Abstract
Paediatric solid tumours account for about 30% of all the paediatric malignancies. They differ from adult tumours in various aspects like incidence, etiopathogenesis, biology, response rate and outcome. Immunohistochemical markers such as CD133, CD44, CD24, CD90, CD34, CD117, CD20 and ALDH 1 (aldehyde dehydrogenase-1) have been proposed to detect cancer stem cells in tumours. CD133 is a marker of tumour initiating cells in many human cancers and therefore, it may be possible to develop future therapies by targeting cancer stem cells via this marker. CD44 is a transmembrane glycoprotein also known as homing cell adhesion molecule. It is a multifunctional cell-adhesion molecule and plays an important role in cell–cell interaction, lymphocyte homing, tumour progression and metastasis. In the present study, we assessed the expression of CD133 and CD44 in paediatric solid tumours and correlated their expression with clinico-pathological parameters in paediatric solid tumours. This study was a cross-sectional observational study conducted in the department of pathology at a tertiary care centre. All the histologically diagnosed paediatric solid tumours for a period of one year and four months were retrieved from the archives. The cases were reviewed and included in the study after obtaining informed consent. Immunohistochemistry using the monoclonal antibodies for CD133 and CD44 was performed in the representative tissue sections of all the cases. Immuno-scores were assessed, and the results were compared using Pearson’s chi-square test. The present study included 50 cases of paediatric solid tumours. The majority (34%) of the patients were in the age group of less than 5 years, with male preponderance (M:F = 2.3:1). The tumours included were Wilms tumour, yolk sac tumour, rhabdomyosarcoma, lymphoma, neuroblastoma, hepatoblastoma, gastrointestinal stromal tumour (GIST), medulloblastomas, pilocytic astrocytomas, ependymomas and glioblastoma. On immunohistochemical analysis, high expression of CD133 and CD44 was found. A significant association between the expression of CD133 and various tumour groups was observed (p = 0.004). However, CD44 showed variable expression in different tumour groups. Both CD133 and CD44 identified cancer stem cell in paediatric solid tumours. A further validation is warranted to investigate their potential role in therapy and prognosis.
Keywords: Paediatric Solid Tumours, Immunohistochemistry, Stem Cell Marker, CD133, CD44
Introduction
Paediatric solid tumours account for about 30% of all the paediatric malignancies [1]. The incidence of paediatric solid tumours is 15 per 100,000 children annually. The common paediatric solid tumours include brain tumours (25%), lymphomas (10%), neuroblastoma (8%), Wilms tumour (6%) and bone tumours (5%) [2]. Paediatric solid tumours differ from adult tumours in various aspects including incidence, etiopathogenesis, biology, response rate and outcome. With recent therapeutic advances, the cure rate of approximately 75% has been achieved in these tumours.
Stem cells are a class of undifferentiated cells that are characterized by their prolonged self-renewal capacity and by their asymmetric replication. Recently, a sub population of stem cells called cancer stem cells or tumour stem cells has been identified in many tumours including breast, brain, pancreas, prostate, melanomas, liver, colon, head and neck [3, 4]. These cancer stem cells may be linked to the clinical aggressiveness and therapeutic failure [3]. Immunohistochemical markers such as CD133, CD44, CD24, CD90, CD34, CD117, CD20 and ALDH 1 (aldehyde dehydrogenase-1) have been proposed to detect cancer stem cells in tumours [5, 6]. CD133 is a cell membrane glycoprotein having a molecular weight of 120 kD which is encoded by the PROM1 gene on chromosome 4p15 which codes for a five trans membrane glycoprotein [7]. CD 44 is a transmembrane glycoprotein also called as homing cell adhesion molecule. It has been identified as a stem cell marker in breast, head and neck, pancreas and colon cancers [8, 9]. These markers specify a subpopulation of cells that have a greater proliferative capacity or are more resistant to radiotherapy and chemotherapy [6]. In the present study, expression of CD133 and CD44 was correlated with clinico-pathological parameters in paediatric solid tumours.
