| Control ( n = 30) | 194.20 ± 16.90 | 54.30 ± 19.44 | 134.76 ± 12.84 | 145.23 ± 47.56 |
| OSCC vs. control, P -value b | 0.006 | <0.001 | <0.001 | 0.128 |
a Normal ranges: TC = 150–230 mg/dl; HDL = 35–60 mg/dl; LDL = 100–129 mg/dl; TG = 150 mg/dl.
b Statistical P -value comparison of mean serum lipid profile levels; P < 0.05 indicates statistical significance.
Serum lipid profile in the different stages of OSCC
Table 3 shows the distribution of mean serum lipid profile levels in OSCC subjects according to tumour stage. Forty-one (46%) patients had early stage OSCC and 49 (54%) had advanced stage OSCC. The intergroup evaluation of the serum lipid profile in early and advanced stage carcinoma showed no significant correlation of serum TC, LDL, HDL, or TG with the stages ( P > 0.05). There was no significant difference when all the lipid levels were compared between the early and advanced stages of OSCC.
| Group | Mean ± SD values of lipids (mg/dl) a | |||
|---|---|---|---|---|
| TC | HDL | LDL | TG | |
| Early stage OSCC ( n = 41) | 176.41 ± 34.51 | 41.87 ± 10.65 | 104.87 ± 22.58 | 129.43 ± 52.37 |
| Advanced stage OSCC ( n = 49) | 179.83 ± 25.00 | 43.59 ± 11.11 | 107.79 ± 23.61 | 128.26 ± 52.00 |
| Early vs. advanced stage OSCC, P -value b | 0.588 | 0.460 | 0.553 | 0.916 |
a Normal ranges: TC = 150–230 mg/dl; HDL = 35–60 mg/dl; LDL = 100–129 mg/dl; TG = 150 mg/dl.
b Statistical P -value comparison of mean serum lipid profile levels; P < 0.05 indicates statistical significance.
Serum lipid profile for the different grades of OSCC
The OSCC was graded histologically as well-differentiated, moderately differentiated, or poorly differentiated, depending on the degree of differentiation. A total of 63 cases had well-differentiated OSCC, 25 had moderately differentiated OSCC, and two had poorly differentiated OSCC. Table 4 shows the distribution of mean serum lipid profile levels in the total 90 OSCC subjects according to the histopathological grade. There was no statistically significant difference in the lipid profile levels between the different grades of OSCC ( P > 0.05). In the present study, serum lipid profile levels in well-differentiated, moderately differentiated, and poorly differentiated carcinoma showed no significant correlation with serum TC, LDL, HDL, or TG.
| Group | Mean ± SD values of lipids (mg/dl) a | |||
|---|---|---|---|---|
| TC | HDL | LDL | TG | |
| Well-differentiated OSCC ( n = 63) | 177.34 ± 30.01 | 41.58 ± 10.66 | 106.44 ± 23.57 | 131.12 ± 50.12 |
| Moderately to poorly differentiated OSCC ( n = 27) | 179.68 ± 29.86 | 45.88 ± 11.46 | 103.84 ± 20.91 | 128.20 ± 55.38 |
| Well vs. moderately to poorly differentiated OSCC, P -value b | 0.743 | 0.099 | 0.631 | 0.811 |
a Normal ranges: TC = 150–230 mg/dl; HDL = 35–60 mg/dl; LDL = 100–129 mg/dl; TG = 150 mg/dl.
b Statistical P -value comparison of mean serum lipid profile levels; P < 0.05 indicates statistical significance.
