LYMPHOEPITHELIAL LESIONS

By Ekta Jajodia

DEFINITION

TYPES

1. Benign lymphoepithelial cyst (BLEC)

2. Benign lymphoepithelial lesion (BLEL)

3. Lymphoepithelial -like carcinoma

4. Lymphoepithelial carcinoma/ lymphoepithelioma

5. Miscellaneous

•As the name suggest there must be two components–

epithelium and lymphoid population

BENIGN LYMPHOEPITHELIAL CYST

1. BLEC of oral cavity (anterior floor of mouth)

2. BLEC of salivary gland

3. HIV associated BLEC of the parotid gland

4. Branchial cleft cyst

5. Cystic Warthin’s tumor

6. Branchial cleft cyst-like formation sometimes seen in

Hashimoto’s thyroiditis

7. Multilocular thymic cyst

8. BLEC of Pancreas

BLEC OF SALIVARY GLAND

• Mostly seen in parotid gland

• Unilateral and unicystic lesion

• Histo – epithelial lined cyst – usually stratified squamous

epithelium

• Cyst wall shows – dense lymphocytic aggregates with

germinal centre formation

•Av age -45yrs

• Proposed theory –

1. Develop from remnants of branchial arch system –

this theory is disputed now

2. From NEISSE NICHOLSON RESTS - salivary

ductal or acinar inclusions in intra- or peri parotid

lymph nodes

• To distinguish from Warthin’s tumor – LE cyst is

unilocular, has minimal papillary configuration and

absence of oncocytic columnar cells

• Various studies have suggested that CMV and HHV-8

have no role in the etiology of LE cyst

• However, EBV is more frequently found in LE cyst than

in normal parotid gland

• But its role as an etiological factor of LE cyst is still

controversial

Ref - Role of Cytomegalovirus, Epstein-Barr Virus, and Human Herpes Virus-8 in Benign Lymphoepithelial Cysts of the Parotid Gland, Yen el al, Laryngoscope 114: August 2004

BRANCHIAL CLEFT CYST

• Derived from 2nd branchial apparatus in region of

bifurcation of common carotid artery

• Smooth walled cyst with mucoid or watery content

• lining – non-keratinising stratified squamous epithelium

or a ciliated columnar respiratory like epithelium

• Scattered lymphoid aggregates are typically located

beneath epithelium- germinal centres may be quite

prominent

• If a mucinous type epithelium is seen in cystic lesion

from neck, which also has a bland squamous component

– it is necessary to consider a possibility of a low

grade mucoepidermoid carcinoma

MULTILOCULAR THYMIC CYST

• Thymic cyst are divided into 2 types – Unilocular and

multilocular

• UNILOCULAR THYMIC CYST –

• Of developmental origin

•Arise from remnants of 3rd branchial pouch- derived

thymopharyngeal duct

• Located in neck more often than in mediastinum –

anywhere between angle of mandible to manubrium

sterni

• Wall is thin and inflammation is usually lacking

• Epithelial lining is flattened , cuboidal or columnar and

rarely squamous

•Not a LE cyst

• MULTILOCULAR THYMIC CYST –

•Acquired process

•Always accompanied by inflammation and fibrosis

• lining – flat, cuboidal or ciliated columnar and (often)

squamous – single or stratified

• Cholesterol granulomas are common

• These must be distinguished from thymoma undergoing

cystic degeneration and from cystic lymphangioma

•The DUBOIS ABSCESS described in thymus of

neonates with congenital syphilis also belong to this

category

Ref – surgical pathology by Rosai and Ackerman (10th ed)

HISTOLOGICAL CLASSIFICATION OF PANCREATIC CYST

1. CONGENITAL –

a. Polycystic disease

b. Cystic fibrosis

c. Dermoid

d. Duplicative

2. RETENTION-

a. Parasitic

b. Associated with obstructive lesions of pancreas

3. PSEUDOCYST

4. BLEC

5. CYSTIC NEOPLASM

BLEC OF PANCREAS

• Unilocular or multilocular lesion – generally filled with

keratinous debris

• May protrude from pancreatic surface

• Cyst lined by mature keratinised stratified squamous

epithelium

• Occasional cuboidal or transitional appearing areas

• Uniform dense surrounding lymphoid tissue

• No acute inflammation

• Surrounding pancreatic tissue normal or focally atrophic

HOW TO DISTINGUISH FROM OTHER CYSTIC LESION OF PANCREAS

1. PSEUDOCYST – no epithelial lining

2. DERMOID CYST – a. presence of hair follicles and

sebaceous glands

b. Absence of lymphoid tissue

3. RETENTION CYST – Small , m/l , lined by columnar

or cuboidal epithelium without surrounding lymphoid

tissue. These cyst may communicate with large

pancreatic ducts

BENIGN LYMPHOEPITHELIAL LESION

1. Salivary gland – Mikulicz disease

2. Cutaneous lymphadenoma

3. Spiradenoma

• BLEL – reactive lymphoid component with scattered

tightly cohesive islands of epithelial cells (epimyoepithelial

islands) - hallmark

Mikulicz disease –•Aka – Lymphoepithelial sialadenitis(LESA)/

Myoepithelial sialadenitis (MESA)

