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Squamous Cell Carcinoma of the Head and Neck

HNSCC

Squamous cell carcinoma comprises more than 90% of all head and neck cancers. Cigarette smoking, alcohol consumption and human papillomavirus (HPV) infection are established risk factors. A painless asymptomatic mass may be the only symptom, whereas numerous complaints may be reported depending on tumor location. The diagnosis is made by clinical and imaging studies. Surgery, chemotherapy and radiation are used based on tumor staging.

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Presentation

Making the diagnosis of SCCHN in its early stages may be difficult, as an asymptomatic course is frequently observed. However, numerous symptoms may be encountered, depending on the location of the tumor. Erythroplakia and leukoplakia, as well as painful mucosal ulcerations may be seen in tumors of the oral cavity, while otalgia, paresthesias, nerve palsies, trismus and halitosis are additional signs of SCCHN [3]. Laryngeal tumors may cause cough, dysphagia, hoarseness and other voice changes. Many patients report a painless mass in the neck [3], which should be a sufficient sign for a detailed workup. Chronic sinusitis, epistaxis, cervical lymph node enlargement and facial pain may be reported as well.

Cervical Lymphadenopathy
  • These tumors often present with cervical lymphadenopathy resulting in a fine needle aspiration (FNA) biopsy.[ncbi.nlm.nih.gov]
  • Steinkamp HJ, Cornehl M, Hosten N, Pegios W, Vogl T, et al. (1995) Cervical lymphadenopathy: ratio of long- to short-axis diameter as a predictor of malignancy. Br J Radiol 68: 266-270.[omicsonline.org]
Hoarseness
  • Symptoms include lump or sore, sore throat, hoarse of voice, difficulty in swallowing etc (NCI Factsheet, 2013). Treatment for HNSCC is predominantly based on the stage of the disease.[en.wikipedia.org]
  • Laryngeal tumors may cause cough, dysphagia, hoarseness and other voice changes. Many patients report a painless mass in the neck, which should be a sufficient sign for a detailed workup.[symptoma.com]
  • Differential diagnosis Other causes of presenting features, including persistent hoarseness, sore throat, cough, earache, neck lumps and mouth lesions.[patient.info]
  • […] on the location, the cancer can cause abnormal patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore throat, earache, pain when swallowing or difficulty swallowing, a hoarse[ghr.nlm.nih.gov]
  • Hoarseness or a change in the voice can be the first sign of cancer of the voice box.[entnet.org]
Cough
  • The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than with standard therapy were cough and dyspnea.[mdedge.com]
  • In Checkmate 141, the most common adverse reactions ( 10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.[news.bms.com]
  • Laryngeal tumors may cause cough, dysphagia, hoarseness and other voice changes. Many patients report a painless mass in the neck, which should be a sufficient sign for a detailed workup.[symptoma.com]
  • Symptoms of pneumonitis may include shortness of breath, chest pain, or new or worse cough. Intestinal problems (colitis) that can lead to tears or holes in your intestine.[keytruda.com]
  • The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than IC were cough and dyspnea.[fda.gov]
Dyspnea
  • The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than with standard therapy were cough and dyspnea.[mdedge.com]
  • In Checkmate 141, the most common adverse reactions ( 10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.[news.bms.com]
  • The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than IC were cough and dyspnea.[fda.gov]
  • In case of subglottic tumor, dyspnea and stridor are frequent clinical features. SCC arising in the trachea may cause dyspnea, wheezing or stridor, acute respiratory failure, cough, haemoptysis, and hoarseness (Barnes et al., 2005; Thompson, 2006).[atlasgeneticsoncology.org]
Stridor
  • In case of subglottic tumor, dyspnea and stridor are frequent clinical features. SCC arising in the trachea may cause dyspnea, wheezing or stridor, acute respiratory failure, cough, haemoptysis, and hoarseness (Barnes et al., 2005; Thompson, 2006).[atlasgeneticsoncology.org]
  • Stridor (requires same-day referral). Unresolved head or neck mass which persists for more than three weeks. Unilateral serosanguineous nasal discharge which persists for more than three weeks, particularly with associated symptoms.[patient.info]