Serum lipid profile in lymph node metastasis and non-metastasis cases
For the OSCC cases included in this study, cervical lymph node metastasis was noted in 36 cases (40%); 54 cases (60%) were without metastasis. Table 5 shows the distribution of mean serum lipid profile levels in OSCC subjects according to lymph node status. The mean serum lipid profile levels were not significantly different in OSCC subjects with metastasis and without metastasis ( P > 0.05).
| Group | Mean ± SD values of lipids (mg/dl) a | |||
|---|---|---|---|---|
| TC | HDL | LDL | TG | |
| LN metastasis present ( n = 36) | 181.00 ± 25.72 | 43.86 ± 11.57 | 108.63 ± 24.54 | 124.91 ± 50.43 |
| LN metastasis absent ( n = 54) | 176.46 ± 32.01 | 42.11 ± 10.44 | 105.01 ± 22.14 | 131.38 ± 53.13 |
| Present vs. absent, P -value b | 0.479 | 0.458 | 0.469 | 0.565 |
a Normal ranges: TC = 150–230 mg/dl; HDL = 35–60 mg/dl; LDL = 100–129 mg/dl; TG = 150 mg/dl.
b Statistical P -value comparison of mean serum lipid profile levels; P < 0.05 indicates statistical significance.
Serum lipid profile in tobacco users and non-tobacco users
Table 6 shows the distribution of mean serum lipid profile levels in the 90 OSCC subjects according to their tobacco use status: TU and NTU. Eighty subjects were TU and 10 were NTU. OSCC patients consuming tobacco showed lower mean TC, LDL, and TG values than the patients who were NTU. Among OSCC patients, statistically significant decreases in serum TC, LDL, and TG levels ( P < 0.05) were observed in TU as compared to NTU.
| Group | Mean ± SD values of lipids (mg/dl) a | |||
|---|---|---|---|---|
| TC | HDL | LDL | TG | |
| Tobacco users ( n = 80) | 175.11 ± 27.81 | 43.38 ± 10.98 | 104.50 ± 23.16 | 123.75 ± 50.55 |
| Non-tobacco users ( n = 10) | 203.60 ± 32.66 | 38.30 ± 9.37 | 122.20 ± 15.62 | 169.20 ± 46.34 |
| Tobacco users vs. non-tobacco users, P -value b | 0.004 | 0.166 | 0.021 | 0.008 |
a Normal ranges: TC = 150–230 mg/dl; HDL = 35–60 mg/dl; LDL = 100–129 mg/dl; TG = 150 mg/dl.
b Statistical P -value comparison of mean serum lipid profile levels; P < 0.05 indicates statistical significance.
Among the OSCC patients, 10 (11%) were without a tobacco habit, 9 (10%) were tobacco smokers, 55 (61%) were tobacco chewers, and 16 (18%) had a combination of tobacco habits. Serum TC and TG levels differed significantly among patients without a habit, tobacco smokers, tobacco chewers, and patients with a combination of habits ( P < 0.05) in the intergroup evaluation of serum lipid profile levels among OSCC patients ( Table 7 ). TC levels differed significantly between those with no habit and smokers ( P = 0.001), between those with no habit and a combination of habits ( P = 0.022), and between tobacco chewers and smokers ( P = 0.030). TG levels differed significantly between patients with no habit and smokers ( P = 0.003).
| Parameters | Sum of squares | df | Mean square | F | Sig. | |
|---|---|---|---|---|---|---|
| TC | Between groups | 13,472.118 | 3 | 4490.706 | 5.992 | 0.001 |
| Within groups | 64,451.937 | 86 | 749.441 | |||
| Total | 77,924.056 | 89 | ||||
| HDL | Between groups | 457.971 | 3 | 152.657 | 1.302 | 0.279 |
| Within groups | 10,085.818 | 86 | 117.277 | |||
| Total | 10,543.789 | 89 | ||||
| LDL | Between groups | 3717.295 | 3 | 1239.098 | 2.441 | 0.070 |
| Within groups | 43,653.105 | 86 | 507.594 | |||
| Total | 47,370.400 | 89 | ||||
| TG | Between groups | 32,132.873 | 3 | 10,710.958 | 4.440 | 0.006 |
| Within groups | 207,445.527 | 86 | 2412.157 | |||
| Total | 239,578.400 | 89 | ||||
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