Extranodal lymphomas of the head and neck

Annals of Diagnostic P

Review article

Extranodal lymphomas of the head and neck

Francisco Vega, MD, PhD, Pei Lin, MD, L. Jeffrey Medeiros, MD4

Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

Abstract Malignant lymphomas represent approximately 5% of all malignant neoplasms of the head and neck

1092-9134/$ – see fro

doi:10.1016/j.anndiag

4 Corresponding

E-mail address: jm

and may involve nodal or extranodal sites. Nodal head and neck lymphomas are similar to other

nodal sites and are not further reviewed here. The head and neck region is the second most frequent

anatomical site of extranodal lymphomas (after the gastrointestinal tract). Most are non–Hodgkin’s

lymphomas of B-cell lineage, and overall diffuse large B-cell lymphoma is the most common type.

Hodgkin’s lymphoma rarely occurs in extranodal sites. Other hematologic neoplasms that commonly

involve extranodal sites of the head and neck are also discussed. In this review, we begin by

discussing lymphomas involving the head and neck according to anatomical site. Then we discuss

specifically the pathological findings of extranodal marginal zone lymphoma of mucosa-associated

lymphoid tissue, plasmablastic lymphoma, extramedullary plasmacytoma, and extranodal natural

killer/T-cell lymphoma of nasal type.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Head and neck; Extranodal lymphoma; MALT lymphoma

1. Malignant lymphomas of Waldeyer’s ring

Waldeyer’s ring is composed of lymphoid tissue of the

nasopharynx, palatine tonsils, base of tongue, and oropha-

ryngeal wall.Waldeyer’s ring is the secondmost common site

of extranodal lymphomas after the gastrointestinal tract.

These tumors represent 15% to 20% of all lymphomas and

approximately half of extranodal lymphomas of the head and

neck [1,2].

Affected patients are usually adults older than 50 years,

and men are more frequently affected [1-3]. The most

common presenting symptoms are airway obstruction,

altered hearing, and pain. Physical examination usually

reveals a mass or an ulcer. The tonsils are the most common

site of involvement, representing over more than 50% of all

tumors, followed in frequency by the nasopharynx and base

of tongue [1-3].

Waldeyer’s ring lymphomas are predominantly non–

Hodgkin’s lymphomas of B-cell lineage, representing 80%

to 90% of cases [4,5]. The most common type of lymphoma

involving Waldeyer’s ring is diffuse large B-cell lymphoma

nt matter D 2005 Elsevier Inc. All rights reserved.

path.2005.09.020

author. Tel.: +1 713 794 5446; fax: +1 713 745 0736.

[email protected] (L.J. Medeiros).

(DLBCL), in 70% to 80% of cases, and this is particularly

true for patients with localized disease [4-7]. Patients with

DLBCL involving Waldeyer’s ring (compared with nodal

DLBCL) present more frequently with early-stage disease,

absence of B symptoms, no bone marrow infiltration,

normal serum lactate dehydrogenase, and low- to low/

intermediate-risk international prognostic index [7].

Histologically, DLBCLs are composed of intermediate to

large-sized cells that may be noncleaved, cleaved, or immu-

noblastic (Fig. 1). Immunophenotypic studies, performed

by either flow cytometry or immunohistochemistry, show

B-cell lineage with expression of pan–B-cell antigens

(CD19, CD20, CD22, CD79A, PAX5/BSAP) and absence

of T-cell antigens (Fig. 1). Monotypic surface immunoglo-

bulin is often detected by flow cytometry but not by immuno-

histochemistry (surface immunoglobulin is destroyed by

routine processing).