Pain
  • In most cases, painful lesions on the tongue and the mucosa of the cheeks or tongue, ear pain, nerve palsies, bad breath, voice changes, nose bleeding and painful swallowing may be reported, depending on the location of the tumor.[symptoma.com]
  • Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC[ncbi.nlm.nih.gov]
  • In Checkmate 017 and 057, the most common adverse reactions ( 20%) in patients receiving OPDIVO (n 418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.[news.bms.com]
  • Common side effects of KEYTRUDA include feeling tired; pain, including pain in muscles, bones, or joints and stomach area (abdominal) pain; decreased appetite; itching; diarrhea; nausea; rash; fever; cough; shortness of breath; and constipation.[keytruda.com]
  • There was a significant improvement in some domains, such as pain and anxiety.[parjournal.net]
Thyroid Nodule
  • Only about one in 20 thyroid nodules are cancerous. In general, thyroid cancer is one of the least deadly cancers of the head and neck. The two most common types of thyroid cancer are called papillary carcinoma and follicular carcinoma.[entnet.org]
Trismus
  • Mucosal ulcerations, leukoplakia, nerve palsies, trismus, halithosis, otalgia and pain, depending on the site and location of the tumor may be encountered.[symptoma.com]
  • Later, 5 patients developed grade 3 trismus and 1 a grade 3 noninfectious sialadenitis. Relapse has a poor prognosis. High toxicity was observed when surgery, RT, and CT were combined.[karger.com]
Halitosis
  • Erythroplakia and leukoplakia, as well as painful mucosal ulcerations may be seen in tumors of the oral cavity, while otalgia, paresthesias, nerve palsies, trismus and halitosis are additional signs of SCCHN.[symptoma.com]
Angioedema
  • There was one treatment-related death (angioedema). Panitumumab monotherapy had limited activity in previously treated patients with recurrent or metastatic SCCHN. 2015 Wiley Periodicals, Inc. Head Neck 38: E1756-E1761, 2016.[ncbi.nlm.nih.gov]
Otalgia
  • Mucosal ulcerations, leukoplakia, nerve palsies, trismus, halithosis, otalgia and pain, depending on the site and location of the tumor may be encountered.[symptoma.com]
Neck Mass
  • Location of an isolated neck mass may predict the location of the primary site based on lymph drainage.[medicine.uiowa.edu]
  • In the setting of a patient presenting with a neck mass, ultrasound and ultrasound-guided final needle aspiration with cytology are invaluable. MRI is also increasingly used, although availability in many regions is limited.[radiopaedia.org]
  • Fine-needle aspiration cytology should be used in the investigation of head and neck masses. Lesions that are harder to reach may require endoscopy.[patient.info]
  • If an adult has a neck mass that does not go away, a needle biopsy and/or CT scan may be necessary to diagnose the cause.[entnet.org]
  • Signs and symptoms of oral cavity and pharynx cancer may include a neck mass; persistent red or white patches, lumps, or thickening of throat or mouth tissues; or oropharyngeal lesions that bleed easily or do not heal.[accc-iclio.org]
Epistaxis
  • Chronic sinusitis, epistaxis, cervical lymph node enlargement and facial pain may be reported as well.[symptoma.com]
  • Nasal and paranasal sinuses Patients with SCC arising in the nasal or paranasal sinuses may complain of nasal fullness, stuffiness, or obstruction, but also of epistaxis, rhinorrhea, pain, paraesthesia, swelling of the nose and cheek or of a palatal bulge[atlasgeneticsoncology.org]
Facial Pain
  • Chronic sinusitis, epistaxis, cervical lymph node enlargement and facial pain may be reported as well.[symptoma.com]
  • Facial palsy, weakness or severe facial pain or numbness. Orbital masses.[patient.info]
Paresthesia
  • Erythroplakia and leukoplakia, as well as painful mucosal ulcerations may be seen in tumors of the oral cavity, while otalgia, paresthesias, nerve palsies, trismus and halitosis are additional signs of SCCHN.[symptoma.com]
  • If nerve is involved by the tumor, it causes paresthesias of that area [24]. The tumor commonly presents on sun-exposed areas (e.g. back of the hand, scalp, lip, and superior surface of pinna) [25,26].[austinpublishinggroup.com]
Neglect
  • Munro AJ, Sebag-Montefioro D (1992) Opportunity cost – a neglected aspect of cancer treatment. Br J Cancer 65: 309–310 PubMed Google Scholar 27. Statistisches Bundesamt (2000) Gesundheitsberichterstattung des Bundes.[link.springer.com]

