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BMES 5984 - Review Paper
Oral Cancer, its Treatment, and Rebuilding the Affected Area
Introduction
In this short review paper, the basic physical properties of oral cavity, oral cancer,
treatment options and reconstruction of the tissues and bones are presented. Cancer,
being one of the top causes for death in the world, needs more attention and research to
prevent the incidents and to comfort the patients. Every year the number of patients
diagnosed with cancer, especially oral cancer, increases and reaches upto half a million.
If diagnosed early, the survival rates go upto 80 to 90%. With the help of improving
technology, today the patients are treated better. The techniques not only include the
removal of the tumors but also replacing the lost and damaged tissues. Free flap
reconstruction method is a common method used to correct the defects of of the face
and neck after the tumors are surgically removed.
Oral Cavity
The oral cavity includes the lips, the buccal mucosa (inside lining of lips and cheeks), the
teeth, the gums, the tongue, the floor below the tongue, the hard palate (roof of the
mouth), and the region behind the wisdom teeth (retromolar trigone). The oral cavity
and oropharynx support breathing, talking, eating, chewing, and swallowing. Small
salivary glands throughout this area produce saliva that keeps the mouth moist and aids
food digestion (www.cancer.org).
Human oral cavity is covered by stratified squamous epithelium that makes up the soft
tissues. The areas associated with mastication such as the hard palate and the gingiva
are subject to mechanical forces and hence have a keratinized epithelium as the
epidermis of the skin. A collagenous connective tissue below the basement membrane
attaches the keratinized epithelium to the underlying tissues. Unlike the skin,
keratinized areas of the oral cavity lack a cornified surface (Wertz et al., 1993; Nicolazzo
et al., 2005).
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The buccal regions have a non-keratinized epithelium to enhance flexibility to support
speech and chewing. The cells in non-keratinized mucosa are larger and flatter and they
accumulate lipids and cytokeratins whereas they do not form bundles as in keratinized
epithelia. The tongue is covered by a special epithelium attached tightly to the tongue
muscle and is a combination of keratinized and non-keratinized epithelium. The oral
cavity is shown in Figure 1 below (Squier and Hill, 1989; Squier and Wertz, 1996).
Figure-1. Oral cavity
Oral Cancer
Cancer is in the top three causes of death in USA and risk to develop cancer depends on
a person’s lifestyle. Alcohol consumption and smoking are the main risk factors for oral
cancer. Oral cancer is diagnosed in about quarter million patients in the world each year
with a majority of males. The highest occurrence of oral cancer is in Melanesia
exceeding an average of 25 incidences per 100,000 people for males and females. The
rates for men are higher throughout the world (except southern Asia) due to higher use
of tobacco and alcohol. Also solar irradiation is a risk factor for lip cancer, especially in
Australia. Compared to other types of cancer, mortality is on average due to good
survival chance (Parkin et al., 2005). American Cancer Society estimates that
approximately 35,000 people will be diagnosed by oral cancer and about 25% will die in
2007. The common sites for oral cancers are the tongue, the lip, and the floor of the
mouth with a 28%, 23%, and 16% occurrence rates respectively.
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In human body normal cells grow, multiple (divide), and die. Until adulthood the cells
divide faster to support growth, and then the cells only divide to repair or replace
damaged and old cells. Cancer is the uncontrollable growth of abnormal cells anywhere
in the body because of a damage to cell DNA or inherited damaged DNA from parents.
Normally the damage is repaired by the body, however in cancer cells DNA is not
repaired. Hence, instead of dying, cancer cells continue to multiple and form tumors.
The cells may also travel to the other parts of the body and start growing and replacing
the normal tissue which is called metastasis. There are two types of tumors: benign and
malignant. Benign tumors do not spread and are very rarely life threatening whereas
malignant tumors may spread and cause the death of the patient if not diagnosed and
treated properly. (Blot et al., 1988; www.cancer.org).
Benign tumors include fibroma, granular cell tumor, keratoacanthoma, leiomyoma,
osteochondroma, lipoma, schwannoma, neurofibroma, papilloma, pyogenic granuloma,
rhabdomyoma, and odontogenic tumors. The usual treatment is to surgically
remove such tumors as they are unlikely to come back. Some illustrations for benign
tumors are shown in Figure-2. Malignant tumors are caused by squamous cell
carcinomas. These flat cells normally line the oral cavity, however the abnormal
squamous cells form a collection causing either in-situ or invasive squamous cell cancer.
In the in-situ case the cancer cells remain in the lining, in the latter case the cancer cells
spread into the deeper tissue of oral cavity (Bsoui et al., 2005). In Figure-2 some
illustrations for malignant tumors is shown.