• Parotid(85%) > SM gland (15%)

• Is a manifestation of Sjogren’s syndrome – components

of which are-

1. Keratoconjunctivitis

2. Xerostomia

3. Rheumatoid arthritis

4. Hypergammaglobulinemia

•Histologically – the lymphoid infiltrates are

predominantly T-cells

•Acinar atrophy

• Ductal hyperplasia/ epimyoepithelial islands – which are

permeated by reactive lymphocytes (predominantly B-

cells)

• hyaline substance deposited between cells- Basement

membrane material

• Lymphoid follicles +/-

•Current evidence suggest – the epithelial islands lack

myoepithelial cells – so epimyoepithelial term is a

misnomer

• So the term Lymphoepithelial lesion(LEL) is preferred

• Increased risk of developing NHL – this should not be

confused with the entity malignant LEL/ LE carcinoma

CUTANEOUS LYMPHADENOMA

• aka – benign lymphoepithelial tumor of skin/

adamantinoid trichoblastoma

• Rare basaloid tumor

• Site – face, rarely in legs

•Asymptomatic erythematous to skin colored

papules/nodules and <1cm in size

• Histo – well defined unencapsulated dermal nodules

• c/o 3 histologic elements – dermal nests, fibrotic stroma

and inflammatory infiltrate

• dermal nests – irregular shaped lobules of epithelial cells

composed of large glycogenated cells with peripheral

pallisading. Cells have large vesicular nuclei with

prominent nucleoli

• Inflammation – mixed population of mature T and B-

lymphoctes . Germinal centre formation may be seen

• IHC – epithelial cells – CK

peripheral cells – bcl2

• D/D – lymphoepithelial like carcinoma – origin from

adnexal structure

• in skin – MC in head and neck regions

• Not associated with EBV

• Dermal or sc nodules c/o infiltrating lobules and cords of

eosinophilic epithelioid cells with surrounding dense

lymphoplasmacytic infiltration

Ref – Surgical pahtology of the head and neck (3rd ed) by Leone Barnes

SPIRADENOMA

• Benign dermal neoplasm

• can show either eccrine or apocrine differentiation

• MC site – face and upper trunk

• Pain is the main clinical characteristic

• Histo – solid neoplasm c/o round and smooth bordered

nodules of 2 types of cells

• periphery – small dark basaloid cells with hyperchromatic

nuclei

• centre- larger cells with vesicular nuclei and abundant

pale cytoplasm

• Characteristic feature – presence of eosinophilic PAS

+ve globules (BM material) throughout the neoplasm

• Lymphocytic parotid gland enlargement in the HIV

infection can be classified into three categories:

1) PGL (persistent generalised lymphadenopathy)

2) BLEL (benign lymphoepithelial lesion)

3) BLEC (benign lymphoepithelial cyst)

Ref - The Benign Lymphoepithelial Cyst and a Classification System for Lymphocytic Parotid Gland Enlargement in the Pediatric HIV Population, Dave et al; Laryngoscope 117: January 2007

HIV- ASSOCIATED SALIVARY GLAND DISEASE

PGL

• Reactive follicular hyperplasia is demonstrated in the

intraparotid lymph nodes of HIV patients with parotid

gland enlargement

• p24 core Ag of HIV can be demonstrated in follicular

dendritic cells and interfollicular histiocytes by IHC

BLEL

• The pathologic features of BLEL include a triad of:

1) lymphocytic infiltration with replacement of the

salivary gland parenchyma

2) intraductal epithelial proliferation with formation of

solid epimyoepithelial islands

3) atrophy with destruction of salivary gland acini

• Carries a risk of malignant transformation

BLEC

• The cysts are usually bilateral (upto80%), multiple

(upto90%), painless, and involve the superficial lobe of

parotid

• Rarely does BLEC involve the submandibular gland

• PGL may be a precursor to BLEC formation

• BLEC do not undergo malignant transformation

• Cystic parotid gland enlargement is an indication for HIV

testing

ROLE OF FNAC

• FNA of BLEC usually yields a straw- or yellow- colored

fluid

• Cytology reveals a triad of:

1) heterogeneous lymphoid population (lymphocytes,

histiocytes, plasma cells)

2) scattered foamy macrophages

3) Anucleated squamous cells

• These findings are often present within a proteinaceous

background

LYMPHOEPITHELIOMA –

LIKE CARCINOMA

1. Lung – variant of large cell carcinoma (subpleural

peripheral nodules)

