NASOPHARYNX CARSINOMA

Definisi Dan Gejala Klinis

Karsinoma nasofaring adalah benjolan yang muncul di area nasofaring (dinding belakang hidung ), cenderung ganas. Tanda-tandanya adalah telinga gemrebeg, hidung buntu, kadang-kadang ingus disertai darah. timbul benjolan di leher. keadaan ini sebenarnya sudah masuk stadium lanjut.

Tidak heran karena stadium dini yang disangka penderita adalah pilek biasa, maka dibiarkan saja. Biasanya pasien mulai berobat bila sudah ada benjolan  di leher. Kondisi yang lebih berat kadang2 muncul rasa tebal di pipi, bicara pelo, tersendak bila minum, kesulitan menelan, pandangan mata dobel, sakit kepala berat, bahkan sesak nafas bila pada stadium akhir.

Karsinoma nasofaring merupakan tumor ganas daerah kepala dan leher yang banyak ditemukan di Indonesia. Hampir 60% tumor ganas kepala dan leher merupakan karsinoma nasofaring, kemudian diikuti oleh tumor hidung dan sinus paranasalis (18%), tumor ganas laring (16%), dan tumor ganas rongga mulut, tonsil, hipofaring dalam persentase rendah. Berdasarkan data laboratorium Patologi Anatomi, tumor ganas nasofaring selalu berada dalam kedudukan lima besar dari tumor ganas tubuh manusia bersama tumor ganas serviks, tumor payudara, tumor getah bening dan tumor kulit.
Di Indonesia, frekuensi penyakit ini hampir merata di setiap daerah. Di RS Dr. Cipto Mangunkusumo Jakarta ditemukan lebih dari 100 kasus setahun, RS Hasan Sadikin Bandung rata-rata 60 kasus setahun, RS Ujung Pandang ditemukan 25 kasus setahun, RS Palembang ditemukan 25 kasus setahun, 15 kasus setahun di Denpasar dan 11 kasus ditemukan di Padang dan Bukittinggi. Demikian pula angka-angka yang didapatkan di Medan, Semarang dan Surabaya menunjukkan bahwa tumor ganas ini terdapat merata di Indonesia. Dalam pengamatan dari pengunjung poliklinik tumor THT RSCM, pasien karsinoma nasofaring dari suku Cina sedikit lebih banyak dari suku lain.1 Insiden karsinoma nasofaring terjadi pada dua puncak umur, yaitu pada usia 15-25 tahun dan usia 60-69 tahun. Kejadian karsinoma lebih sering pada laki-laki (rasio 2,5-3 : 1).
Karsinoma nasofaring ini diduga berhubungan kuat dengan infeksi virus Epstein-Barr, karena pada hampir semua pasien karsinoma nasofaring ditemukan kadar titer anti virus EB yang cukup tinggi. Namun, infeksi virus Epstein-Barr ini bukan merupakan satu-satunya faktor yang mempengaruhi timbulnya karsinoma nasofaring. Faktor-faktor lain yang diduga berperan dalam timbulnya karsinoma nasofaring adalah letak geografis, rasial, jenis kelamin, genetik, pekerjaan, lingkungan, kebiasaan hidup, kebudayaan, sosial ekonomi, infeksi kuman atau parasit. Massa dalam nasofaring seringkali tenang sampai massa ini mencapai ukuran yang cukup mengganggu struktur sekitarnya.

Pada stadium dini gejala klinis sangat tidak khas, mirip dengan penyakit hidung lainnya seperti rinitis, epistaksis, polip atau sinusitis. Adanya  kemungkinan karsinoma nasofaring sebagai berikut:

1. Setiap ada benjolan di leher, terutama yang terletak di bawah prosesus mastoid dan belakang angulus mandibula, ingatlah selalu akan adanya karsinoma nasofaring.

2. Dugaan karsinoma nasofaring diperkuat bila gejala tumor di leher ditambah dengan gejala hidung atau gejala telinga atau gejala mata dan gejala kranial.

3. Dugaan karsinoma nasofaring hampir pasti, bila ada gejala lengkap

Pada stadium lanjut, di mana sudah ada penyebaran, terdapat 5 (lima) gejala klinis yang dikemukakan oleh penderita karsinoma nasofaring, yaitu :

1. Gejala hidung, biasanya penderita mulai dengan keluhan seperti pilek-pilek, keluar ingus encer, atau kental dan berbau, epistaksis kadang-kadang terjadi sewaktu mengeluar-

kan ingus atau bisa spontan, dan bila tumor cukup besar dapat mengeluh hidung tersumbat.