Figure-2. Benign and malignant tumors of oral cavity
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Treatment of Oral Cancer
The common treatment methods include surgery, radiation, chemotherapy, and
administration of growth inhibitors (combined with radiation). The location and the
stage of cancer play an important role in selecting the treatment method. There are
couple options to remove the cancer and to restore the appearance and function of the
tissues affected (Menedenhall et al., 2005).
By primary tumor resection, the whole tumor and some of the normal tissue around it
are removed. Removing the surrounding normal tissue enhances the complete removal
of the cancer form the area. Based on the size and place of the tumor the surgery may be
completed through mouth or through an incision in the neck or by splitting the jaw
bone. The tumor might also spread to the jaw bone or to the hard palate, and it that case
part or all of the bone should be removed by surgery. If the size and place of the tumor
causes major shape and tissue destruction, the area should be treated with a
reconstructive surgery. This will be discussed in the latter section. Lip cancer is removed
by Mohs surgery that suggests removing the abnormal tissue slice by slice so that the
most of the normal tissue can be protected.
Cancer cells may be destroyed or damaged by radiation therapy by utilizing high energy
rays or particles. However this method is mainly used for small cancers, or after
removing the tumors by surgery to make sure all the cancer cells are destroyed and
removed. External beam radiation utilizes a beam of radiation outside the body. The
strength and duration of the treatment is based on the size of the tumor and usually
takes several weeks. Another method is internal radiation (brachytherapy) that radiates
the cancer cells by placing radioactive metal rods near the tumor inside the body. In this
case the patients stay in the hospital in special rooms for a few days before the rods are
removed (Calais et al., 1999).
Another option for cancer treatment is chemotherapy. The anticancer drugs are
administered to the patients orally or by shots. This method enables the drugs to reach
the tumors and cancer cells as they enter the bloodstream and are carried throughout
the body. As well as applied as a single treatment, chemotherapy may be applied in
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conjunction with the others. It may be utilized to minimize the tumors before surgery
(neoadjuvant), or may be combined with radiation to skip a surgery. The most
commonly used drugs for oral cancers are cisplatin and 5-fluorouracil and may be used
in combination with other drugs to increase the strength of the therapy. Unfortunately,
over time cancer cells become resistant to the drugs and the tumors cannot be treated
further. Also efficiency of orally administered drugs may vary among patients due to
variable absorbtion (McLeod and Evans, 1999).
Growth factors are hormone-like compounds that promote cell growth by activating
them by attaching to their specific receptors. Cancer cells contain more growth factor
receptors and are stimulated more by the body’s natural growth factors. Hence the
growth factors synthesized by the body enhance the growth of malignant cells.
Epidermal growth factor (EGF) has been linked to oral cancers. There are new drugs
developed and tested that target and block the receptors so that growth and healing of
cancer cells are prevented or reduced. So far the chemotherapy drug cetuximab has been
proven to reduce and destroy oral cancer when administered in conjunction with
radiation (Baselga et al., 2002).
All of the treatments explained above have adverse side effects to the patients and the
normal cells of the body. The surgery may cause infection, disfiguration, and even death
in some cases. The infection can be treated medically and the reconstruction surgery
may correct the shape of the wounded area. Jaw bone damage is also treated with the
latter method if the bone cannot heal by itself. Radiation therapy may have temporary
and permanent side effects. The minor ones include redness and soreness of the mouth
tissues, sunburn like discomfort in the surrounding area. The soreness of the mouth
may affect the nutrition of the patient. During this treatment, taste buds and salivary
glands maybe damaged and the sense of taste may be lost permanently with a dry mouth
syndrome. To avoid these, the strength and application area of the radiation can be
determined more precisely. Chemotherapy drugs kill or damage both malignant and
normal cells. The side effects depend on the type and amount of drugs administered and
treatment duration. Minor effects include gastro-intestinal problems, loss or
dysfunction of taste (metallic taste), and loss of hair. Blood cells are also damaged
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causing susceptibility to infection, bleeding, and fatigue. Other drugs may be used to
reduce the side effects, and most of them get better after the treatment is complete
(Comeau et al., 2001).
Tissue and Bone Reconstruction
As mentioned in the treatments section, after the larger tumors are surgically removed
or after long treatment with radiation, the bones and tissue may be damaged and
disfigured in the mouth, throat and neck. The worst complication that is encountered
with radiation therapy is osteoradionecrosis (ORN). It slowly develops in the mandible
and it decreases the quality of life and healing of the patient. The ORN of the mandible
is defined as the bone exposed to irradiation and that fails to heal over three months
even in the absence of a tumor. ORN is observed in about 10% of the patients
undergoing radiation therapy. If it is in a small area it may treated with conservative
therapy, however if there is massive necrosis of the soft and bone tissues a
reconstructive surgery might be the best and only solution (Wong et al., 1997).