Other lymphoma types also may involve Waldeyer’s

ring, although much less common than DLBCL. In a recent

study by Solomides et al [4], other lymphomas involving

Waldeyer’s ring included extranodal marginal zone B-cell

lymphoma of mucosa-associated lymphoid tissue (MALT-

lymphoma) 15%, peripheral T-cell lymphoma 8%, follic-

ular lymphoma 6%, and mantle cell lymphoma 3%. The

latter 3 tumors often are a part of disseminated disease at

athology 9 (2005) 340–350

Fig. 1. Diffuse large B-cell lymphoma of tonsil. A and B, The tonsil parenchyma is replaced by lymphoma with a diffuse pattern predominantly composed of

large noncleaved cells. Occasional large cleaved cells and immunoblasts are also present. Surface epithelium of the tonsil is seen in the lower right corner of the

figure (A, hematoxylin and eosin, original magnification �100; B, hematoxylin and eosin, �1,000). C, The large cells are positive for CD20 and negative for

CD5 (inset). (C, immunohistochemistry, CD20 and inset CD5, original magnification �100).

F. Vega et al. / Annals of Diagnostic Pathology 9 (2005) 340–350 341

time of diagnosis. Hodgkin’s lymphoma can rarely involve

Waldeyer’s ring. The most frequent subtypes are the

lymphocyte-rich classical and nodular sclerosis types [8].

The neoplastic cells in Hodgkin’s lymphoma are typically

positive for CD15 and CD30 and are negative for CD45.

Extranodal marginal zone B-cell lymphoma of MALT

shares many histological features with MALT-lymphomas

involving other anatomical sites (see following sections).

Because Waldeyer’s ring can be considered as a site of

normal MALT (similar to the ileum), one might expect to

observe a higher incidence of lymphomas of MALT origin.

However, it is possible that many DLBCLs are of MALT

origin [9]. It is also true that benign lymphoid cells normally

infiltrate the epithelium associated with Waldeyer’s ring.

Thus, lymphoepithelial lesions cannot be used as evidence

of a low-grade component of MALT-lymphoma in patients

with DLBCL. Lymphoepithelial lesions also can be associ-

ated with any type of lymphoma involving Waldeyer’s ring

and cannot be used as evidence of MALT origin. Thus,

MALT-lymphoma may be underdiagnosed when involving

Waldeyer’s ring.

Patients with infectious mononucleosis have tonsillar

enlargement that may be pronounced. In most cases, the

enlargement is bilateral, and this is a useful distinguishing

Fig. 2. Extranodal marginal zone B-cell lymphoma of MALT involving the or

surrounded by pale areas (hematoxylin and eosin, original magnification �20). B

composed of small lymphoid cells, cells with plasmacytoid differentiation, plasma

intracytoplasmic inclusion of immunoglobulin related products) are seen (hema

express monotypic immunoglobulin j light chain (C, immunohistochemistry, j l

feature from lymphomas. Infectious mononucleosis also can

be confused with Hodgkin’s lymphoma. In infectious

mononucleosis, the immunoblasts and the Reed-Sternberg–

like cells are CD30 positive (like Hodgkin’s lymphoma), but

they express CD45 (leucocyte common antigen; LCA) and

lack of CD15 expression (unlike Hodgkin’s lymphoma).

2. Malignant lymphomas of upper respiratory tract

Lymphoproliferative diseases of the nasal cavity, para-

nasal sinuses, and nasopharynx are uncommon, constituting

less than the 5% of all extranodal lymphomas [10]. In the

past, the limited clinical and pathological experience with

these lesions has resulted in controversies regarding patho-

logical classification, natural history, and optimal manage-

ment. Historically, an ambiguous nomenclature has been

applied to lesions in this region. Terms have included

polymorphic reticulosis, pseudolymphoma, midline granu-

loma syndrome, and lethal midline granuloma. Over the past

decade, it has become appreciated that these lesions are

lymphomas of the sinonasal tract, rendering previously used

nomenclature obsolete.

In the Western countries, most lymphomas in these

anatomical sites are DLBCL. These tumors are most common

bit. A, Low-power reactive lymphoid follicles with germinal centers are

, In these pale areas, the neoplastic cell population is heterogeneous and is

cells, and scattered large cells. Some cells with Russell bodies (eosinophilic

toxylin and eosin, original magnification �1000). C, The neoplastic cells

ight chain and inset k light chain; original magnification �100).

