5. Discussion Chapter
5.9 Reflexivity
xxxiv Due approval for the study was obtained from the Research & Ethical committee of Lagos University Teaching Hospital (LUTH).
xxxv CHAPTER FIVE
(5.1) RESULTS
A total of seven thousands four hundred and eleven (7411) cancer cases were seen during the study period. Seventy five (75) of these were histologically confirmed nasopharyngeal malignancy, these constituted approximately 1.1% of the total cancer seen. The annual incidence, sex and age
distribution are shown in Figures 1and 2
There were 47 males (63%) and 28 females (37%) with a male to female ratio of 1.7:1. The age ranged from 3 to 75 years with an overall mean age of 44.1years. The females had a mean age of 44.5 years (age range 14 – 70years) while the mean age for males was 41.7 years (age range 3 – 75years).
The peak age of incidence was 40 -49 years age group (26.7%) closely followed by 50 – 59 years age group (21.3%), (figure1).
Figure 2 shows the total annual incidence of nasopharyngeal malignancy, which rose sharply from six cases in 2006 to thirteen cases in 2008. Similar incidence of thirteen cases was recorded in 2009 and then there was a sharp decrease in 2010 and 2011 to 6 and 4 cases respectively. However, this incidence rose sharply again to eleven cases in 2012.
These patterns of annual incidence were seen in both sexes (male and female) but were more pronounced in the male gender, however there is no significant association between this yearly distribution and the sex, (p = 0.412)
The commonest symptom at presentation was cervical lymphadenopathy thirty (34) patients (36.2%), (bilateral cervical lymphadenopathy were seen in four (4) of these patients), followed by nasal blockage (22.3%) and epistaxis (16.0%) while the least common presentation was cranial nerve palsy (1.1%). Other symptoms seen were hearing impairment 6.4%, proptosis 5.3%, nasal discharge 4.3%, visual impairment 4.3%, ear pain 2.1% and weight loss 2.1% as shown in figure 3
Figures 5-10 show representative photomicrographs of different histologic variants of nasopharyngeal malignancy seen in this study. The undifferentiated carcinoma (type III WHO classification) was the commonest histological type, constituting 37 (49.3%) cases. This comprised of Schmincke’s type 18 (48.6%) cases, Regaud’s type 14 (37.8%) cases and the remaining 5 (13.5%) cases having
overlapping features of the two aforementioned entities. These three variants of undifferentiated carcinoma were seen more frequently in males than females. The differentiated, non-keratinizing squamous cell carcinoma (type II WHO classification) was 18 (24%) cases, while keratinizing squamous cell carcinoma (type I WHO classification) was 7 (9.3%) cases. All the other histologic
xxxvi types were, non- Hodgkin lymphoma constituting 10 (13.3%) cases and were all B-cell lymphoma, however, three (3) of these cases were previously diagnosed as undifferentiated carcinoma but with immunostaining, the tumor cells were found to be positive to CD45 and CD20 antibodies but were negative to cytokeratin (AE1/AE 3) antibody. Well differentiated adenocarcinoma 2 (2.7%) cases and low grade mucoepidermoid carcinoma 1 (1.3%) case constituted the remaining types. (Table I and II).
Thirty five (35) cases were available for EBV LMP-1 immunohistochemical (IHC) study.
Figure 4 shows the result of the EBV studies. LMP-I IHC were positive in thirty (86%) of the samples and five (14%) of the cases were negative.
According to histological types, all the 14 cases of undifferentiated carcinoma (WHO type III), 2 cases of adenocarcinoma and 5 cases of non-Hodgkin lymphoma that were studied for EBV were all positive. Seven of eleven cases of differentiated non- keratinizing squamous cell carcinoma (WHO type II) were EBV positive and two of three cases of keratinizing squamous cell carcinoma (WHO type 1) were EBV positive. Although there was a tendency for a greater proportion of patients with non-squamous carcinoma to be EBV positive, the results were not significant (type I v type II, III and others), p = 0.067, this was probably because of smaller number of cases studied.