The reconstructive surgery removes the healthy and transferable tissues and bones from
other parts of the body, such as abdomen, legs, or arms, to reshape and place them
instead of the disfigured or missing tissue and bones. With improved microvascular
techniques the reconstructive surgery has been enhanced over the last decade. The main
aim of the free tissue transfer is to restore the functionality and aesthetic quality of the
disfigured mandible (Infante Cossio et al., 2004). The donor tissue for free flaps is
selected based on the size of the defect, type of the tissue, bone requirement, and
deformation of the donor site. The donor tissue should contain enough bulk and
flexibility to reestablish the shape and the function. Also the condition of the donor
tissues should be analyzed prior to surgery. It is essential to assess the regional vascular
status and to consider the effects of previous surgery, body habitus, and the medical
condition of the patient.
Free flap reconstruction surgeries have fewer complications with better aesthetic and
functional results. However, although they offer a lot of improvement for the patient’s
discomfort and wellness, free flap reconstructive surgeries have a few disadvantages.
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The operation takes a long time as two teams of surgeons with special training have to
operate on the patient (one to remove free flap, one to do the reconstructive surgery).
The ablative procedure may limit the availability of recipient vessels. Another important
issue is the recurrence of tumors in the same site (Vaughan et al., 1992).
The free flaps that are generally used in reconstructive head and neck surgery include
the iliac crest-internal oblique osseomyocutaneous, rectus abdominis, latissimus dorsi,
fibular, radial forearm, and jejunal flaps. Among these various reconstructive options,
the fibular flap is proven to be the best tissue as it provides a large area for the
reconstruction of complex defects. The fibular flap offers great versatility in
reconstruction of both the soft-tissue and bone defects. Since its introduction by
Hidalgo in late 80’s, the fibular flap has become the main choice for reconstruction of
segmental mandibular defects (Okumus et al., 2005).
Fibula is a long, tubular, and strong bone that can maintain implants for dental
rehabilitation. The long length of the bone enables the doctors to reconstruct any sized
mandibular defect. Because the donor site and reconstruction sites are far away, the two
team approach is easier to perform. Also the donor site morbidity is not very common
and normally the main side effects include local sensory loss and weakness in the toes.
On the other hand, the fibular flap has very limited soft tissue to maintain a normal
shape for the mandible (Arena et al., 1989). Few pictures for fibular flap reconstruction
are shown in Figure-4.
Figure-4. Fibular flap reconstruction of mandible
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1a: ORN of left mandibular body with necrosis of the skin and intraoral mucosa, and
exposure of the osteosynthesis plate; 1b: previous panoramic radiography; 1c: fibular
osteocutaneous flap on left side with cutaneous double-paddle; 1d: post operative
panoramic radiography of the reconstruction following the segmental mandibulectomy;
1e and 1f: extra- and intraoral view of skin paddles (Infante Cossio et al., 2004).
An Example
The study by Anthony et al. (1997) is a good example of the fibular flap reconstructive
surgery. In their research, fibular free flaps were used to reconstruct lateral segmental
mandible defects. Seventeen patients (12 males, 5 females) with an average age of 54
years (with a range of 29 to 76 years) were treated over about a six year period. The size
of the defects varied from 2.5 to 9 cm with an average of 6.3 cm. Nine of the patients had
recurring cancer and sixteen of them received radiation therapy. An average
reconstruction surgery for these patients was about 4 hours long. Due to plate fracture,
malocclusion, and orocutaneous fistula, three patients died after the surgery. Five of the
patients underwent skin grafting on their donor legs. Cellulitis, transient neuropraxia,
and swelling of the leg were among donor site morbidities. Twelve patients had dental
rehabilitation and six patients had implants. Fourteen patients attained very good
functional and aesthetical results. Eleven patients can consume regular food and sixteen
patients can handle at least a soft diet. Five of the patients had a recurring tumor about
9 months after the surgery and survived for an average of 21 months. The observances
and results indicate that fibular free flap reconstructive surgery is reliable with low
morbidity rate. It also provides good ground for dental and speech rehabilitation. Even
for the patients with a limited life expectancy this surgery is recommended to improve
the quality of the life of the patients during their last days.
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Conclusions
Any type of cancer and cancer treatment is very hard for the patients (and their
relatives) to go through. With the new and improving techniques, the wearisome and
common disease of today’s world is treated in the best possible way discovered yet. The
treatment options and well established reconstruction methods help fighting this
disease and making patients more comfortable by reducing the marks of the side effects.
It was very interesting (and a bit depressing) to learn about the oral cancer, treatment
methods, and unique and extraordinary reconstruction surgery applications.
References
American Cancer Society. 2007. Cancer Facts and Figures 2007. Atlanta, GA.
Anthony, J.P.; Foster, R.D.; Kaplan, M.J.; Singer, M.I.; Pogrel M. A. 1997. Fibular free
flap reconstruction of the true lateral mandibular defect. Ann. plast. surg. 38:2137-
2146.