Fig. 3. Extranodal marginal zone B-cell lymphoma of MALT involving conjunctiva. A, Fleshy bsalmon-pink Q swelling of the conjunctiva (courtesy of Dr F.

Cabanillas). B and C, Immediately beneath the epithelium, the tumor exhibits extensive plasmacytoid differentiation, whereas in the deeper portion, the tumor

F. Vega et al. / Annals of Diagnostic Pathology 9 (2005) 340–350342

in the elderly and are located in the paranasal sinuses. By

contrast, in Eastern countries and South America, T- or

natural killer (NK)–cell lymphomas are relatively more

common, and patients present at a younger age with tumors

located in the nasal cavity [11-13]. Other neoplasms that may

involve the nasal and paranasal sinuses are extramedullary

plasmacytoma, MALT-lymphoma, and Burkitt’s lymphoma.

Patients present with signs of nasal obstruction, nasal

tumor mass, facial swelling and discharge, epistaxis, visual

disturbances, and headaches. Overall, low-grade tumors tend

to form masses in the involved nasal cavity or paranasal sinus

and cause obstruction, whereas high-grade lymphomas cause

more aggressive symptoms such as facial edema, epistaxis,

and facial pain [11].

3. Malignant lymphomas of ocular and conjunctiva

The ocular adnexal structures are the second most

frequent anatomical site in the head and neck involved by

malignant lymphoma. Lymphomas represent approximately

10% of tumors at these sites [14,15]. Patients with

lymphomas of ocular adnexal structures most frequently

are older adults who present with slow onset of erythema,

pain, conjunctival chemosis, or distorted vision [15]. Women

are affected slightly more often than men. The orbit is most

commonly involved in 60% to 70% of cases, followed by the

conjunctiva in 10% to 20% of cases [14,16]. Approximately

10% to 15% of patients present with or develop bilateral

involvement [16].

Extranodal marginal zone B-cell lymphoma of MALT is

the most common lymphoma type to involve ocular adnexal

structures, representing 60% to 70% of all lymphomas

[15,17]. The histological findings of these tumors are similar

to those of other sites (see below), but ocular adnexal

MALT-lymphomas have some distinctive features (Figs. 2

and 3). For example, lymphoepithelial lesions are not

observed in orbital tumors as there is no epithelium at this

site (Fig. 2). In contrast, conjunctival tumors can have well-

developed lymphoepithelial lesions and are often multifocal

[18]. There is evidence of association between Chlamydia

psittaci and ocular adnexal lymphomas [19]. Antibiotic

therapy with doxycycline has been associated with lympho-

ma regression [20].

A variety of other lymphoma types may involve ocular

adnexal structures as a part of disseminated disease. In one

study at the Massachusetts General Hospital, Boston, Mass,

approximately 20% of patients who presented with orbital

or conjunctival lymphomas were shown to have systemic

disease by staging studies [16]. Low-grade follicular

lymphomas are most common, but patients with DLBCL,

mantle cell lymphoma, and small lymphocytic lymphoma

may rarely present with involvement of ocular adnexal

structures [16,17].

4. Malignant lymphomas of the salivary glands

Salivary gland lymphomas represent approximately 3%

of all salivary gland tumors [21,22]. The parotid gland is

most commonly affected in 80% of cases, followed by the

submandibular gland (16%), sublingual gland (2%), and

minor salivary glands (2%) [21]. Patients with lymphomas of

the salivary glands are most commonly adults with a male to

female ratio of approximately 1 to 2 [22]. Patients most often

present with a painless mass and a small subset of patients

have facial nerve paresis or pain [21]. Twenty percent of

patients with salivary gland lymphomas have clinical or

laboratory evidence of Sjfgren’s syndrome [22]. The most

common histological types of lymphoma at this site are

DLBCL and MALT-lymphoma (Fig. 4).