Workup

The first and most important step in the diagnostic workup is a meticulous and detailed physical examination with a particular emphasis on the ear, nose and throat. Anterior rhinoscopy may reveal a tumor in the nasal cavity, whereas indirect laryngoscopy and simple inspection of the sublingual space, but of the lips and other structures as well, may provide enough clues for a detailed investigation. If a clinical suspicion is made based on findings obtained during physical examination, imaging studies such as radiography, CT, or MRI are highly useful in determining the exact location of the tumor and its appropriate stage [9]. To confirm SCCHN, endoscopy followed by biopsy of the tumor is necessary in order to determine optimal therapeutic strategies [3].

Treatment

Treatment should be initiated as soon as the diagnosis is confirmed, but only when SCCHN is appropriately staged, as strategies significantly vary [9]. Surgery, chemotherapy and radiation are all used, but prior to their initiation, it is important to correct the patient's nutritional and metabolic status [9]. For early stages, the role of surgery is pivotal and many physicians recommend follow-up radiotherapy for preventive purposes, but currently there are no randomized clinical trials to support its beneficial role [9]. Thus, surgical excision of the tumor is the primary strategy in patients with stages I-II [2] [3]. In stages III-IV, the combination of surgery (often necessitating reconstructive procedures after tumor excision), chemotherapy and radiation is used [3] [9]. Platinum analogs such as cisplatin, cetuximab (epidermal growth factor receptor antagonist) or 5-fluorouracil are considered as first-line chemotherapeutic agents [9]. Tumor recurrence is not uncommon, particularly in advanced stages, which is why close follow-ups and appropriate therapeutic measures should be taken, but neither radiation nor chemotherapy have shown long-term success [3].

Prognosis

SCCHN has a poor overall prognosis, as long term-survival rates are only 50% despite all available forms of treatment [4]. The prognosis is determined based on the TNM classification of tumors at the time of diagnosis [3] [8] [9]:

  • Stage I - Tumor size of less than < 2 cm (T1) without regional lymph node metastasis (N0).
  • Stage II - Diameter between 2-4 cm (T2) with N0.
  • Stage III - Tumor size of > 4 cm (T3) or presence of one regional lymph node that is < 3 cm in diameter (N1).
  • Stage IV - T1-3 together with one of the following: involvement of multiple nodes or one between 3-6 cm in diameter (N2); invasion of specific anatomical structures that can make the tumor resectable or irresectable (T4a and 4b) and any form of regional lymph node involvement, including single node diameter > 6 cm (N0-3); or presence of distant metastases (IVA, IVB and IVC, respectively).

If the diagnosis of SCCHN is made in stage I, 5-year survival rates have shown to be as high as 90%, whereas stage IV carries a 40% 5-year survival rate [3]. Based on these findings, the importance of an early diagnosis is pivotal.

Etiology

More than 85% SCCHNs are associated with alcohol consumption and tobacco smoking [3], and it is assumed that the malignant genetic mutations are induced by carcinogenic substances and metabolic effects of these substances. Additionally, oncogenic HPVs are recognized causes of oropharyngeal SCCs [6]. Genetic mutations on chromosomes 3,5 and 8 have been observed in both HPV+ and HPV- SCCHNs [6]. Specifically, mutations various proto-oncogenes, tumor suppressor genes ant pro/antiapoptotic genes such as caspase 8, HRS, FAT1, NOTCH, p53, TRAF3 and many other have been identified [4], and their respective roles in initiation of malignant transformation and subsequent growth have been discovered [1].