2. Gejala telinga, biasanya berupa berkurangnya pendengaran, tinitus atau nyeri di daerah telinga. Gejala ini disebabkan tumor meluas ke sekitar muara tuba Eustachii, sehingga terjadi penyumbatan saluran tuba dan terjadi tuli konduktif.

3. Gejala pembesaran leher, berupa pembesaran kelenjar limfe ujung prosesus mastoid dan di belakang angulus mandibula, sebagai akibat penyebaran secara limfogen dari karsinoma nasofaring.

4. Gejala mata, berupa gangguan visus atau diplopia atau oftalmoplegia. Diplopia terjadi karena saraf otak ke VI yang letaknya tepat di atas foramen lacerum menjadi korban lebih dahulu. Bila proses makin melanjut akan terkena juga n.III dan IV yang menyebabkan kelumpuhan mata atau oftalmoplegia.

5. Gejala kranial, di sini terdapat kelumpuhan saraf kranial, biasanya di dahului gejala subyektif berupa nyeri kepala dan minum keluar ke hidung.

Secara histopatologi terdapat 3 bentuk karsinoma nasofaring, yaitu karsinoma sel skuamosa, karsinoma tidak berkeratinisasi dan karsinoma tidak berdiferensiasi. Terdapat juga bentuk kombinasi diantara 3 bentuk karsinoma nasofaring tersebut. Penentuan stadium karsinoma nasofaring adalah berdasarkan sistem TNM menurut UICC (1992).

Risk factors

In areas where nasopharyngeal carcinoma is most common, researchers have identified several risk factors, including:

• Salt-cured foods. Chemicals released in steam when cooking salt-cured foods may enter the nasal cavity, increasing the risk of nasopharyngeal carcinoma. In China, nasopharyngeal carcinoma has been linked to high consumption of salted fish.
• Preserved meats. Preserved meats contain high levels of nitrates, which may increase the risk of nasopharyngeal carcinoma.
• Epstein-Barr virus. This common virus usually produces mild signs and symptoms, such as those of a cold. Sometimes it can cause infectious mononucleosis. Epstein-Barr virus is also linked to several rare cancers, including nasopharyngeal carcinoma.
• Family history. Having a family member with nasopharyngeal carcinoma increases your risk of the disease.

Nasopharyngeal carcinoma isn't as closely linked to smoking and excessive alcohol use as most other head and neck cancers are.

Gambaran Makroskopis/ Gross

Pictures and Imaging of Nasopharyngeal Squamous Cell Carcinoma.

This elderly woman presented with epistaxis.  On nasal endoscopy, a fleshy globular nasopharyngeal tumor is noted.  The tumor is friable, easily bleeding and hangs from the vault of the nasopharynx. Histologic diagnosis:  squamous cell carcinoma.

  

Right nasal endoscopy, showing the fleshy nasopharyngeal tumor in the vault of the nasopharynx. Note the right Eustachian tube orifice.

 

Gambaran Miroskopis

Immunohistochemical staining for (A) CD 80^- and (B) CD80 (+1) in undifferentiated carcinoma of the nasopharynx (×400); (C) CD 86^- in non-keratinizing squamous cell and (D) CD86 (+2) in undifferentiated carcinoma of the nasopharynx (×400).

Mikroskopis Selain Pengecatan HE

Pemeriksaan Sitologi

Karsinoma nasofaring memerlukan pemeriksaan endoskopi untuk memastikan benarkah ada tumor di dinding belakang hidung. Bila ada sebaiknya dilakukan biopsi untuk mendapatkan hasil patologi anatomi yang menentukan jenis keganasan dari tumor ini. Selanjutnya pemeriksaan ct-scan diperlukan untuk melihat perluasan tumor dan untuk menenttukan stadiumnya. Dengan mengetahui jenis tumor dan stadiunya maka kita dapat meramalkan kemungkinan hidup penderita dan menentukan jenis terapi yang sebaiknya kita berikan.

Screening and diagnosis

Screening
In the United States, routine screening for nasopharyngeal carcinoma isn't done because the disease is rare. But in areas of the world where nasopharyngeal carcinoma is much more common, for instance in southern China, doctors may offer screenings to people thought to be at high risk of the disease. Screenings may include blood tests to determine whether a person carries the Epstein-Barr virus or careful examinations of the nasopharynx using a tiny camera attached to the end of a flexible tube (endoscope).

Diagnosis
Diagnosing nasopharyngeal carcinoma usually begins with a general examination. Your doctor will ask questions about your signs and symptoms. He or she may press on your neck to feel for swelling in your lymph nodes. Because early signs and symptoms of nasopharyngeal carcinoma aren't specific to the disease, it's common to be misdiagnosed at first. It may take several months of investigating other avenues before a definitive diagnosis is made.