Materials and Methods
This was a cross-sectional observational study conducted at a tertiary care institute in New Delhi, India. The study included histologically diagnosed cases of paediatric solid tumours, below 18 years of age, between November 2017 and March 2019. The clinical data were obtained from patients’ record. Informed consent was taken from all the patients.
Immunohistochemistry
The immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue sections using standard streptavidin–biotin peroxidase complex methods. The slides prepared were stained using mouse monoclonal anti-CD44 (clone BSB-12, isotype IgG2a, Bio SB-USA, ready to use (RTU)antibodies) and rabbit polyclonal anti-CD133 (dilution 1:200, Novus, USA) as primary antibodies. Human tonsil section was used as a positive control for CD44 antibody and human kidney tissue was used as a positive control for CD133 antibody.
Immunohistochemical Evaluation
Membranous staining for both CD133 and CD44 was regarded as positive. Immunostaining scoring system for CD44 was calculated after calculating intensity score (0 = no staining, 1 = weak staining, 2 = moderate staining, 3 = strong staining) and proportion score (0 = nonreacting, 1 ≥ 0–1%, 2 = ≥ 2–10% reacting, 3 ≥ 11–33% reacting, 4 ≥ 34–66% reacting, 5 ≥ 67–100% reacting). Total score was calculated after adding intensity score (IS) and proportion score (PS) (total score = PS + IS = 0–8). Score of 3–8 was considered positive (Fig. 1). The immunostaining scoring for CD133 was done by calculating percentage of positive tumour cells and was as follows: 0 = no expression, 1 = 1–10%, 2 = 11–50%, 3 = 51–100%. Tumours with CD133 expression in over 10% of whole tumour area was considered positive (i.e. scores 2 and 3) (Fig. 2).
Fig. 1.
Immunohistochemical expression of CD44. a Strong expression of CD44 in tonsil tissue as a positive control (IHC,100X). b CD44 expression, score of 2(IS, 1 + PS, 1 = 2) in astrocytoma (IHC, 100X). c CD44 expression, score of 6 (IS, 2 + PS, 4 = 6) in ependymoma (IHC, 100X). CD44 expression, score of 8 (IS, 3 + PS, 5 = 8) in medulloblastoma (IHC, 100X)
Fig. 2.
a Wilms tumour showing blastemal and epithelial component (H&E, 100X). b Hodgkin lymphoma showing Reed-Sternberg cells in background of reactive lymphoid background (H&E, 200X). c Yolk sac tumour showing germ cells arranged in reticular pattern (H&E, 100X). d, e and f Strong positive expression of CD133 in Wilms tumour, Hodgkin lymphoma and yolk sac tumour respectively (IHC, 100X)
Statistical Analysis
Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± SD and median. Qualitative variables were correlated using chi-square test/Fisher’s exact test. A p-value of < 0.05 was considered statistically significant. The data was analysed using Statistical Package for Social Sciences (SPSS) version 21.0.
Results
There was a total of fifty cases included in the study, of which 34% (17/50) were < 5 years of age, 28%(14/50) were in the range 6–10 years, 22% (11/50) were in the range 11–15 years and 16% (8/50) were in the age group 16–18 years with a M:F ratio of 2.3:1 (Table 1).
Table 1.
Distribution of cases according to age and sex
| Sex | Total | |||
|---|---|---|---|---|
| Male | Female | |||
| Age | ≤ 5 years | 11 | 6 | 17 |
| 6–10 years | 12 | 2 | 14 | |
| 11–15 years | 6 | 5 | 11 | |
| 16–18 years | 6 | 2 | 8 | |
| Total | 35 | 15 | 50 | |
The paediatric solid tumours observed in this study were Wilms tumour, yolk sac tumour, rhabdomyosarcoma, lymphoma, neuroblastoma, hepatoblastoma, gastrointestinal stromal tumour (GIST), medulloblastomas, pilocytic astrocytomas, ependymomas and glioblastoma. Medulloblastoma and pilocytic astrocytomas were the most frequent tumours with each constituting 20% (10/50) of cases followed by Wilms tumour constituting 14% (7/50) of the cases. Eighty percent (8/10) cases of medulloblastoma were in children below 10 years of age (Fig. 3). All the 7 cases of Wilms tumour were in the age group < 5 years and presented with complaints of lump in the abdomen.