Epidemiology

SCCHN is considered to be the sixth most common cancer in the world [1], with more than 600 000 new cases and 300 000 death documented every year [5]. Various reports have solidified the importance of alcohol, tobacco and HPV infection in the pathogenesis of SCCHN. Namely, 3/4 cases are associated with use of tobacco, (both cigarettes and smokeless tobacco) [10], alcohol consumption or infection by oncogenic forms of HPV, which is transmitted by sexual intercourse [6]. A strong gender predilection toward males was seen in Europe reports, as incidence rates of 36 per 100 000 males and 7 per 100 000 females were established, respectively [9]. A significant risk factor for SCCHN was determined in patients suffering from Fanconi anemia, especially at a young age [11].

Sex distribution
Age distribution

Pathophysiology

Abnormal activation of nuclear factor kappa B (NF-κB) through numerous mutations induced by HPV and carcinogens found in tobacco are hallmarks of the pathogenesis model in SCCHN [4]. Mutations of caspase 8, HRAS, FAT1, NOTCH, FADD, TP53 and CDKN2A proteins were observed, which have their respective functions at various stages of the cell cycle - tumor initiation, proliferation, differentiation and progression [4]. Tumor suppressor gene (p53) mutations and abnormal retinoblastoma (RBb)/ARF tumor suppressor pathways have also been determined [1]. The β−catenin signaling pathway, known for its role in maintaining cell polarity and their differentiation is now an important topic of research, as its role in the SCCHN is also considered as important [4].

Prevention

The focus on prevention is turned to cessation of tobacco use and overt alcohol consumption. In fact, certain studies have established that almost a quarter of patients would not develop SCCHN in the absence of tobacco and alcohol [5]. Additionally, the introduction of HPV vaccination in the general population may prove to be an important preventive strategy as well [7]. One of the most basic measures of prevention, however, is close monitoring of at-risk patients during their regular check-ups, primarily through carefully performed physical examinations and proper investigations in the setting of high clinical suspicion.

Summary

Squamous cell carcinoma of the head and neck (SCCHN) is established as the sixth common malignant disease worldwide [1], comprising tumors of the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx [2]. Approximately 90% of all head and neck tumors are squamous cell carcinomas, excluding thyroid and skin cancers [3]. Numerous mutations of tumor suppressor and pro-apoptotic genes and aberrations of transcription factors and oncogenes involved in the cell cycle have been observed in the pathogenesis model [4]. Approximately 75% of all SCCHNs are attributed to tobacco smoking, alcohol abuse and oncogenic forms of human papillomavirus (HPV) [5], and they are considered as the most important risk factors [5]. Epstein-Barr virus was determined as the underlying cause of nasopharyngeal carcinoma in more than 95% of cases. HPV-caused SCC is considered as a distinct clinical entity, primarily because of its higher frequency in younger Caucasian males and much better survival rates compared to tobacco and alcohol-related SCCHN [6]. Additionally, HPV is exclusively contracted through sexual behavior [6]. Epidemiology studies suggest that almost 600,000 new cases and more than 300,000 deaths occur each year worldwide [5]. Such high mortality rates most likely result from a low detection rate in the early stages of the diseases, due to an initially asymptomatic course [7]. Mucosal ulcerations, leukoplakia, nerve palsies, trismus, halithosis, otalgia and pain, depending on the site and location of the tumor may be encountered [3]. To establish a clinical suspicion toward head and neck malignancy, a thorough ear, nose and throat (ENT), as well as neurological exam may be sufficient, whereas imaging studies including plain radiography, computed tomography (CT) and magnetic resonance imaging (MRI) are used for confirmation [3]. Endoscopic examination of the head and neck with subsequent biopsy, however, is considered as the gold standard in diagnosing SCCHN [9]. Imaging studies and biopsy are equally important in determining the clinical stage of the tumor (according to the TNM classification) [9], as treatment principles significantly vary. Surgery, often with adjunctive radiation therapy, is recommended in milder stages of the disease [2], while various forms of combined chemotherapy and radiation are used in patients in whom the diagnosis of stage III or IV is made [9]. Despite treatment, the overall survival rate of patients with SCCHN is 50% [4]. For these reasons, preventive strategies through reduction in alcohol consumption and cessation of tobacco smoking, as well as regular screening of at-risk patients, are vital in both early detection and reduction in overall number of cases. The introduction of a HPV vaccine in regular medical practice is an effective measure against several types of HPV-induced cancer, including SCCHN [7].

