There's an article by Kourelis K, et al. in J BUON, 2013, that states that, even when it has a worse prognosis, Oral Ca in young patients exhibits just around 8% ER. Another by Zuguchi M et al in Cancer Sci 2012 points that the presence of ER beta in Squamous H&N Ca Cells is a bad prognosis factor. Shatalova EG et al, in Cancer Prev Res (Phil) 2011, indicated that Estrogen and Cytochrome P450 1B1 contribute to both early and end stage H&N Carcinogenesis, and that by IHC, ER and CYP1B1 were elevated in HNSCC relative to normal epithelium, Estrogens had no influence in apoptosis of SCH&NCa, but Fulvestrant had an apoptosis promoting effect in Leukemia cells. For Chandanos E, Eur J Cancer 2009, Estrogens are protective against Esophageal SCCa, and Goulioumis AK et al, in Oncol Rep 2009, remarked that the presence of ER-beta could protect tumor cell from acquiring Epithelial-Mesenchimal Transition features.

I had a 40 y.o. female patient, wife of a man suffering from hemophilia and with an history of Blood products transfussions, that had a side tongue carcinoma in an early stage, that was apparently cured by surgery. She had a mild lymphocitosis, that finally was identified as a Chronic T-Cell Lymphocytic Leukemia, or monoclonal T lymphocites; HTLV-1 and 2 testing was negative, but as the region you're living may be considered has having a higher prevalence of HTLV-1 and 2 infection than Spain, it may be considered is it's worth checking for this or another cause of blunted immunity that may have had an influence in the develpment of the Oral Cancer in your patient; as a matter of curiosity, Tackacs D et al, in Oral Oncol 2011 signal a decreased Oral Ca Risk by moderate alcohol consumption in non-smoker postmenopausal women.

Srivastava VK et al, in Biochem Biophys Res Commun 2011, published that Centochroman (Ormeloxifene) , a non-steroidal anti-estrogen used for birth regulation purposes in India, had an anti-prolipherative effect in H&NSCC by modulating PI3K / mTOR pathway,and also STAT3, and they suggest testing CC as a therapy mean in this type of Cancer.

Park SJ et al, in cancer Lett 2010, signaled an additive anti-cancer effect on Oral Squamous Cell Carcinoma by Combined Cetuximab and Genistein. Egloff AM et al, in Clin Can Res 2009, published about Cross-Talk between ER and EGFR in H&N SCC.

CHU ST et al, in J Recept Signal Transduct Res 2007, reported about Tamoxifen induced Cell Death in human Oral Cancer Cells, all of this may open ways for therapy, but in this field, you easily find yourself having too many data.

Regarding Cancer epidemiological and therapy outcome data gathering, it must be considered that, as the process of data collection and analysis takes time, when you've finished having an image about the ethiology and best therapy approaches in your environment, the actual situation may have changed, and the info you collected with great effort no longer being useful.

Carcinogenesis is a process that takes some time, and when you discover the Cancer, the causes that promoted it or stimulated the malignization of the cells in the tumor you're facing may no longer be there, or be totally different, for example, COPD is a know factor for Dementia, and a factor that may be surprisingly present in high frequency both in Dementia and Cancer in never-smoker women, as old time kitchens were an environment plenty of smoke, that induces both Lung Function impairments and Cancer; when the patient comes to your office, she may have ceased using coal or other smoke producing cooking procedures from decades ago, but the harm done is still there. Do we have enough time and ways precise enough for obtaining a selective history on disease promoting events or environmental causes not present wehn the patient comes in? Who knows? Salud †

Some studies showed 2nd hand smoking has more damaging effect. Mu hunch is the more woen suffer from 2nd hand smoking in developing countries. Also, women tend to have better tolerance than men which may postpone their visit to doctors.

I think the fact is common among the ladies who chew battle nuts. So the crude tobacco prepn. may be the offending factor.

.

Betel nuts or tocacco chewing maybe a cause but hard to explain since both genders do them in places have with such tradition. Then, we can not explain the phenomenon where betel nuts chewing is not a common practice.

Yes Ru-Jeng. In Jordan we don't have the habit of betel nut. Most smoking ladies practice narghile smoking and less number smoke cigarettes. Oral cancer victims of female gender are noticed to be non-smokers. But can passive smoking increase the risk for them? or there are some genetic factors?

Hi Najla: That is what I thought about. Second-hand smoking is known to be more carcinogenic than primary smoking. I guess in your culture women may have less chance to go outside of the house than Western world that leads to more exposure to concentrated smoke inside of the house. Sure we can not rule out the contribution of genetic factors. However, other than breast cancer, ovarian cancer, and cervical cancer I can not think of any other caner that affect women more than men.