Fig. 3.
Percentage distribution of paediatric solid tumours (n = 50 cases)
Expression of CD133 in Various Histologically Diagnosed Paediatric Solid Tumours
In our study, CD133 expression was analysed in paediatric solid tumours of various age groups. Overall, 82% (41/50) cases expressed CD133 while 18% (9/50) cases were negative. A total of 94.1% (16/17) and 85.7% (12/14) cases which were in less than 5-year and 6–10-year age groups respectively showed positive expression of CD133. However, there was no significant association between the CD133 expression and various age groups (p-value 0.203) (Table 2).
Table 2.
Expression of CD133 and CD44 with age
| Age | Total | p-value | |||||
|---|---|---|---|---|---|---|---|
| ≤ 5 yrs | 6–10 yrs | 11–15 yrs | 16–18 yrs | ||||
| Expression of CD 133 | Positive | 16 | 12 | 7 | 6 | 41 | .203 |
| Negative | 1 | 2 | 4 | 2 | 9 | ||
| Expression of CD 44 (IS + PS) | Positive | 13 | 12 | 10 | 7 | 42 | .75 |
| Negative | 4 | 2 | 1 | 1 | 8 | ||
Wilms tumour 100% (7/7), yolk sac tumour 100% (3/3), rhabdomyosarcoma 100% (3/3), lymphomas 100% (5/5), neuroblastoma 100% (1/1), GIST 100% (1/1) and hepatoblastoma 100% (1/1) showed positive expression of CD133. In the central nervous system tumours, six out of ten (60%) cases of pilocytic astrocytomas were immunonegative for CD133, whereas all the four cases of glioblastoma (100%) and ten cases of medulloblastomas (100%) which are WHO grade 4 tumours expressed CD133. Ependymomas showed heterogeneous expression of CD133 (Table 3). A significant association between the expression of CD133 and various tumour groups (P-value 0.004) was observed (Fig. 4).
Table 3.
Comparison of expression of CD133 and CD44 in various tumour groups
| Tumour type Immunostains | CD44 | CD133 | ||
|---|---|---|---|---|
| Positive | Negative | Positive | Negative | |
| Wilms tumour | 5 | 2 | 7 | 0 |
| Yolk sac tumour | 2 | 1 | 3 | 0 |
| Rhabdomyosarcoma | 2 | 1 | 3 | 0 |
| Lymphoma | 5 | 0 | 5 | 0 |
| Medulloblastoma | 7 | 3 | 10 | 0 |
| Pilocytic astrocytoma | 10 | 0 | 4 | 6 |
| Ependymoma | 5 | 0 | 2 | 3 |
| Glioblastoma | 4 | 0 | 4 | 0 |
| Neuroblastoma | 1 | 0 | 1 | 0 |
| Hepatoblastoma | 1 | 0 | 1 | 0 |
| GIST | 0 | 1 | 1 | 0 |
Fig. 4.
Expression of CD133 in various paediatric solid tumour groups
Expression of CD44 in Various Histologically Diagnosed Paediatric Solid Tumours
Expression of CD44 was assessed in paediatric solid tumours of various age groups. Eighty-four percent (42/50) cases showed positive expression for CD44 while 16% (8/50) cases did not express CD44. 76.4% (13/17) cases in age group below 5 years and 85.7% (12/14) cases in age group between 6 and 10 years showed positive expression for CD44. However, there was no significant association between the various age groups (P-value 0.75) (Table 2).
Positive expression of CD44 was seen in Wilms tumour (71.4%, 5/7), yolk sac tumour (66.6%, 2/3), rhabdomyosarcoma (66.6%, 2/3), lymphomas (100%, 5/5), neuroblastoma (100%, 1/1) and hepatoblastoma (100%, 1/1). However, one case of GIST included in this study was negative (Table 3). In central nervous system tumours, all showed positive expression for CD44 irrespective of their WHO grade. However, no significant relationship could be derived between the expression of CD44 and various tumour groups. Also, no relationship was obtained between the expression of CD44 and tumour grade (p-value 0.181) (Fig. 5).