2. Thymus – type of thymic carcinoma

3. Urinary tract – type of infiltrating urothelial carcinoma

4. Prostate – variant of adenocarcinoma

5. Cervix

6. Vulva

7. Vagina

LYMPHOEPITHELIAL CARCINOMA

1. Nasal cavity > PNS

2. Nasopharynx

3. larynx> hypopharynx(pyriform sinus) > trachea

4. Oral cavity (tonsils> base of tongue), oropharynx and

eosophagus

5. Salivary gland

EBV ASSOCIATION

• Evidence of its association includes-

1. Raised levels of antibodies, esp IgA; against EBV

2. Presence of EBV DNA or RNA in all tumor cells

3. Presence of EBV in clonal episomal form – indicating

that virus has entered tumor cell before clonal

expansion

4. Presence of EBV in precursor lesions of

nasopharyngeal carcinoma; but not in normal

nasopharyngeal epithelium

• EBV infection in NPC exhibits type2 latency pattern –

i.e expression of EBV nuclear antigen-1 (EBNA1) and

latent membrane protein-1 (LMP1), but not the

immunogenic EBNA 2-6

• EBV encoded early RNA (EBER) expressed in

abundance

• For EBV detection – Non-keratinising NPC is

associated with EBV in practically 100% cases

• LMP1 +ve in 30-40% cases - so not reliable

• In-situ hybridisation for EBER – simplest and most

reliable

Ref - WHO classification of nasopharynx(2005)

LYMPHOEPITHELIAL CARCINOMA OF NASOPHARYNX

3 types of epithelial carcinoma

Keratinising SCC Basaloid SCC

Non keratinising Ca

Differentiated undifferentiated

Regaud(nests) Schmincke(individually)

• In the nonkeratinising type density of lymphocytes and

plasma cells are highly variable

No or few lymphocytes within the tumor island

Abundant lymphocytes/ plasma cells infiltrate tumor islands, breaking them up into tiny clusters and single cells

Termed as lymphoepithelialcarcinoma

LE CARCINOMA OF NASAL CAVITY AND PNS

• Often mistaken for sino nasal undifferentiated

carcinoma (SNUC)

• SNUC – exhibits extensive necrosis, mitosis and

angiolymphatic invasion

•Almost always negative for EBV

• Usually negative for CK 5/6 and CK13 (LE Ca is +ve)

•Another D/D – primary nasopharyngeal carcinoma –

can only be excluded by demonstrating absence of tumor

in nasopharynx

LE CARCINOMA OF SALIVARY GLANDS

• 0.4% of salivary gland neoplasms

• D/D –

1. Metastatic undifferentiated nasopharyngeal carcinoma

of the lymphoepithelioma type – to r/o careful

evaluation of nasopharynx is necessary

2. Metastatic amelanotic melanoma of face or scalp – to

r/o- IHC – CK, HMB-45, Melan A

3. Large cell lymphocytic and histiocytic neoplasm

4. BLEL/LESA – can be diagnosed based on cytologic

features and absence of invasion

EXTRANODAL MARZINAL ZONE B-CELL LYMPHOMA OF MALT TYPE

1. Stomach

2. Small intestine

3. Colon/rectum

4. Lung

5. Thymus

6. Salivary glands

7. Skin

• Shows unifocal/multifocal involvement of extranodal

tissues

• neoplastic lymphoid infiltrate is usually diffuse

• Comprises of mixture of cell types

• MC cell type is – centrocyte-like – small to medium

sized cells, slightly folded or elongated angulated nuclei,

moderately dense chromatin, inconspicuous nucleoli and

small amount of pale cytoplasm

• In MALTomas, LELs are frequently formed as a result

of invasion and expansion of epithelial structure by

lymphoma cells – characteristic feature

• Lymphoma cells within and around epithelial structures

may assume a centrocyte like or monocytoid like B-cell

appearance – producing pale collars around LELs

• Sheets of plasma cells with or without Dutcher bodies –

2nd important feature

• IHC – Pan B-cell markers – CD19, CD79a and PAX5 +ve

• Frequently express IgM

• CD5, CD23, BCL6, CyclinD1 -ve

MEDULLARY CARCINOMA

Ref – Rosen’s breast pathology (3rd ed) pg :454-455

• Usually lymphoplasmacytic(LP) infiltrate involve

periphery as well as substance of the tumor (limited to

fibrovascular stroma between islands of tumor cells)

• Sometimes, it can be devoid of fibrovascular stroma and

LP infiltrate mingles intimately with carcinoma cells-

these are referred to as lymphoepithelioma-like carcinoma

• Intense LP infiltrate can also occur in non-medullary

IDC, but when plasma cells predominate- more likely to

be medullary carcinoma

THYROID LESIONS WITH LYMPHOEPITHELIAL FEATURES

1. Lymphocytic thyroiditis

2. Lymphoma

3. Papillary thyroid carcinoma (warthin-like and tall cell

variant)

4. Ectopic thymoma

5. BLEL

6. Carcinoma with thymus like differentiation (CASTLE)

7. Metastatic carcinoma to intra or peri- thyroid lymph

nodes

8. Neoplasm arising in a b/g of lymphocytic thyroiditis

LYMPHOID RICH SALIVARY GLAND LESIONS

1. Chronic sialadenitis

2. BLEL

3. BLEC

4. Intraparotid lymph node hyperplasia

5 Warthin tumor

6. Malignant lymphoma/MALT lymphoma

7. Lymphoepithelial carcinoma

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