If nasopharyngeal carcinoma is suspected, your doctor will use an endoscope to see inside your nasopharynx and look for abnormalities. The endoscope may be inserted through your nose or through the opening in the back of your throat that leads up into your nasopharynx. Endoscopy may require local anesthesia.

Your doctor may also use the endoscope or another instrument to take a small tissue sample (biopsy) to be tested for cancer. Beyond diagnosing nasopharyngeal cancer, a biopsy also tells your doctor the type of nasopharyngeal carcinoma you have. Nasopharyngeal carcinoma is divided into three types based on the appearance of the cells when viewed under a microscope. Your doctor factors in your type of nasopharyngeal carcinoma when selecting your treatment.

Staging
Once the diagnosis is confirmed, your doctor orders other tests to determine the extent (stage) of the cancer, such as:

• Magnetic resonance imaging (MRI). MRI helps show whether the cancer has expanded to nearby soft tissues in the head and neck.
• Computerized tomography (CT). CT scans show whether the cancer has expanded into the surrounding bone.
• Bone scan. A bone scan is used to determine whether cancer has spread (metastasized) to other bones in your body.
• Chest X-ray or CT scan. X-ray or CT scan of the chest may show whether cancer has metastasized to the lungs.
• Lymph node biopsy. Doctors check the lymph nodes in your neck (cervical nodes) for signs of cancer by performing a biopsy. In some cases you may undergo surgery to remove an entire lymph node through a small incision in the skin. In other cases biopsy may be performed using a procedure called fine-needle aspiration where your doctor inserts a needle into the lymph nodes to search for cancer cells.

Once your doctor has determined the extent of your cancer, he or she assigns it a stage. The stage is used along with several other factors to determine your treatment plan and your prognosis. The stages of nasopharyngeal carcinoma include:

• Stage 0. The cancer is limited to the lining of the nasopharynx. Also called nasopharyngeal carcinoma in situ.
• Stage I. Cancer is confined to the nasopharynx.
• Stage II. Cancer may have spread beyond the nasopharynx to the nasal cavity or to the soft tissues of the throat, including the soft palate, the base of the tongue or the tonsils. Or cancer has spread to the lymph nodes on one side of the neck and may or may not have spread to the soft tissues of the throat.
• Stage III. Cancer has spread to the lymph nodes on both sides of the neck and may or may not have spread to the soft tissues of the throat. Or cancer has spread to the throat and the lymph nodes on one or both sides of the neck. Or cancer has spread to nearby bones and the lymph nodes on one or both sides of the neck.
• Stage IV. Cancer may have spread to the nerves in the face, the lower portion of the throat, the bones of the skull or the bones around the eyes. Or cancer has spread to the lymph nodes in the neck, causing them to grow larger than 6 centimeters. Or cancer has spread to other parts of the body.

Staging in various parts of the world may be done on a different scale. For instance, a staging system used in Asia includes a stage V.

Treatment

You and your doctor work together to devise a treatment plan based on several factors, such as the stage of your cancer, the type of cells involved, your treatment goals and the side effects you're willing to tolerate. Treatment for nasopharyngeal carcinoma usually begins with radiation therapy. While surgery is the mainstay of treatment for many cancers, navigating the nasopharynx with surgical tools is delicate. Nasopharyngeal carcinoma is particularly sensitive to radiation therapy, making it the first line of treatment. Surgery and chemotherapy are used in certain cases.

Radiation
Radiation therapy treats cancer with high-energy beams. Radiation therapy destroys quickly growing cells, including cancer cells, in the area where the beams are focused. During treatment you're positioned on a table and a large machine is maneuvered around you to the precise spot where it can target your cancer. You typically receive radiation treatment five days a week for six or seven weeks. You'll also receive radiation to your neck, even if there's no evidence your cancer has spread beyond your nasopharynx. This reduces the chance that your cancer will spread and the chance that your cancer will recur. Radiation therapy carries a risk of side effects, including hearing loss, dry mouth, sores in the mouth and throat, and an increased risk of tongue cancer and bone cancer. Your nasopharynx is situated among some delicate organs, such as your brain, spinal cord, thyroid gland, eyes and ears. Your radiation therapy team works to protect these organs, but that can't always be done.

Internal radiation therapy (brachytherapy) is sometimes used in recurrent nasopharyngeal carcinoma. With this treatment, radioactive seeds or wires are positioned in the tumor or very close to it.