Fig. 5.
Expression of CD44 in various paediatric solid tumour groups
Discussion
Cancer stem cells (CSCs) comprise a small subset of tumour cells that show stem cell characteristics like self-renewal, the capability to develop into multiple lineages and the potential to proliferate extensively [10]. The cancer stem cell hypothesis is well known from studies in leukaemias, breast cancer, colon cancer and pancreatic cancer, where a subpopulation of tumourigenic cancer cells capable of initiating new tumour can be identified based on cell surface markers [11].
In the present study, the maximum number of cases (34%, 17/50) was seen in the age group of less than 5 years which was in concordance with Dawani et al. [12] and Jussawala et al. [13] where they also found that 47.2% and 42% of paediatric tumours were in that age group. There was male predominance in the present study. Punia RS et al. [14] in their study on 385 paediatric tumours found that 231 (60%) were male and 154 (40%) were female with a M:F ratio of 1.5:1. Kusumakumary P et al. [15] in a retrospective study on 1828 paediatric tumours also found male predominance.
Histological Diagnosis
Central nervous system tumours were the most common tumours encountered and constituted 58% of all the cases. Our findings are in agreement with Sharma N et al. [16] who in a retrospective study of three hundred and three paediatric tumours found that central nervous system tumours accounted for 25.74% of all the cases. Kline NE et al. [1] also found that the most common types of solid tumours in children were brain tumours followed by neuroblastoma, rhabdomyosarcoma, Wilms’ tumour and osteosarcoma.
Correlation of Expression of CD133 with Age
CD133 expression was found in 82% (41/50) of the cases. A total of 94.4% (16/17) and 85.7% (12/14) cases which were in less than 5-year and 6–10-year age group respectively showed positive expression of CD133. However, there was no significant association between the CD133 expression and various age groups (P-value = 0.203). This was in contrast to the study by Mehrazma M et al. [17] who studied 105 paediatric solid tumours including 32 WTs, 20 NBs, 30 Hodgkin and non-Hodgkin lymphomas, and less common tumours, including Hepatoblastomas and Yolk Sac tumours. They found CD133 expression in younger children (< 51 months) was significantly higher than children over this age (p-value = 0.025). It could be because the tumours included in the two studies differed.
Correlation of Expression of CD133 with Histological Diagnosis
Wilms Tumour
All 7 cases of Wilms tumour showed positive expression of CD133 in the present study. No direct association was found between the stage and CD133 expression. Mehrazma M et al. [17] in their study on 32 cases of Wilms tumour found a similar proportion of tumours expressing CD133 (Table 4). However, they found statistically significant correlation between the CD133 expression and the stage of WTs. The present study had a smaller number of cases, which may explain this result.
Table 4.