Myoepithelial sialadenitis (MESA), also commonly re-

ferred to as benign lymphoepithelial lesion, is a precursor

lesion for non–Hodgkin’s lymphoma [22]. In the major

salivary glands, MESA is characterized histologically by

2 components: extensive lymphoid infiltration and epimyo-

Fig. 4. Extranodal marginal zone B-cell lymphoma of MALT of parotid gland. A and B, The salivary gland parenchyma is replaced by lymphoma composed o

small cells with abundant pale cytoplasm. Note the presence of reactive germinal centers as well as numerous small lymphoid cells invading the epithelial ducts

(lymphoepithelial lesions) (A and B, hematoxylin and eosin; A, original magnification �100; B, original magnification �400).


epithelial islands [22,23]. Epimyoepithelial islands are nests

of ductal epithelial cells that are extensively infiltrated by

small lymphoid cells. Often, abundant hyaline basal lamina

material accompanies the epithelial cells, indicating that

epimyoepithelial islands originate as ducts that subsequently

collapse. In theminor salivary glands, the changes are similar,

although epimyoepithelial islands may be smaller or absent.

Over time, the lymphoid infiltrate progressively replaces

acinar tissue, resulting in atrophy, and is associated with

reactive lymphoid follicles.

Myoepithelial sialadenitis and closely related lympho-

epithelial cysts can also occur in HIV-positive patients [24].

Excluding the cystic component, the histological findings in

lymphoepithelial cysts are similar to those in MESA.

Human immunodeficiency virus has been identified within

the follicular dendritic cells of these lesions [24]. Patients

with MESA are at increased risk of developing non–

Hodgkin’s lymphoma [22]. The risk of malignant lym-

phoma in patients with MESA and Sjfgren’s syndrome has

been estimated to be 43.8 times greater than that of general

population [22].

Most lymphomas arising in the salivary gland are

lymphomas ofMALTorigin and can be divided into 2 groups:

low-grade and DLBCL [23,25]. Historically, DLBCLs

arising in the setting of MESAwere the first to be recognized

because of their cytological atypia. The increased risk of

MALT-lymphomas was recognized later, with the availability

of immunohistochemical and molecular methods [23].

Histologically,MALT-lymphoma forms part of a spectrum

with MESA, as has been described by others [23,26,27]. The

presence of atypical lymphoid cells with abundant pale

cytoplasm (centrocyte-like or monocytoid B cells) forming

wide zones surrounding epimyoepithelial islands is a useful

histological finding to suggest that MALT-lymphoma is

evolving from MESA. Lymphoepithelial lesions are not

helpful in distinguishing MESA from MALT-lymphoma as

they occur in both conditions. As the neoplasm progresses,

epimyoepithelial islands are destroyed, reactive follicles are

infiltrated and replaced, and the process extends outside the

salivary gland and may exhibit perineural invasion [23,26].

f

Diffuse large B-cell lymphoma arises at a later stage in this

sequence of events, with accrual of sheets of large cells and

accompanying mitotic figures.

Not all lymphomas that involve the salivary glands are

truly of extranodal origin. The parotid gland is closely

associated with many lymph nodes surrounding the gland

and within the parenchyma. These lymph nodes may be

replaced by nodal lymphomas that secondarily replace the

parotid gland. At the time of histological analysis, it may not

be possible to determine the site of origin of the neoplasm

without immunophenotypic or molecular studies. Some

investigators consider these nodal lymphomas to be primary

lymphomas of the parotid gland, further confusing the

issue [21].

Lymphomas also are rarely associated with Warthin’s

tumor, with approximately 20 cases reported in the literature.

Most of these neoplasms have been follicular lymphoma,

DLBCL, or small lymphocytic lymphoma, neoplasms that

typically arise in nodal sites. Extranodal marginal zone

B-cell lymphoma of MALT is rare. Others have suggested

that Warthin’s tumor arises from salivary gland inclusions

within lymph node, explaining the types of lymphoma that

most often occur with Warthin’s tumors [28].