Chemotherapy
Chemotherapy uses drugs to treat cancer. Unlike radiation therapy, which is focused on one part of your body, chemotherapy travels throughout your body. Chemotherapy works by attacking quickly growing cells, including cancer cells. Some healthy cells are also killed by chemotherapy, which can cause side effects, including fatigue, hair loss, and nausea and vomiting. Chemotherapy may be used to treat nasopharyngeal carcinoma in three ways:

• Chemotherapy at the same time as radiation therapy (concomitant therapy). Chemotherapy enhances the effectiveness of radiation therapy. Using the two treatments together may reduce the need for high doses of radiation, which reduces the side effects associated with radiation therapy. Chemotherapy also reduces the risk that your body will become resistant to radiation therapy. However, side effects of chemotherapy are added to the side effects of radiation therapy, making concomitant therapy difficult to tolerate.
• Chemotherapy after radiation therapy (adjuvant therapy). Your doctor might recommend adjuvant chemotherapy after radiation therapy alone or after concomitant therapy. Adjuvant chemotherapy is used to attack any remaining cancer cells in your body, including those that may have broken off from the original tumor and spread elsewhere. Some controversy exists as to whether adjuvant chemotherapy actually improves survival in people with nasopharyngeal carcinoma. Many people who undergo adjuvant therapy after concomitant therapy are unable to tolerate the side effects and must discontinue treatment.
• Chemotherapy before radiation therapy (neoadjuvant therapy). Neoadjuvant chemotherapy works in the same way as adjuvant chemotherapy, but it's administered before radiation therapy alone or before concomitant therapy. Some people find they experience fewer side effects if they undergo chemotherapy before the rest of their treatment. However, little research has been done on neoadjuvant chemotherapy, so it's considered experimental.

What chemotherapy drugs you receive and how often will be determined by your doctor. The side effects you're likely to experience will depend on which drugs you receive.

Surgery
Surgery is usually reserved for recurrent nasopharyngeal carcinoma. Surgery to remove cancerous lymph nodes in the neck is the most common surgery for nasopharyngeal carcinoma. Surgery to remove a tumor from the nasopharynx requires surgeons to make an incision in the roof of your mouth in order to access the area.

Terapi kanker nasofaring terutama meliputi radioterapi, operasi dan kemoterapi. Radioterapi merupakan terapi paling efektif, setiap pasien yang pada waktu diagnosis belum menunjukkan metastasis multipel harus terlebih dulu menerima radioterapi, atau radioterapi plus kemoterapi. Bila lesi relative terbatas, tanpa penyebaran ke klavikula ke bawah, metastasis ke kelenjar limfe servikal kurang dari 8cm, dapat dilakukan radioterapi radikal, bila terdapat satu metastasis jauh atau kelenjar limfe servikal lebih besar dari 8cm dapat dilakukan radioterapi paliatif. Karena umumnya kanker nasofaring adalah karsinoma sel skuamosa diferensiasi buruk atau tidak berdiferensiasi, derajat keganasan tinggi, cepat pertumbuhannya, maka sering kali lebih peka terhadap kemoterapi dibandingkan karsinoma sefaloservikal lain. Dengan kemoterapi obat tunggal angka remisi sekitar 30%, dengan kemoterapi kombinasi dapat mencapai 66%. Regimen kemoterapi kombinasi yang sering digunakan adalah PF, yaitu cisplatin ditambah fluorourasil, 21-28 hari sebagai satu kuur. Ditambah kalsium folinat untuk meningkatkan efek terapi. Operasi bukan pilihan pertama pada karsinoma nasofaring, umumnya hanya digunakan terhadap lesi yang tersisa pasca kemoterapi atau radioterapi. Masalah dalam terapi karsinoma nasofaring sekarang ini adalah: efektivitas jangka pendek baik, efektivitas jangka panjang tidak ideal.

Bagaimana meningkatkan efektivitas? Setelah terapi konvensional gagal, bagaimana terapinya? Tindakan yang dapat dilakukan adalah:

1. Kemoterapi: sebelum radioterapi, sebelum terjad ifibrosis akibat radioterapi, ketika vaskularisasi masih baik, gunakan kemoterapi, dapat mengurangi sel kanker, meningkatkan sensitivitas radioterapi. Kemoterapi pasca radioterapi dapat membasmi mikrokarsinoma yang tersisa, mengurangi metastasis jauh.