Comparison of CD133 and CD44 expression with previous studies
| CD133 | CD44 | |||
|---|---|---|---|---|
| Tumour type | Present study | Studies in literature | Present study | Studies in literature |
| Wilms tumour | 100% (7/7) | Mehrazma M et al. [17] — 87% (28/32) | 5/7 (71.4%) | Katarzyna T et al. [18] — 18/38 (47.37%) |
| Neuroblastoma | 100% (1/1) | Tong QS et al. [19] — 46.9% (15/32) | 1/1 (100%) | V. Combaret et al. [20] — 37/52 (71.12%) |
| Lymphoma | 100% (5/5) | Mehrazma M et al.[17] — 72% (22/30) | 5/5 (100%) | Mehrazma M et al. [17] — 21/30 (77%) |
| Rhabdomyosarcoma | 100% (3/3) | - | 1/2 (50%) | G Humphrey et al. [21] — 12/27 (44.44%) |
| Yolk sac tumour | 100% (3/3) | Suzuki S et al. [22] — 100% (5/5) | 2/1 (50%) | _ |
| GIST | 100% (1/1) | Chen J et al. [23]. — 95% | 0/1 (0%) | - |
| Gliomas | 52.9% (10/19) | Zhang M et al. [24] — 78.4% (98/125) | 19/19 (100%) not associated with tumour grades | - |
| Medulloblastoma | 100% (10/10) | - | 7/10 (70%) | - |
Rhabdomyosarcoma (RMS), Yolk Sac Tumour (YST), Neuroblastoma, Hepatoblastoma, and GIST
In the present study, two out of three cases of rhabdomyosarcoma were positive for CD133 with score of 2 and 3 while one case was negative. Walter D et al. [25] in their study on 76 embryonal RMS patients found that high expression of CD133 correlated with poor overall survival (Table 4). Ovarian yolk sac tumours (YSTs) are rare and highly malignant tumours. In the present study, all the three cases of yolk sac tumour showed positive expression of CD133 with score of 3. Suzuki S et al. [22] found positive expression of CD133 in all of the five yolk sac tumours studied. A similar observation was also seen in the present study (Table 4). One case each of hepatoblastoma and neuroblastoma included in this study was positive for CD133. Tong QS et al. [19] in their study on 32 patients of neuroblastoma found that CD133 expression was 46.9% (Table 4). They also concluded that expression of CD133 increases with stage and was associated with unfavourable histology. In our study, we could not derive the relationship of CD133 with stage and prognosis of these tumours due to limited number of cases. One case of GIST included in this study was also positive with score of 2. Chen J et al. [23] showed 95% of GIST had higher expression of CD133 (Table 4). However, they concluded that CD133 is universally overexpressed in GIST and does not represent cancer stem cell marker.
Lymphomas
All the cases of lymphoma included in the present study showed positivity for CD133. Reed-Sternberg cells in Hodgkin lymphoma showed strong positivity for CD133. Mehrazma M et al. [17] in their study found that 22 out of 30 lymphoma cases showed positive expression for CD133 (Table 4). However, they did not find any significant correlation between CD133 positivity and any tumour characteristics of lymphomas.
Central Nervous System Tumours
Of the 10 cases of pilocytic astrocytoma, 4 cases showed positive expression for CD133 with score of 2 while 6 cases did not express CD133. All the 4 glioblastoma cases were positive for CD133. Our study was in concordance with the study of Zhang M et al. [24] in which they found that expression levels of CD133 became significantly higher as the glioma grade advanced (p < 0.05) (Table 4).
All the 10 cases of medulloblastoma were positive for CD133. Medulloblastoma being a WHO grade 4 tumour is highly malignant and carries poor prognosis. Raso A et al. [26] in their study found that significantly higher expression of CD133 was found both in patients with poorer prognosis (p = 0.007) and in those with metastasis (p = 0.03) (Table 4).
In our study, there was a statistically significant relationship between the expression of CD133 and various tumour groups calculated using Pearson chi square test (p-value 0.004). However, the relationship between the gliomas and CD133 expression appears to be much more complex than just a linear relationship. Further studies are needed to verify the role of CD133 in gliomas.
Correlation of Expression of CD 44 with Age
In the present study, the proportion of the tumours expressing CD44 (84%) was similar to that of CD133, and maximum proportion of positive CD44 results (76.4%) were seen in children younger than 5 years of age. However, CD44 expression and various age groups did not show any significant correlation.
Correlation of Expression of CD 44 with Histological Diagnosis
Wilms Tumour
Five out of seven cases of Wilms tumour included in the present study expressed CD44. Of these, two cases had a CD44 score of 3, two cases each showed score of 5, while one case showed positive expression with score of 4. Katarzyna T et al. [18] found CD44 expression in 18 cases (47.37%) (Table 4). They found a significant correlation between the expression CD44 and with the histologic type of tumour (p = 0.006). CD44 expression was strong in cases of blastemal type showing diffuse anaplasia. A low number of cases precluded evaluation of this relationship in the present study.
