Nasal cavity and nasopharynx
Nasopharyngeal carcinoma
Nonkeratinizing squamous cell carcinoma - undifferentiated

Author: Bin Xu, M.D.
Editorial Board Member Review: Kelly Magliocca, D.D.S., M.P.H.
Deputy Editor Review: Debra Zynger, M.D.

Revised: 31 July 2018, last major update May 2018

Copyright: (c) 2004-2018, PathologyOutlines.com, Inc.

PubMed Search: Nonkeratinizing nasopharyngeal carcinoma
Cite this page: Xu, B. Nonkeratinizing squamous cell carcinoma - undifferentiated. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/nasalnonkeratinizingundiff.html. Accessed August 14th, 2018.
Definition / general
  • Nasopharyngeal carcinoma originates from the nasopharyngeal mucosa showing histologic or immunophenotypic evidence of squamous differentiation
  • WHO classification of nasopharyngeal carcinoma (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017):
    • Keratinizing squamous cell carcinoma
    • Nonkeratinizing squamous cell carcinoma
      • Differentiated subtype
      • Undifferentiated subtype
    • Basaloid squamous cell carcinoma
  • Undifferentiated is the most common subtype
Essential features
  • Endemic in China, Southeast Asia and North Africa but rare in Caucasians (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017, Semin Diagn Pathol 2015;32:54)
  • Most are positive for Epstein-Barr virus (EBV) / Epstein-Barr encoded RNA (EBER)
  • Syncytial growth pattern, vesicular nuclei with prominent central nucleoli and reactive lymphoid stroma
  • Propensity to metastasize to neck lymph nodes, therefore prudent to perform EBER (for nasopharyngeal carcinoma) and p16 / HPV (for oropharyngeal squamous cell carcinoma) on a neck lymph node with nonkeratinizing squamous cell carcinoma of unknown primary
Terminology
  • Also known as lymphoepithelioma, Rigaud and Schmincke types of lymphoepithelioma and undifferentiated carcinoma (WHO type III)
  • Lymphoepithelioma is a misnomer as the tumor is purely of epithelial origin and the lymphocytes present are not neoplastic; some cases lack lymphocytes
ICD coding
ICD-O:
  • Nonkeratinizing squamous cell carcinoma: 8072 / 3
  • Keratinizing squamous cell carcinoma: 8071 / 3
  • Basaloid squamous cell carcinoma: 8083 / 3

ICD-10:
  • Malignant neoplasm of nasopharynx, unspecified: C11.9
  • Malignant neoplasm of nasal cavity: C30.0
  • Malignant neoplasm of maxillary sinus: C31.0
Epidemiology
  • Undifferentiated is the most common subtype, accounting for > 60% of nasopharyngeal carcinoma
    • It is also the most frequent pediatric subtype
  • Endemic in Chinese, Southeast Asians, North Africans (e.g. Algeria and Morocco) and natives of Arctic region (e.g. in Canada and Alaska) (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
  • Highest incidence is in Hong Kong, China with 1 in 40 men developing nasopharyngeal carcinoma before age 75
  • Uncommon in U.S. and Europe, accounting for only 0.25% of all cancers
  • Affects men more than women
  • Peak incidence in fourth to sixth decades
  • Less than 20% occur in pediatric age group
Sites
  • Most common site is nasopharyngeal recess (i.e. fossa of Rosenmüller) followed by superior posterior wall
Etiology
  • Strongly associated with Epstein-Barr virus (EBV) in endemic regions (Semin Diagn Pathol 2015;32:54, Mod Pathol 2017;30:S68)
  • Subset may be attributed to high risk human papillomavirus (HPV) in nonendemic (Neoplasma 2016;63:107) and endemic regions (Cancer 2018;124:530)
  • Other risk factors:
    • Genetic susceptibility, e.g. certain human leukocyte antigen (HLA) class I genotypes
    • High levels of nitrosamines in preserved food, e.g. salted fish
    • Cigarette smoking
    • Occupational exposure to chemical fumes, smoke, formaldehyde and wood dust
Clinical features
  • Commonly presents with painless upper cervical lymphadenopathy secondary to lymph node metastasis or obstructive symptoms related to nasopharyngeal mass, e.g. postnasal drip, nasal discharge, epistaxis, serous otitis media and tinnitus
  • Headache and symptoms of cranial nerve involvement in advanced disease with skull base involvement
Laboratory
  • Positive Epstein-Barr virus (EBV) serology
  • Elevated circulating EBV DNA or RNA, e.g. plasma or serum EBV encoded small RNA (EBERs)
Radiology description
Radiology images

