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Otolaryngeal system (ENT)

Nasopharyngeal carcinoma (NPC)

Nasopharyngeal carcinoma (NPC), previously known as lymphoepithelioma, is a malignancy arising from the epithelium of the nasopharynx.


Epidemiology

Approximately one third of nasopharyngeal carcinomas of the undifferentiated type are diagnosed in adolescents or young adults. Although rare, NPC accounts for one third of childhood nasopharyngeal neoplasms (data from USA)


Classification

Classification of tumors according to the 8th edition of the AJCC staging manual
Classification of NPC according to the 8th edition of the AJCC staging manual | Manasan, C. V., Atun, J. M., & Jr, J. C. (2019). Immunohistochemical Expression of WT1 in Nasopharyngeal Carcinoma Among Filipino Patients in a Tertiary Hospital. PJP, 4(1), Article 1. https://philippinejournalofpathology.org/index.php/PJP/article/view/127

Etiopathogenesis

NPC results from an interplay of environmental factors, genetic structure, and EBV infection is involved in the etiology of the disease.

Environmental factors:

  • Smoking
  • Nitrosamines containing food agents

Genetic susceptibility:

NPC is endemic to China, the malignancy shows a variable rate of occurrence ranging from high incidence in the Southern part of China to a low rate in the White population and Northern China with the incidence ranging from 15 to 50 per 100000.

EBV associated malignancy:

EBV latently infects NPC cells and sporadically enters into viral productive lytic infection. Type II latency is maintained, and thus, EBV gene expression is restricted to EBNA1, LMP1, LMP2, EBERs, and BART-encoded miRNAs. Of these genes, LMP1 is a primary oncoprotein encoded by EBV and, therefore, has been enthusiastically studied by many researchers
The role of EBV-encoded RNAs and proteins in the development of NPC
The role of EBV-encoded RNAs and proteins in the development of NPC | Nakanishi, Y., Wakisaka, N., Kondo, S. et al. Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma. Cancer Metastasis Rev 36, 435–447 (2017). https://doi.org/10.1007/s10555-017-9693-x

Presentation

NPC usually originates in the lateral wall of the nasopharynx, which includes the fossa of Rosenmuller. It can then extend within or out of the nasopharynx to the other lateral wall and/or posterosuperiorly to the base of the skull or the palate, nasal cavity or oropharynx. It then typically metastases to cervical lymph nodes. Distant metastases may occur in bone, lung, mediastinum and, more rarely, the liver.

Painless cervical lymphadenopathy (M/C feature, 60-90%)

Cervical lymphadenopathy is the initial presentation in many patients, and the diagnosis of NPC is often made by lymph node biopsy.

Symptoms related to the primary tumor:

Symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis of the soft palate, hearing loss and cranial nerve palsies. Larger growths may produce nasal obstruction or bleeding and a “nasal twang”.
  • Nasal symptoms: A subset of patients present with nasal symptoms ranging from nasal obstruction, blood-tinged nasal discharge, and post-nasal drip to denasalization of voice (rhinolalia clausa) and cacosmia. Symptomatology is proportionate to the size of growth and the extent of local involvement. Around 80% of the individuals suffering from the disease present with nasal symptoms
  • Otological symptoms: Patients present with symptoms secondary to eustachian tube blockage, i.e., conductive hearing loss, effusions and fullness, and tinnitus. Half of the patients with NPC have some form of otological complaint during the disease caused because of the growing mass obstructing the outflow of the eustachian tube.
  • Neurological symptoms: Intracranial extension is prevalent among 8% to 12% of the demographic — various forms of cranial nerve involvement present with the associated symptom. The most commonly involved nerve is the abducens nerve.
  • Nodal involvement: One of the most common presenting features would be an enlarged neck node. Lymph nodes of the apex of the posterior triangle and the upper jugular are most commonly involved initially. Supraclavicular nodes are the last to be involved and are a sign of advanced disease

Trotter’s triad:

  • Conductive deafness (eustachian tube blockage)
  • Ipsilateral temporoparietal neuralgia (CN V3 involvement)
  • Palatal paralysis (CN X invovlement)

Diagnosis

Screrning for EBV infection:

Strategies for the screening of nasopharyngeal carcinoma
Strategies for the screening of nasopharyngeal carcinoma: Note. EBV-related markers are the most useful biomarkers in early screening for NPC. Samples for screening could be serum, plasma, whole blood, NP brushing, and saliva. Serological antibodies, such as VCA/IgA and EA/IgA, are the most widely used in the population-based screening. In addition, EBV DNA is a good indicator with high sensitivity and specificity. Notably, EBV-encoded microRNAs, genetic susceptibility loci, and high-risk EBV subtypes are also helpful for comprehensive screening and should be taken into consideration. | Zhu, Q.-Y., Zhao, G.-X., Li, Y., Talakatta, G., Mai, H.-Q., Le, Q.-T., Young, L. S., & Zeng, M.-S. (2021). Advances in pathogenesis and precision medicine for nasopharyngeal carcinoma. MedComm, 2(2), 175–206. https://doi.org/10.1002/mco2.32