Figures 11 - 13 show representative photomicrographs of EBV LMP-I IHC positive cases.
xxxvii Table 2: shows sex distribution of different histologic types of nasopharyngeal cancer
KEYS
NKSCC- non-keratinizing squamous cell carcinoma KSCC- keratinizing squamous cell carcinoma NHL- non-Hodgkin lymphoma
MC- mucoepidermoid carcinoma FREQ- frequency
% - percentage
Table 3: shows sex distribution of subtypes of WHO type III nasopharyngeal carcinoma
Subtype Frequency Total Percentage
Male Female
Schmincke 11 7 18 48.6
Regaud 9 5 14 37.8
UNDIFFERENTIATED
CARCINOMA NKSCC KSCC NHL
ADENOCAR
CINOMA MC
Total
FREQ. % FREQ. % FREQ. % FREQ. % FREQ. % FREQ. % FREQ. %
Male 23 62.2 9 50 5 71.4 8 80 1 50 1 100 47 62.7
Female 14 37.8 9 50 2 28.6 2 20 1 50 0 0 28 37.3
Total 37 100 18 100 7 100 10 100 2 100 1 100 75 100
Total
% 49.3 24 9.3 13.3 2.7 1.3
100
xxxviii
Mixed 3 2 5 13.6
Total 23 14 37 100
Percentage 62.2 37.8 ---- ---
xxxix Figure 1- Bar chart comparing age and sex distribution of nasopharyngeal cancer
xl Figure 2:- Graph showing yearly distribution by sex of patients with nasopharyngeal cancer
Years
Frequency
xli Figure 3: - Bar chart showing common clinical presentation by patients with nasopharyngeal cancer
Percentage(%)
Clinical Presentation
xlii
Figure 4: - Bar chart showing the association of different histologic types of nasopharyngeal cancer with EBV
Frequency
Types of NPC
xliii Figure 5: – Photomicrograph showing well differentiated nasopharyngeal adenocarcinoma (H&E x 100); This shows well formed malignant glands infiltraing the stroma
xliv
Figure 6: - Photomicrograph of WHO type I keratinizing squamous cell carcinoma showing nests of malignant squamous cells with individual cell keratinization as well as keratin pearl (black arrows) formation (H&E X400)
xlv Figure 7: – Photomicrograph of WHO type II non-keratinizing squamous cell carcinoma (H&E x100): This shows nests of well- defined malignant epithelial cells infiltrating the stroma
xlvi Figure 8:- Photomicrograph of WHO type III undifferentiatiated carcinoma (regaud type)
H&E X400; This shows well defined aggregates of malignant epithelial cells with indistinct cell margins and surrounded by fibrous tissue and lymphocytic inflammatory cells.
xlvii Figure 9: – Photomicrograph of WHO type III undifferentiated nellsasopharyngeal carcinoma (schmincke type) H&E x400; This shows diffuse sheets of large epithelial cells with oval, round vesicular nuclei, promionent nucleoli (white arrows) admixed with lymphocytic inflammatory cells
xlviii Figure 10:- Photomicrograph of nasopharyngeal non-Hodgkin lymphoma (H&E x400); This shows monomorphic sheets of lymphocytes infiltrating the stroma and forming
lymphoepithelial lesion (white arrows)
xlix Figure 11- Photomicrograph showing EBV LMP-I positive immunohistochemistry staining in WHO type III undifferentiated carcinoma (Regaud type) at X400 magnification
l Figure 12 – Photomicrograph of WHO type II non-keratinizing squamous cell carcinoma showing positive EBV LMP-I IHC staining in tumour cells at X400 magnification
li Figure 13 - Photomicrograph showing EBV LMP-I IHC positive in tumour cells of schmincke type of WHO type III Undifferentiated carcinoma at X400 magnification
CHAPTER SIX
(6.1). DISCUSSION
Nasopharyngeal malignancy (NPC) has been reported as the commonest head and neck cancer in Nigeria24.
However, it is an uncommon cancer worldwide except for the areas of endemicity earlier mentioned2. It accounts for approximately 1.1% of the total cancer seen in this study. This figure is however slightly lower than the reports from Ibadan in the same south western area of Nigeria and
lii other parts of the country where earlier studies have been done 18, 19, 20, 21, 22, but the previous study done in Lagos only considered NPC as a component of head and neck cancer and it accounted for 16.8% of the head and neck cancer24.
Similarly, even though earlier surveys of cancer in the African continent suggested that NPC was rare among malignant tumours as documented by Gelfand in Zimbabwe, Shapiro et al among Bantu in South Africa, Edington in Ghana, Davies in Uganda6, 7, 8, 9. Follow up studies from different parts of Africa and different regions of Nigeria as well as in this study show that the disease is not as rare as earlier reported10,11, 12, 19.