5. Malignant lymphomas of the thyroid gland

Malignant lymphomas represent 4% to 5% of all thyroid

gland neoplasms [29]. Women are more commonly affected

with a male to female ratio of 1 to 3 (or 4). This ratio reflects

the strong association between thyroid gland lymphoma and

Hashimoto’s thyroiditis, which also most commonly affects

women [29,30]. The relative risk of developing thyroid gland

lymphoma in patients with Hashimoto’s thyroiditis is

estimated to be 67 to 80 times greater than the general

population [29,31]. Similar to the salivary gland described

above, DLBCL and MALT-lymphoma are the most common

types of lymphoma involving the thyroid gland, andDLBCLs

were recognized initially. The advent of immunohistochem-

ical and molecular studies subsequently facilitated the

recognition of MALT-lymphoma. These studies also showed


that most small cell carcinomas of the thyroid gland, reported

in the past, were actually DLBCL [32].

Clinically, patients with lymphoma of the thyroid gland

are usually adults older than 50 years. Patients may com-

plain of an enlarging thyroid mass, hoarseness, stridor or

dysphagia, or may be asymptomatic [14]. Physical exami-

nation most often reveals a large thyroid gland.

Diffuse large B-cell lymphoma is the most common type

of lymphoma to involve the thyroid gland [29,30,33]. In a

recent study at our hospital, 72% of patients with localized

lymphoma of the thyroid gland had DLBCL [31]. Most

DLBCLs are probably of MALTorigin, and in many of these

cases, MALT-lymphoma and/or Hashimoto’s thyroiditis is

also recognized in the thyroid gland, but these findings are

not invariable (Fig. 5). The smaller the biopsy specimen, the

less likely that MALT-lymphoma or Hashimoto’s thyroiditis

will be identified.

In our experience, pure MALT-lymphomas of the thyroid

gland are not common [34]. Usually, DLBCL is also present.

Although histologically similar to MALT-lymphomas at

other sites, some features ofMALT-lymphomas in the thyroid

gland are relatively distinctive [30,33]. Lymphoepithelial

lesions are marked in MALT-lymphomas involving the

thyroid gland. Extranodal marginal zone B-cell lymphoma

of MALT at this site also can have extensive plasmacytoid

differentiation resembling plasmacytoma. In these cases, one

clue to suggest MALT-lymphoma is that the neoplastic cells

infiltrating follicular epithelium often resemble lymphoid

cells, even when the remainder of the tumor resembles

plasmacytoma. Neoplastic cells also may selectively accu-

mulate in thyroid follicles imparting a nodular appearance

and resembling follicular lymphoma.

It is important to remember that nodal lymphomas

may disseminate to the thyroid gland [29]. Also, patients

with nodal lymphomas with localized disease in the neck

(stage I or II) may present with a thyroid mass involved

by lymphoma. At our hospital, approximately 20% of

patients with localized lymphoma involving the thyroid

gland had systemic types of lymphoma, mostly follicular

Fig. 5. Diffuse large B-cell lymphoma of thyroid gland. A, Thyroid gland parenchy

figure shows the lymphoma with a diffuse pattern of growth, whereas the lower

original magnification �100). B, Medium-power view showing tumor cells surrou

lymphoid cells (hematoxylin and eosin, original magnification �400).

lymphoma, and occasionally small lymphocytic lym-

phoma, precursor T-cell lymphoblastic lymphoma, or

Burkitt’s lymphoma [34]. Most of these patients had

stage II disease with histological or radiological evidence

of lymphadenopathy.

6. Malignant lymphomas of the larynx

Malignant lymphomas of the larynx are rare, accounting

for less than 1% of all laryngeal tumors [35,36]. Plasmacy-

toma, MALT-lymphoma, and DLBCL are the most frequent

types of lymphoma observed in the larynx [35]. Natural

killer/T-cell lymphoma can also involve primarily the larynx,

but most cases represent an extension from the upper

respiratory tract [37].

Patients with laryngeal non–Hodgkin’s lymphoma com-

monly present with progressive hoarseness, dysphonia,

cough, dysphagia, or with a sensation of a lump in the throat.

Lymphomas of the larynx involve most frequently the

supraglottic area, in particular, the epiglottis and aryepiglottic

folds. The glottic or subglottic regions are more rarely

involved. Radiologically, the lesion produced by lymphoma

is often homogeneous, with well-defined margins, in contrast

with carcinoma, which is more infiltrative and less bulky

[38]. Plasmacytoma usually presents as a polypoid, unilater-

al, smooth sessile mass, with no ulceration, and occurs most

frequently in the epiglottis.