I don't have accurate statistics regarding the prevalence of oral cancer in Jordan according to gender. Last year though, I saw 4 non-smoker women and 2 smoker men with an advanced oral cancer. Diagnosis for the ladies was delayed because no one could believe that the tongue ulcer is actually cancer

So, maybe you need to take cultural issue into account. Maybe in Jordan women are just reluctant, or feel uncomfortable, to be seen by doctors.

On the contrary. All these women were seen by a number of dentists and physicians and no one was keen to do the proper examination so the delay in diagnosis was because of medical negligence not because of reluctance of patients.

Then I have no good explanation.

As far as the genetic factor is concerned, it is equal for both sex. To the best of my knowledge the peoples of Jordan drink less. But that is also equal for the both sex. What about the use of Oral Contraceptive and use of hormonal therapy?

dear najila

in our country in IRAQ the incedance in male is more than in femal and in femal there is no relation to smooking but now we investagate the relation to HPV the high risk group with cases of OSCC enen though the HPV-related OSCC presented with good prognosis

Good question Tatini. Relevant literature reports that the likely potential for oral cancer is higher in leukoplakia affecting non-smokers. As for oral cancer, I notice that ladies who get oral cancer de novo are usually non-smokers. So how can we explain that? and what other factors may be involved? Is it HPV for example?

The points raised by Ikram may be valid concerning the hormonal therapy. I have to point out though that most of these women are middle-aged or elderly. The point raised by Maha is also important. So Maha, have you found any correlation between HPV and OSCC in Iraq?

Is oral hygene practice different between genders in your country? In Taiwan betel chewing is the number one contributing factor for oral cancer and chronic abrasion is consider a risk factor. Is the diet difefernt between genders?

Generally speaking, Jordanian females may have better oral hygiene practices than males. As for the diet there are no differences. Other factors that may play a role include tobacco use habits. Although cigarettes seem to be more popular among males, I believe that there is a good number of females who smoke cigarettes although they don't like to admit that. Being a smoker woman is against tradition especially for single girls!

Do you have strong data to assume this difference in prognosis ?

I agree with Chloe that a few cases is too early to say there is a difference between genders. However, I think a discussion is good for scientists.

In non-tobacco induced cancer, the carcinogenicity is mediated either by Virus (HPV, and most often Oropharynx) or may be the mutation was inherited. If it is inherited, the mean age would be much less. In either case, the prognosis would be poor when compared to a tobacco induced cancer. Probably gender creeps in because, males use tobacco more commonly than females and this is a world wide phenomenon.

In absence of a known carcingenic exposure, the prognosis of a OSCC is often very poor. Delay in reporting/diagnosis may add to this. In my opinion, hormonal influences may help to spread but not be a factor in causation of the cancer

dear najla we do study on 33 OSCC patients 84% were positive for HPV-16 and 33 healthy control with 34% HPV-16 now in our center we collecting data of HPV-16/18 infection in cervix and corrleated to detection of HPV -16/18in the saliva of the HPV positive women to investgat the role of HPV

in another study on lung cancer high % of HPV-16/18-related group was reported

so it is quit abvious this matter could play important role in carcinogensis

dr. Rooban mention that oropharnx OSCC most offen due to HPV this studies most of them done in USA so we need aprecised data in middle east to be sure is it in oral or oropharnx or tonsil

To answer Chloe I would say that I don't have accurate stats for oral cancer in Jordan. Unfortunately OSCC is understudied in Arabian countries as Maha explained, although we have all the risk factors involved of tobacco, alcohol, viruses, etc. The role of genetics and viruses should be investigated further as Rooban and Tatini suggested.

Dear Tatini as many studies has been done on HPV in relation to OSCC lt they find no significant relation to smoking and alcohol consumption so Ithink of non sextual rout HPV -HR infection and because of latent nature of HPV infection make it difficalt to determine the real story behind its role ,but i still think the high % of HPV detection in OSCC could be non-sextual

Hello Najla, A very interesting question,, As mentioned by others malignancies develop by an interaction of genetic and environmental factors...so in a malignancy initiated without an identifiable environmental factor(habitual exposure, infections etc) the cause has to be genetic or may be immune system aberration, in which ever case the chances of poor prognosis is greater since the tumor would have arisen without any external stimulus..which suggests the system is more prone to a produce and support cancerous cells and changes.