The disease tends to occur more in males than in females in this study, in a ratio of 1.7:1 which is consistent with what has been reported in the literature 13 -23.
The mean age in this study is 44.1years which compares favourably with the study in Ibadan that falls within the same South Western Nigeria where the mean age was 41.1 years 19. It is also similar to findings from studies in Jos 22, 23, but, it is slightly lower than the report from Ilorin and slightly higher when compared with the report from Sokoto18, 21. However, the mean age of incidence is a decade lower than seen in patients from Northern America, Western Europe and China1. The reason for this is unknown; however, it may not be unconnected with the life expectancy in Nigeria which is lower compared to these countries 90. The peak age of incidence is in the fifth decade showing that majority of the patients (26.7%) presented at the height of their productivity between 40 – 49 years with likely far reaching implications for socioeconomic output. However, it is noted that the single peak age of incidence in this study is similar to the second peak in the previous studies from other parts of the
Country with bimodal age distribution where the first peak occurred at second or third decade of life
16, 18, 19. The peak age of incidence in this study is about a decade lower when compared to patients from endemic region such as South East Asia which also shows bimodal age distribution 41. The least age at presentation in this study is 3 years which is in contrast to what was seen in some parts of Nigeria and Southern China 18, 19, 22, 43. Report from Uganda, Kenya, Sudan, and Tunisia (intermediate risk region) showed that NPC were frequently seen at younger age group (0-19 year), but the reason for this was not known43. The obscure location of this cancer coupled with its vague, non-specific symptoms make it difficult to diagnose, thus most patients present at the advanced stage of the disease. The most common form of presentation in this study was cervical lymphadenopathy (36.2%), which unfortunately indicates advanced disease (stage III to IV), (appendix I). Other common symptoms seen were nasal blockage (22.3%), epistaxis (16.0%), hearing impairment (6.4%) and nasal
liii discharge (4.3%), these forms of clinical presentations are similar to reports in patients from different parts of Nigeria as well as in both the endemic and non-endemic areas of the world18, 19, 21, 48.
Other important but less common symptomatology seen in this study includes neuro –ophthalmic manifestations such as proptosis (5.3%), visual impairment (4.3%) and cranial nerve palsy (1.1%), which sometimes may be the sole presentation and as such misleading with resultant delay in treatment. These symptoms also signify advanced disease with poor prognosis49. Nasopharyngeal malignancy can also present early, but the symptoms are vague and non-specific, these include nasal congestion, nasal discharge, recurrent ear infection, and otalgia (ear pain) as reported in this study, other parts of Nigeria and in endemic regions18, 20, 21, 38. Thus, screening patients with these symptoms as is done in areas endemic for NPC, even though Nigeria is not an endemic area, will aid in its early detection and diagnosis and thus, curative medical intervention. Most lesions in this study were WHO type III undifferentiated carcinoma (49.3%) which is similar to findings in other centres across the country as well as in the endemic regions of the world, even though Nigeria is not a high-incidence country 18-22, 38 The undifferentiated carcinoma is also the predominant histological type seen in children and adolescent in this study which is consistent with the finding of the previous studies in Ibadan and Sokoto 19, 21, but no children or adolescent was found in the studies at Ilorin and Jos 18, 23. The undifferentiated carcinoma comprised of Schmincke type (24.0%), Regauld type (18.7), with the remaining 6.7% (mixed type) having overlapping features of these two entities. Other histological variants in the study include differentiated keratinizing squamous cell carcinoma (24%), non-Hodgkin lymphoma (13.3%), keratinizing squamous cell carcinoma (9.3%), adenocarcinoma (2.7%), and mucoepidermoid carcinoma (1.3%). These variants are also seen in the studies from other parts of the country, Kenya, Britain, Denmark and China 19, 23,37,39,40. This confirms the reports that various tissues found in the nasopharynx can give rise to malignancy 31, 32 The three patients who were above 70 years in this study have WHO type I keratinizing squamous cell carcinoma (KSCC) which is consistent with what has been reported in the literature that the KSCC variant occur more in the elderly 75, 76. It is important to note that immunohistochemistry using cytokeratin, CD45, CD20 and CD3 antibodies, as was done in this study, three (3) of the cases which were previously diagnosed as undifferentiated carcinoma (schmincke type) were confirmed and re-classified as B-cell non-Hodgkin lymphoma and this confirms reports that these antibodies are reliable markers for nasopharyngeal cancer31.