Imaging studies:

  • Multislice computed tomography (CT) scan (head, neck and chest): Staging investigations
  • Magnetic resonance imaging (MRI) (skull base): Useful especially in locally advanced tumours
  • Positron emission tomography–computed tomography (PET–CT): Reserved for suspected occult primary tumour in nasopharynx

Ultrasound (USG) guided FNAC:

Ultrasound guided FNAC of suspected cervical lymph node metastases is recommended, if they cannot be definitively labelled as malignant on cross-sectional imaging

Tissue biopsy:

Nasopharyngeal carcinoma (NPC) comprises three histological types. All NPCs share morphological and immunohistochemical features of squamous differentiation to varying degrees.
  • Non-keratinising carcinoma (differentiated and undifferentiated subtypes): M/C
  • Keratinising carcinoma
  • Basaloid SCC

UICC/AJCC TNM staging:

This tumor is stagged according to the Union for International Cancer Control (UICC), and the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system. The 7th edition of the UICC/JNCC staging system was replaced by the 8th edition (last update) in 2016.
UICC/AJCC 8th edition staging of nasopharyngeal carcinoma
Summary of UICC/AJCC 8th edition staging of nasopharyngeal carcinoma. | Contributed by Mohammad H. Almomani, MBBS
Nasopharyngeal carcinoma staging groups according to the 8th edition of UICC/AJCC
Nasopharyngeal carcinoma staging groups according to the 8th edition of UICC/AJCC. | Contributed by Mohammad H. Almomani, MBBS

Differential diagnosois:

Benign conditions:

  • Nasopharyngeal polyposis
  • Angiofibromas

Malignant lesions:

  • Lymphomas,
  • Salivary gland tumors
  • Sinonasal carcinomas
  • Malignant mucosal melanomas

Management

The recommended treatment schedule consists of three courses of neoadjuvant chemotherapy, irradiation, and adjuvant interferon (IFN)-beta therapy.

Algorithm for the management of nasopharyngeal carcinoma
Algorithm for the management of nasopharyngeal carcinoma | Gairola M, Prabhash K, Babu G, Chaturvedi P, Kuriakose M, Birur P, Anand AK, Kaushal A, Mahajan A, Syiemlieh J, Singhal M, Ramachandra P, Goyal S, John S, Nayyar R, Patil VM, Rao V, Roshan V, Rath G K. Indian clinical practice consensus guidelines for the management of nasopharyngeal cancer. Indian J Cancer 2020;57, Suppl S1:9-11

Radiotherapy:

Radiation is the management of choice for the loco-regional lesion. Radiotherapy is effective in all cases except those for distant metastasis hence from stage I to stage IVB. NPC shows a tendency for quick spread regionally, especially as the nasopharynx is a small cavity so spread to paranasopharyngeal spaces, musculature, and nodes common. Also, progressively involving the contralateral side is not a rare occurrence. Consequently, a dose of approximately 65 Gy for primary tumor with 50 to 55 Gy is also necessary for nodal negative necks. Radiotherapy is also employed when treatment failure or recurrence occurs. It has been proven useful in both local recurrence and nodal failures. In such cases, brachytherapy is considered keeping in mind the friability of the local tissue, the general condition of the patient, and the impact on vital organs of the region
  • Intensity-modulated radiotherapy (IMRT): Newer delivery system that comes equipped with a CT taking slices of the area involved. The physician specifies the targeted area of the beam and modulates the intensity of the beam employed.
  • Brachytherapy: Targeted radiotherapy through implantation of gold grains or iridium implants, jacketed for localized radiotherapy, via a split incision of the soft palate. The technique is useful for localized tumor bulk that has not shown any intracranial extension. The technique spares any local vital organ damage.

Chemoradiotherapy:

NPC is highly sensitive to radiation and chemotherapy. In locally advanced regional disease, concomitant chemoradiotherapy is the mainstay of management. The disease responds better with induction, and concurrent therapy is significant in shrinking the tumor bulk.
  • First-line agent: Cisplatin (100 mg every third week)
  • Palliative chemotherapy (NPC with distant poly-metastasis): Cisplatin and 5-fluorouracil

Surgical management:

Surgical intervention is employed only as a salvage option. The nasopharynx is a small and deep area that is hard to access, thus making the surgical approach to it sometimes difficult and inappropriate. However, when encoutnering locally recurring disease, patients should be given the option of surgical intervention. Surgery is also one of the key modes of management for distant oligo-metastasis in conjunction with radiotherapy and radio ablation.
  • Nasopharyngectomies
  • Radical neck dissections: Indicated in extensive neck involvement and in recurring disease

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