Of course a failure to elicit environmental factors should not be equated with their absence.

A very reasonable answer, thank you Mandana.Do you think that we can do specific genetic tests for cancer victims with unknown risk factors?

I am afraid as far as I know so far there are no such tests for oral carcinoma... may be some one else from the discussion will have specific information on this..

good question dear Najla

Thank you Keto.

Dear Najla, the topic being discussed is very interesting. As opined by many, delayed diagnosis might be the reason for poor prognosis among women, as there is negligeance in the initial period, and the cancer being diagnosed in a later stage. To support this statement I did a biopsy on oral growth of a 64 year old lady today, who thought the growth was due to teeth bite. But actually she also had lymph node metastasis, clinically making the cancer of higher stage. However in our experiece, when we compare prognosis of a similar staged cancer in men and women, non smoking women had a better prognosis than men. Many researches inferred that HPV in Oral cancer has a better prognosis, as the case in many females with oral cancer.

Thank you Vadish. Do you have any relevant study that links HPV-associated SCC with the prognosis aspect?

Good morning Najla.. We, at Nitte University, Mangalore have started a study on this aspect. The study is in preliminary stage, in the stage of diagnosis of HPV in Head-Neck Ca. Regarding prognosis, we may need more time to comment. During the process, I had gone through quite a number of studies, and my previous comments are based on them, not my own experience. Will definitely keep you updated whenever we get a conclusion... Thank you

All the best Vadish with your research. One of the contributers on this forum, Maha Al sened, is also working on a similar aspect in Iraq. It would be nice to see the results of both studies.

There is a recent interesting research from Australia (Koo et al, 2013) about this topic. The researchers point out to the increasing proportion of non-smoker non-drinker patients with oral cancer. among this population the male:female ratio is almost 1:1. They also believe that there are certain etiological and genetic differences between this group and the smoker group of oral cancer patients. This leads to a significantly worse disease-specific mortality. Although HPV is implicated, they believe that it may confer a worse prognosis in tumors of oral tongue.

I think That an oral cancer is a more logic finding in smokers than in non smokers patients, if these last develop an oral cancer this may mean that chromosomic aberrations are more important

This is a very good question, that we have debated many times in our department

Thank you Ahmad. I first thought that delayed diagnosis is the reason behind poor prognosis. I asked this question to know if there are other reasons. The article I pointed out to (Koo et al, 2013) supports genetic and other reasons that worsen the prognosis. Contrary to what I used to believe, if HPV is implicated in etiology, it worsens the prognosis! I think that researchers should focus on this type of oral cancer because its victims may increase with time.

Is it possible that another mechanism exists in the worse results of H&N cancer therapy for women than for men, it may be that women do metabolize carcinogens to a more dangerous extent and nature, specially those in tobacco, that is still the number one cause of H&N cancer, along with alcohol and malnutrition, specifically of micronutrients and Vitamins, these carciongens produce what is called 'field carcinogenesis' being in the roots of the high incidence of second primary tumors and tumors in other organs of those suffering a H&N Ca, and also women in her active sex hormone period use to have lower levels of Iron and Iron reserves, as stated by Ferritin and TIBC, and this ferropenia also worsens outcome, anemia worsens this effect. Data from the Women's Health Initiative and the Million Women Study also suggest an specifc noxious effect of female hormones on the outcome of some common cancers. Salut †

Sorry, I've just realized the place of work of the person opening the question, and no need to say, that in a Muslim Country Environment, influence of Tobacco and Alcohol on Carcinogenesis, specially in women, is different than for example, in the USA. Don't know about the rate of HPV positivity in H&N Cancers in women there, but HPV related H&N carcinomas do have a better prognosis than those lacking the virus as part of the carcinogenesis mechanisms, and as also a cultural difference in the incidence of H&N cancer HPV positivity in these places can be postulated, that HPV positivity in women's H&N Cancer there is lower than in other places, the tumors may be more aggressive, as the presence of this good outcome prognostic factor, HPV positivity, may be lower than elsewhere.

But The role of HPV infection in oral oral cancer is steel debated. A systematic review published in the oral and maxillofacial clinic of north America ( 2011) by natarajan et al. sated that alcohol and tobacco steel the principal etiologic factor and that HPV is not an important factor

Thank you Jose. I appreciate your comments and don't be sorry as in muslim countries we have women who smoke and men who drink, so the risk factors for oscc still exist. The thing is that in Jordan like many Arabic countries many women smoke cigarettes but they deny because a smoker woman is still a social taboo. A new smoking epidemic that started approximately in mid 1990's is smoking narghile (waterpipe). This smoking method is not tabooed by society so women and girls of all ages are so into it.