Patient Information

Squamous cell carcinoma of the head and neck (SCCHN) is a group of tumors located in the oral and nasal cavity, the pharynx and the neck that share their morphological characteristics, excluding the thyroid and skin malignancies. SCCHN is considered as the sixth most common malignancy worldwide, with more than 600,000 new cases and more than 300,000 deaths every year. More than 75% of cases are associated with either alcohol consumption or tobacco (both in the form of cigarettes and smokeless tobacco), whereas a distinct form of SCCHN, oropharyngeal squamous cell carcinoma, is strongly associated with an infection by human papilloma virus (HPV). Presumably, the presence of carcinogenic substances found inside cigarettes and the effect of alcohol and HPV infection trigger numerous genetic mutations that cause impaired function of proteins involved in various stages of the cell cycle. In addition to tobacco and alcohol, a strong gender predilection toward males has been established. SCCHN has an insidious onset of symptoms, meaning that a significant amount of time may pass before patients report to the physician. In most cases, painful lesions on the tongue and the mucosa of the cheeks or tongue, ear pain, nerve palsies, bad breath, voice changes, nose bleeding and painful swallowing may be reported, depending on the location of the tumor. To make the diagnosis, the physician must conduct a thorough physical examination and support its suspicion by imaging procedures such as radiography (X-rays), computed tomography (CT scan), or magnetic resonance imaging (MRI). Once the exact site of the tumor is found, a biopsy should be performed to obtain a microscopical confirmation. According to the findings obtained by imaging studies and biopsy, this tumor is classified from stages 1 (small diameter without invasion of adjacent structures and lymph nodes) to 4 (severe dissemination into proximal lymph nodes or distant metastases) and once this classification is made, treatment may be initiated. Patients in stages 1-2 may be effectively treated by surgery with adjunctive radiation therapy, whereas advanced stages mandate the combination of surgery, chemotherapy and radiation. The overall prognosis of patients with SCCHN is poor, as long-term survival rates are only 50%. Since the prognosis is in direct relation with the stage (5-year survival rates range from 90% in stage 1 to 40% in stage 4), preventive strategies that include cessation of tobacco use and overt alcohol consumption, as well as HPV vaccination, may significantly reduce the number of cases worldwide. More importantly, physicians need to be aware of this potentially fatal form of malignancy during regular physical examinations of patients who report non-specific ear, nose or throat symptoms, since an early diagnosis yields much better patient outcomes.

References

Article

  1. Rothenberg SM, Ellisen LW. The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest. 2012;122(6):1951-1957.
  2. Marur S, Forastiere AA. Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. Mayo Clin Proc. 2016;91(3):386-396.
  3. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  4. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582.
  5. Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst. 2007;99(10):777-789.
  6. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294-4301.
  7. Ryerson AB, Peters ES, Coughlin SS, Chen VW, Gillison ML, Reichman ME, et al. Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral cavity in the US, 1998-2003. Cancer. 2008;113(10):2901-2909.
  8. Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5(5):489-500.
  9. Grégoire V, Lefebvre JL, Licitra L, Felip E; EHNS-ESMO-ESTRO Guidelines Working Group. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(5):184-186.
  10. Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncol. 2008;9(7):667-675.
  11. Kutler DI, Auerbach AD, Satagopan J, Giampietro PF, Batish SD, Huvos AG, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003;129(1):106-112.

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Last updated: 2018-06-21 16:56