Arena, S.; Fritsch, M.; Hill, E.Y. 1989. Free tissue transfer in head and neck
reconstruction. Am. J. Otolaryngol. 10:110-123.
Baselga, J.; Rischin, D.; Ranson, M.; Calvert, H.; Raymond, .; Kieback, D.G.; Kaye, S.B.;
Gianni, L.; Harris, A.; Bjork, T.; Averbuch, S.D.; Feyereislova, A.; Swaisland, H.;
Rojo, F.; Albanell, J. 2002. Phase I safety, pharmacokinetic, and pharmacodynamic
trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase
inhibitor, in patients with five selected solid tumor types. J Clin. Oncol. 20:21:4292-
4302.
Blot, W.J.; McLaughlin, J.K.; Winn, D.M.; Austin, D.F.; Greenberg, R.S.; Preston-
Martin, S.; Bernstein, L.; Schoenberg, J.B.; Stemhagen, A.; Fraumeni, J.F. 1988.
Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res.
48:3282-3287.
Bsoui, S.A.; Huber, M.A.; Terezhalmy, G.T. 2005. Squamous cell carcinoma of the oral
tissues: A comprehensive review for oral healthcare providers. J. Contemp. Dent.
Pract. 4:1-16.
Calais, G.; Alfonsi, M.; Bardet, E.; Sire, C.; Germain, T.; Bergerot, P.; Tortochaux, B.R.J.;
Oudinot, P.; Bertrand, P. 1999. Randomized trial of radiation therapy versus
concomitant chemotherapy and radiation therapy for advanced-stage oropharynx
carcinoma. J. Nat. Cancer Inst. 91:24:2081-2086.
Comeau, T.B.; Epstein, J.B.; Migas, C. 2001. Taste and smell dysfunction in patients
receiving chemotherapy. Support Care Cancer. 9:575-580.
BMES 5984 9
Pinar Omur 04/17/2007
Hidalgo, D.A. 1989. Fibula free flap: a new method of mandible reconstruction. Plast.
Reconstr. Surg. 84:71-79.
Infante Cossio, P.; Garcia-Perla G.A.; Belmonte C.R.; Sicilia C.D.; Gonzalez P.J.D.;
Gutierrez P.J.L. 2004. Fibular osteoseptocutaneous free flap in the primary
reconstruction after massive radionecrosis of the mandible. Rev. Esp. Cirug. Oral y
Maxilofac. 26:3:178-186.
McLeod, H.L.; Evans, W.E. 1999. Oral cancer chemotherapy: The promise and the
pitfalls. Clin. Cancer Res. 5:2669-2671.
Menedenhall, W.M.; Riggs, C.E.; Cassisi, N.J. 2005. Treatment of head and neck
cancers. In: Cancer: Principles and Practice of Oncology. Editors: DeVita, V.T.;
Hellman, S.; Rosenberg, S.A. Philadelphia, PA. pp. 662-732.
Nicolazzo, J.A.; Reed, B.L.; Finnin, B.C. 2005. Buccal penetration enhancers-How do
they really work? J. Contr. Rel. 105:1 – 15.
Okumus, A.; Emekli, U.; Kabakas, F.; Kuvat, S.V.; Aydin, A.; Hafiz, G.; Aslanov, A.;
Kesim, S.N. 2005. Sculpturing a fibular flap: combined horizontal/vertical
osteotomy and ostectomy for reconstruction of complex craniofacial defects with one
flap. Microsurgery. 25:8:589-595.
Parkin, D.M.; Bray, F.; Ferla, J.; Pisani, P. 2005. Global cancer statistics, 2002. CA
Cancer J. Clin. 55:74–108.
Squier, C.A.; Hill, M.W. 1989. Oral mucosa. In: Oral Histology, Development,
Structure and Function. Editor: Cate, T. St Louis, MO. pp.341-385.
Squier, C.A.; Wertz, P.W. 1996. Structure and function of the oral mucosa and
implications for drug delivery. In: Oral Mucosal Drug Delivery. Editor: Rathbone,
M.J. New York, NY. pp. 1-26.
Vaughan, E.D.; Bainton, R.; Martin, I.C. 1992. Improvements in morbidity of mouth
cancer using microvascular free flap reconstructions. J. Craniomaxillofac. Surg.
20:132-134.
Wertz, P.W.; Swatzendruber, D.C.; Squier, C.A. 1993. Regional variation in the
structure and permeability of oral mucosa and skin. Adv. Drug Del. Sys., 12:1-12.
Wong, J.K.; Wood, R.E.; McLean, M. 1997. Conservative management of
osteoradionecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 84:16-21.
www.cancer.org (visited 04/2007).
*Figure-2 courtesy: (http://www.netterimages.com/image/glandular-and-epithelial-
neoplasms.htm?page=2) (visited 04/2007).
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