Dear Ahmad there is some research going in many centers to elucidate the role of HPV in oscc. Stil if there is a role, it is believed that it worsens the prognosis as Koo et al (2013) suggested.

Dear Najla, The problem in studies on HPV is the definition of oral cavity, in fact, some researcher include the posterior part ( tonsil...) in the oral cavity. Other researchers consider this posterior part as a region in the neck. As we know the role of HPV in neck cancer is well established, but when including part of the neck in the oral cavity we can state that HPV is an etiological factor of oral cancer. But if we exclude this posterior region the role of HPV seems not to be fonded on solid evidences

Dear Ahmad, do you have any references to support your suggestion?

You can read the systematic review of natarajan et al. Published in the oral and maxillofacial clinic of north America, I think it's published in March 2011

OK thanks

It's published in the dental clinic not in oral and maxillofac clinic. I apologize

in males tobacco from smoking is the main etiology and hence once surgically removed has better prognosis. But females non tobacco cancer has other endocrinal parameters responsible for the disease parameter which makes the disease worse, hence poor prognosis

Thank you Raghavendra. Do you think that certain hormones may be implicated in oscc like some other types of cancer?

Najla added a very good question. We know that the hormonal status and also HRT do have an influence in NSCLC outcomes, and it can be postulated that, H&N Ca sharing some features with Lung Cancer, an hormonal influence in H&N Ca may be worth looking at, however, Sexual Steroid Hormones levels is a highly changing data, from time to time in an individual woman, from a woman to another, and it has many connections to things such as BMI and several Nutritional variables, thus, any epidemiological data gathering about this may require many years and very large databases, I'm not aware to which extent the Women's Health Initiative and the Million Women Study addressed specifically H&N Ca in connection with the other variables recorded.

Dear Jose, I absolutely agree with you. I believe that smoking cannot be the only factor for developing H&N Ca. We seem to undermine the genetic and etioogical factors.

Danuta: thanks for your kind comment. As in most tumors, local factors influence incidence, type of tumor and outcome, beggining from lifestyle background, so, it's better that all of this is addressed in a personalized way, in a geographicaly defined region.

Dear Jose and Danuta; there are 2 points that I want to stress. The first is the location of cancer which is oral cancer or tongue cancer since it is different from H & N Ca. The second point is thetheory behind the influence of sex hormones; how can this type of hormones promote oral cancer? Is it the same mechanism as uterine, cervical, and ovarian cancer?

There's an article by Kourelis K, et al. in J BUON, 2013, that states that, even when it has a worse prognosis, Oral Ca in young patients exhibits just around 8% ER. Another by Zuguchi M et al in Cancer Sci 2012 points that the presence of ER beta in Squamous H&N Ca Cells is a bad prognosis factor. Shatalova EG et al, in Cancer Prev Res (Phil) 2011, indicated that Estrogen and Cytochrome P450 1B1 contribute to both early and end stage H&N Carcinogenesis, and that by IHC, ER and CYP1B1 were elevated in HNSCC relative to normal epithelium, Estrogens had no influence in apoptosis of SCH&NCa, but Fulvestrant had an apoptosis promoting effect in Leukemia cells. For Chandanos E, Eur J Cancer 2009, Estrogens are protective against Esophageal SCCa, and Goulioumis AK et al, in Oncol Rep 2009, remarked that the presence of ER-beta could protect tumor cell from acquiring Epithelial-Mesenchimal Transition features.

I had a 40 y.o. female patient, wife of a man suffering from hemophilia and with an history of Blood products transfussions, that had a side tongue carcinoma in an early stage, that was apparently cured by surgery. She had a mild lymphocitosis, that finally was identified as a Chronic T-Cell Lymphocytic Leukemia, or monoclonal T lymphocites; HTLV-1 and 2 testing was negative, but as the region you're living may be considered has having a higher prevalence of HTLV-1 and 2 infection than Spain, it may be considered is it's worth checking for this or another cause of blunted immunity that may have had an influence in the develpment of the Oral Cancer in your patient; as a matter of curiosity, Tackacs D et al, in Oral Oncol 2011 signal a decreased Oral Ca Risk by moderate alcohol consumption in non-smoker postmenopausal women.

Srivastava VK et al, in Biochem Biophys Res Commun 2011, published that Centochroman (Ormeloxifene) , a non-steroidal anti-estrogen used for birth regulation purposes in India, had an anti-prolipherative effect in H&NSCC by modulating PI3K / mTOR pathway,and also STAT3, and they suggest testing CC as a therapy mean in this type of Cancer.