2. Kemoterapi dan radioterapi serentak: dalam proses radioterapi ditambah kemoterapi, dapat menyusutkan tumor, memperbaiki pasokan darah, meningkatkan sensitivitas radioterapi. Banyak obat kemoterapi seperti DDP, MTX, FU, MMC dll. berefek meningkatkan sensitivitas terhadap radiasi, obat tertentu seperti hidroksilurea yang berefek terhadap fase sintesis DNA sel dapat menyeragamkan fase, sehingga kebanyakan sel kanker terhambat pada fase G1 hingga meningkatkan sensitivitas terhadap radioterapi.

3. Kemoterapi dengan kateterisasi ke arteri setempat melalui arteri temporalis superfisialis dilakukan  kateterisasi retrograd menginfuskan obat kemoterapi dapat mencapai konsentrasi obat setempat yang tinggi untuk membasmi kanker. Ini sesuai terutama pada kanker lokal yang tidak remisi pasca radioterapi, atau pada rekurensi lokal menginfiltrasi parafaring dan basis kranial.

4. Terapi fotodinamik: sel kanker dapat secara khusus mengikat zat fotosensitif, mula-mula disuntikkan zat fotosensitif, 48 jam kemudian dimasukkan serat optic hingga ke tepi kanker nasofaring, disalurkan laser merah 630nm. Di bawah penyinaran laser, zat fotosensitif mengatalisis molekul oksigen (O2) menjadi oksigen tunggal yang berefek sitotoksik hingga membasmi sel kanker. Metode ini terutama sesuai bagi kanker yang tersisa di rongga nasofaring atau kasus yang sudah menginfiltrasi basis kranial. Kami dengan metode ini telah menerapi 14 kasus karsinoma nasofaring stadium lanjut, semuanya efektif. Untuk pasien yang kambuh setelah terapi konvensional, metode ini dapat menjadi pilihan utama.

5. Implantasi biji iodium-125: di bawah panduan CT atau endoskop, terhadap lesi yang tertinggal atau rekuren, ditanamkan biji iodium-125. Biji itu dapat melepaskan sinar gama jarak pendek yang menyinari secara kontinu jaringan kanker sekitarnya. Metode ini sederhana, efek sampingnya kecil.

6. Imunoterapi: dari pasien karsinoma nasofaring dikeluarkan darah tepinya, dipisahkan sel mononukleusnya, ditambahkan interleukin-2 dan diinkubasi ekstrakorporal untuk menginduksi produksi sel dendritik. Kemudian dari pasien karsinoma nasofaring dikeluarkan sel kankernya, dinonaktifkan, diinkubasikan bersama sel dendritik selama 7-10 hari, dapat dihasilkan vaksen sel dendritik anti karsinoma nasofaring. Vaksen ini lalu diinfuskan intravena atau diinjeksikan subkutis atau ke dalam kelenjar limfe metastasis. Dengan metode ini kami telah menerapi 31 kasus karsinoma nasofaring stadium lanjut, 9 kasus menunjukkan respons imun yang sangat baik

Complications

Nasopharyngeal carcinoma frequently spreads (metastasizes) beyond the nasopharynx. Most people with nasopharyngeal carcinoma have regional metastases, meaning cancer cells from the initial tumor have migrated to nearby areas, such as lymph nodes in the neck. Cancer cells that spread beyond the head and neck (distant metastases) most commonly travel to the bones and bone marrow, lungs and liver.

Nasopharyngeal carcinoma may also cause "paraneoplastic syndromes." In these rare disorders your body's immune system reacts to the presence of cancer by attacking normal cells. Paraneoplastic syndromes may cause high levels of certain white blood cells in your blood, fever, neurologic problems or joint problems. Once your cancer is treated, your doctor may prescribe medications to control your immune system.

 

Prevention

1.      No sure way exists to prevent nasopharyngeal carcinoma. However, you can take steps to reduce your risk of the disease. For instance, cut back on the amount of salt-cured foods and preserved meats that you eat, or avoid these foods altogether. Chinese people who immigrate to North America and adopt a typical American diet have a reduced risk of nasopharyngeal carcinoma. However, the risk never completely goes away, which indicates that other unknown or uncontrollable risk factors may play a role in developing nasopharyngeal carcinoma.

2.      Pencegahan yang dapat dilakukan pada kasus karsinoma nasofaring adalah dengan pemberian vaksinasi pada penduduk yang bertempat tinggal di daerah dengan resiko tinggi, migrasi penduduk dari daerah resiko tinggi ke daerah lainnya, dan penyuluhan mengenai kebiasaan hidup yang sehat. Disamping itu, pemeriksaan kadar IgA anti VCA dan IgA anti EA secara massal akan sangat bermanfaat dalam menemukan kasus karsinoma nasofaring secara dini