Images hosted on other servers:

CT scan: wedge shaped mass

MRI: well enhanced lesion

Prognostic factors
  • Tumor stage at presentation is the most important prognostic factor (El-Naggar: WHO Classification of Head and Neck Tumours, 4th Edition, 2017)
    • 5 year disease specific survival is 98% for stage I, 95% for stage IIA - B, 86% for stage III and 73% for stage IVA - B
  • High plasma / serum Epstein-Barr virus (EBV) DNA titers are associated with advanced stage, active disease and poor outcome
    • Remission is usually associated with very low EBV titers
  • Other adverse prognostic factors include older age, male gender, large tumor volume and cranial nerve palsy
Case reports
Treatment
Gross description
  • Gross appearance is variable: smooth mucosal bulge, raised nodule with or without surface ulceration, infiltrative mass lesion or occult lesion identified only on microscopy
Microscopic (histologic) description
  • Either syncytial arrangement of cohesive cells with indistinct cell margins (Regaud pattern) or diffuse cellular infiltrate of noncohesive cells (Schmincke pattern) resembling non-Hodgkin lymphoma (growth patterns have no clinical significance)
  • Tumor cells have moderate eosinophilic to amphophilic cytoplasm, round nuclei, prominent eosinophilic nucleoli, vesicular chromatin
  • No significant keratinization
  • Apoptosis and brisk mitotic activity are invariably present
  • Usually (but not always) prominent nonneoplastic lymphoplasmacytic infiltrate accompanying the tumor
  • Necrosis is uncommon
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Bin Xu, M.D.

Undifferentiated nonkeratinizing nasopharyngeal carcinoma

AE1 / AE3+



Contributed by Songyang Yuan, M.D.

Syncytial growth with oval or round vesicular nuclei and prominent nucleoli

CK5 / 6+

EBER+

p63+



Contributed by Andrey Bychkov, M.D., Ph.D.
Missing Image

LMP1 - Undifferentiated
nonkeratinizing
nasopharyngeal carcinoma

Cytology description
  • Clusters of tumor cells with indistinct cell border, vesicular nuclei and prominent central nucleoli
  • Lymphocytes and plasma cells in the background
Cytology images

Images hosted on PathOut server:

Case of the Week #100:

Pap stain

Cell block


Contributed by Marino E. Leon, M.D.

FNA of a neck mass (Diff-Quik)

Positive stains
Negative stains
  • CK7, CK20
  • Other negative stains (may be useful to rule out mimics): CD45, S100, HMB45, MelanA, desmin, myoglobin, myogenin
  • Rarely positive for CK7
Electron microscopy images

Images hosted on other servers:

Lumen formation

Molecular / cytogenetics description
  • Detection of Epstein-Barr virus (EBV) by PCR or ISH (EBER) found in 75 - 100% of cases
Molecular / cytogenetics images

Images hosted on PathOut server:

Contributed by Andrey Bychkov, M.D., Ph.D.
Missing Image

EBER ISH - Undifferentiated
nonkeratinizing
nasopharyngeal carcinoma


Contributed by Bin Xu, M.D.

EBER+

Differential diagnosis
Board review question #1
Recent immigrant from Hong Kong presented with nasal discharge and a nasopharyngeal mass was biopsied. Which of the following statements is false?
  1. In the United States, the lesion most commonly affects Caucasians
  2. Lesion commonly shows a squamous immunophenotype, i.e. positive for high molecular weight cytokeratin and p40
  3. Lesion is most commonly associated with Epstein-Barr virus (EBV)
  4. Radiation therapy is the standard treatment modality for this lesion
Board review answer #1
A. In the United States, the lesion most commonly affects Caucasians
Board review question #2
Which of the following statements about nasopharyngeal carcinoma is false?

  1. B cell clonality may be demonstrated in the undifferentiated type of nonkeratinizing nasopharyngeal carcinoma
  2. Most common subtype of nasopharyngeal carcinoma is the undifferentiated type
  3. Nasopharyngeal carcinoma may be related to EBV or HPV
  4. Nasopharyngeal carcinoma predominantly affects patients from China and Southeast Asia
Board review answer #2
A. B cell clonality may be demonstrated in the undifferentiated type of nonkeratinizing nasopharyngeal carcinoma