Park SJ et al, in cancer Lett 2010, signaled an additive anti-cancer effect on Oral Squamous Cell Carcinoma by Combined Cetuximab and Genistein. Egloff AM et al, in Clin Can Res 2009, published about Cross-Talk between ER and EGFR in H&N SCC.

CHU ST et al, in J Recept Signal Transduct Res 2007, reported about Tamoxifen induced Cell Death in human Oral Cancer Cells, all of this may open ways for therapy, but in this field, you easily find yourself having too many data.

Regarding Cancer epidemiological and therapy outcome data gathering, it must be considered that, as the process of data collection and analysis takes time, when you've finished having an image about the ethiology and best therapy approaches in your environment, the actual situation may have changed, and the info you collected with great effort no longer being useful.

Carcinogenesis is a process that takes some time, and when you discover the Cancer, the causes that promoted it or stimulated the malignization of the cells in the tumor you're facing may no longer be there, or be totally different, for example, COPD is a know factor for Dementia, and a factor that may be surprisingly present in high frequency both in Dementia and Cancer in never-smoker women, as old time kitchens were an environment plenty of smoke, that induces both Lung Function impairments and Cancer; when the patient comes to your office, she may have ceased using coal or other smoke producing cooking procedures from decades ago, but the harm done is still there. Do we have enough time and ways precise enough for obtaining a selective history on disease promoting events or environmental causes not present wehn the patient comes in? Who knows? Salud †

What a great elaboration from you Jose! Thank you for all the nice and relevant literature review, it is worth to be considered a valuable lecture. I am no expert in molecular biology, so I may take some time analysing the data you provided. The examples you mentioned are so true, but in relation to tongue cancer, I just need to know why now?? why do we encounter more oral cancer in females nowadays? or should I say: is there an increasing rate of oral cancer in females?? As far as Jordan is concerned, the types of cancer that are considered a national problem among women are colon and breast cancer. For me as an oral medicine specialist, it is important for me to do something to try and establish diagnosis as early as possible, because patients unfortunately may get lost between doctors of different specialties and all this will definitely worsen prognosis.

Wish I were there... (Pink Floyd sung something alike)

Me too

ive come in late..but have a very factual and relevant observation.

i have been seeing more cases of oral sq.cell ca in young females with no tobacco usage.

there seems to be a strong suspicion of the Human Papilloma Virus being involved.

most of these cases will give history of oral sexual practices.

we need to always think of the HPV virus, esp when tobacco is not being used by the patient at all.

The good issue in this increase in oral cancer due to HPV infection, is that HPV related cancers have a better prognosis than those that do not, but any possible source of malignancy must be avoided.

This addresses specifically the actvatnig pathways in HPV O-P SCC, giving hints for therapy:

BMC Cancer. 2013 Dec 17;13(1):602. [Epub ahead of print]

PIK3CA, HRAS and PTEN in human papillomavirus positive -HPV pos- OroPharyngeal Squamous

Cell Carcinoma.

Chiosea SI, Grandis JR, Lui VW, Diergaarde B, Maxwell JH, Ferris RL, Kim SW,

Luvison A, Miller M, Nikiforova MN.

BACKGROUND: Recent genomic evidence suggests frequent phosphatidylinositide

3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive

oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene

encoding p110alpha catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss

of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate

PI3K pathway.Methods and results: PIK3CA mutations were identified by Sanger

sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including

exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2)

mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified.

HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification

by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21,

20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n

= 4], homozygous deletion [n = 3]).

CONCLUSIONS: Overall, genetic alterations that likely lead to PI3K pathway

activation were identified in 34 of 75 cases (45%) and did not correlate with

disease specific survival. These findings offer a molecular rationale for

therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal

carcinoma.

PMID: 24341335 [PubMed - as supplied by publisher]

it is a very interested information Jose i wish if you have the link to the article about PI3K pathway in patients with HPV-positive oropharyngeal carcinoma i will be grateful if you can send it to me

.

Thanks for your interest.

http://www.biomedcentral.com/1471-2407/13/602

Then with click in the full tex PDF link in the column at the right side, you get it, you know

thanks Jose for this intersting discussion

to me it not easy issue to be answered with certinity . most of the factors mentioned usally evident in both smoker and nonsmoker groups like EGFR or HPV...etc. if the age matter as we all note the worse prognosis in younger patient we may need to know more about the role of tolerase and propably cytochrome P450