This study also confirms the association of EBV with nasopharyngeal malignancy as thirty (86%) of thirty five cases analyzed for EBV LMP-I by IHC were positive. All the fourteen cases of
liv undifferentiated carcinoma were EBV positive which is in consonance with the reports in the literature and more importantly in the endemic areas where this variant is the most common53. There were five cases of NPC where EBV was not detected, four of these cases had type II histology and the remaining one had type I histology. These five patients who were negative for EBV are probably too small to determine any statistical significance in the association of type I and type II histology with EBV as it is well reported that the type I histology is less associated with EBV 76. Although, LMP-I immunohistochemistry (IHC) was reported to be less sensitive compared to in situ hybridization in detecting EBV latency in NPC56, 76, but this study showed that majority of the cases (86%) were positive for EBV LMP-I which is in contrast to the report from Israel that showed a low incidence of LMP-I in NPC56. The reason for this may be due to the small sample size analyzed for EBV or due to increased sensitivity of the test method or due to unknown reason. However more studies are needed in Nigeria to corroborate or disprove this, as the search of the literature shows no evidence of previous EBV study done in the country. It was also noted that the five cases of non-Hodgkin lymphoma and the two cases of the adenocarcinoma analyzed were positive for EBV LMP-I, the reasons for this being that EBV is ubiquitous and latently infects both epithelial and lymphoid cells causing carcinogenic
transformation of these cells32.
lv (6.2). CONCLUSION
In conclusion, the findings in this study are; a male predominance of nasopharyngeal malignancy and that it constituted 1.1% of the total cancer seen within the study period. The peak age of incidence is 40-49 years, carcinoma is the commonest morphologic type consisting of squamous cell carcinoma (keratinizing and non-keratinizing), undifferentiated carcinoma, adenocarcinoma and mucoepidermoid carcinoma. The most common clinical presentation is cervical lymphadenopathy.
Immunohistochemistry shows EBV is strongly associated with the disease and it also confirms cytokeratin, CD45 and CD20 antibodies as reliable markers for the carcinoma and non-Hodgkin lymphoma component of nasopharyngeal malignancy.
Thus, this study of histolopathologic pattern of nasopharyngeal malignancy in LUTH and its association with EBV corroborates similar studies in other centres of the country which show that this malignancy is not a rarer disease in this part of the world as earlier reported 6-9,13.
This study confirms male predominance of NPC in concordance with what obtains in different parts of the country, Africa and globally.
Most patients in this study presented in advanced disease stage as indicated by presentation with cervical lymphadenopathy, and thus by virtue of the anatomical location of this cancer, curative surgical resection may not be achievable.
(6.3). RECOMMENDATIONS
lvi Serologic tests for EBV should be encouraged as elevated antibody titres against EBV viral capsid antigen IgA, early antigen IgG, and latent viral antigens 1 and 2 (EBNA-1, EBNA-2) were found to precede tumor development by several years and these will aid in early detection of nasopharyngeal cancer (NPC).
Thus, a nationally acceptable screening programme of EBV serologic tests combined with endoscopic guided nasopharyngeal biopsy is advised in patients presenting with early symptoms of nasopharyngeal malignancy to reduce the morbidity and mortality associated with this disease.
Going by the aforementioned, there should be more collaboration in investigations, conferences, researches, treatments, referrals and feedbacks between the histopathologist, otolaryngologist, radiologist, radiotherapist and oncologist for the common good of the patients.
There is a need for more studies on the association of EBV LMP-I by IHC in NPC in this centre and in other parts of the country to determine if the pattern of expression of this viral protein compares favourably or differently with findings in other parts of the world.
It is already stated in the literature, that in situ hybridisation to detect nuclear Epstein-Barr virus encoded RNA (EBER) is more sensitive than EBV LMP-I IHC. Further work is required in this centre in order to compare the sensitivity of these two methods.
Now that immunohistochemistry facilities are available in the centre, these should be routinely used in confirming the diagnosis of undifferentiated nasopharyngeal carcinoma, the schmincke type, which histologically and clinically mimics non-Hogkin lymphoma.
Researches should be periodically done in the centre to document and update the incidence of NPC to determine any change in pattern of incidence.
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