Rhabdomyosarcoma (RMS), Yolk Sac Tumour (YST), Neuroblastoma, Hepatoblastoma, and GIST
V. Combaret et al. [20] in their study on 52 neuroblastoma cases found that CD44 was expressed by 71.12% carries prognostic significance in neuroblastoma (Table 4). They found CD44 was expressed in all 22 NBs with favourable prognoses (stages 1, 2 or 4S) as compared to 50% of advanced NB (stages 3 and 4) (P < 10−4), suggesting that the absence, rather than the over expression, of CD44 is a signal of tumour aggressiveness. We were unable to assess this in the present study as only one case of neuroblastoma was included. In a study by G Humphrey et al. [21] on 27 RMS patients, CD44 expression was observed in 44.4% of cases (Table 4), 11 out of 20 RMS cases with favourable prognosis and in one out of 7 cases with unfavourable prognosis. They concluded that expression of CD44 correlates directly with prognosis; however, larger studies are required so that multivariate analysis can be undertaken. Chen J et al. [23] who found in their study on GIST that CD44 is universally expressed in GIST and may represent a lineage rather than a cancer stem cell marker. One case of GIST in our study showed negative expression of CD44.
Lymphomas
All the five cases (5/5) of lymphoma including both Hodgkin and non-Hodgkin lymphoma showed positive expression for CD44. Both the classic Hodgkin lymphoma cases showed strong positivity for CD44 with IS + PS of 8, while 3 cases of Burkitt lymphoma showed positive expression with score of 5, 5 and 7. Our study was in concordance with Mehrazma M et al. [17] who in the analysis of the CD44 expression in lymphomas revealed that 77% (21/30) of lymphomas showed positive staining for CD44 (Table 4).
Central Nervous System Tumours
Based on the observation in the present study, no significant association was obtained between the different grades of CNS tumour and CD44 expression. Similar findings were observed by Ylagan LR et al. [27] who found that low- and high-grade gliomas showed no significant difference in staining for CD44 (p > 0.05) (Table 4). Therefore, CD44 does not seem to correlate with the grade of astrocytomas.
Seven out of ten (7/10) cases of medulloblastoma in the present study were positive for CD44 while 3/10 cases showed negative expression. Kuppner M.C.et al. [28] found that there is a differential expression of CD44 in various CNS tumours, with high expression in gliomas and low expression in meningiomas, medulloblastomas and normal brain. All the five cases of ependymomas in the present study were also positive for CD44. However, not much literature is available regarding the CD44 expression in ependymomas.
The present study adds to the literature evidence of the existence of cancer stem cells in paediatric solid tumours. Additional validation and prospective studies including large samples would be helpful to test the newer targeted therapeutics. A novel anti-CD133 mAb, CMab-43 (IgG2a, kappa), was developed which demonstrated a sensitive and specific reaction against colon cancer cells. Hence, CMab-43 could be advantageous for antibody therapy against CD133-expressing colon cancers [29]. CD133 + tumour-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma. CART133 cells may be a therapeutically tractable strategy to target CD133 + CSCs in human glioblastomas or other treatment-resistant primary cancers without causing serious adverse reactions [30]. Similarly, antibodies to CD44 are being investigated for cancer therapy in human head and neck squamous cell carcinoma and chronic lymphocytic leukaemia [31].
Conclusion
CD133 and CD44 were differentially expressed by the various paediatric solid tumours included in the study. CD133 was frequently expressed by specific histologic tumour types and associated with higher tumour grade. CD44 expression was not associated with tumour histology or tumour grade. Though both CD133 and CD44 are good stem cell markers, CD133 appears to have more clinical relevance than CD44. Further validation of these markers in a larger cohort is recommended to confirm the findings and would also aid in expanding the cancer therapeutic options available, especially for those tumours that do not respond to the current treatment.
Acknowledgements
The authors would like to thank our patient.
Code Availability
Not applicable.
Declarations
Ethics Approval
Ethical approval was taken from the institutions ethical committee.
Conflict of Interest
The authors declare no competing interests.
Footnotes
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