7. Cutaneous lymphomas of the head and neck

Specific types of primary cutaneous lymphomas with

predilection for the head and neck region include primary

cutaneous follicle-center lymphoma, cutaneous marginal

zone B-cell lymphoma (considered as MALT-lymphoma by

many investigators), and some subtypes of DLBCL [39].

Follicle-center cell lymphoma arising in skin can present

as a solitary lesion or groups of plaques and tumors

preferentially located on the scalp or forehead [40]. The

lymphoid infiltrate involves the dermis and sometimes the

ma is partially replaced by large neoplastic cells. The upper right side of the

left part shows associated Hashimoto’s thyroiditis (hematoxylin and eosin

nding thyroid follicles. One of the follicles shows packing of the lumen by

,


subcutis without involvement of the epidermis. Infiltrates

tend to be bottom-heavy. A clear-cut follicular growth pattern

is more commonly observed in lesions arising on the scalp

than those presenting on the trunk [41]. The neoplastic cells

express CD20, CD79, and BCL-6. CD10 is positive in a

subset of cases.

Inmost instances,patientswithcutaneousmarginalzone

lymphoma present with red to purple papules, nodules or

plaques localized preferentially on the trunk, and less often

involving head and neck [42]. Most of these neoplasms

resemble low-grade B-cell lymphomas at other sites. A subset

of cases is referred to in the literature as cutaneous immuno-

cytoma [43].Abottom-heavyor top-heavy arrangement of the

cells can be seen, and the epidermis is not involved. The

infiltrates are composedof small lymphocytes, centrocyte-like

cells, lymphoplasmacytoid cells, and plasma cells, admixed

with a small number of centroblasts- or immunoblasts-like

cells and many reactive T cells. The neoplastic cells express

CD20, CD79a, and BCL-2 but are negative for CD10 and

BCL-6, and these findings are useful in distinguishing these

tumors from follicle-center cell lymphomas [44].

Cases of DLBCL presenting in the head and neck are

generally a cutaneous manifestation of a systemic lympho-

ma. Rare cases of primary cutaneous T-cell/histiocyte-rich

B-cell lymphoma have also been reported [45].

8. MALT lymphoma

Patients with MALT-lymphoma have clinical features

unlike those of patients with nodal low-grade B-cell

lymphomas. Extranodal marginal zone B-cell lymphoma of

MALT tend to remain localized for prolonged intervals, and

patients commonly present with a long history that may be

confused with an inflammatory process. The pattern of

dissemination of MALT-lymphomas is also unusual [46].

These tumors have a predilection for involving other

extranodal sites, with a low frequency of bone marrow

involvement, approximately 10% to 20%. For these reasons,

in the era before immunohistochemical and molecular

methods were routinely used, a patient with MALT-

lymphoma was commonly thought to have pseudolym-

phoma. However, the presence of monoclonality in these

lesions correlates with risk of dissemination and therefore

supports their designation as lymphoma [46,47].

Three histological findings are usually present in MALT-

lymphomas: a population of small and irregular lymphoma

cells, lymphoepithelial lesions, and reactive lymphoid

follicles (Figs. 2-4).

The neoplastic lymphoid cells are a constant and distinc-

tive component. Isaacson [46] designated these cells as

bcentrocyte-likeQ because these cells resemble centrocytes

(small cleaved cells) of the normal germinal center.

However, MALT-lymphoma cells may exhibit a wide range

of cytological appearances. In some cases, the neoplastic

cells have abundant clear (monocytoid) cytoplasm; these

cells resemble monocytoid B cells as are observed in lymph

node sinuses of reactive conditions. In other cases, the

neoplastic cells can resemble small lymphocytes or small-

cleaved cells. In most MALT-lymphomas, occasional large

lymphoid cells are scattered among the small lymphoma

cells. When these cells become numerous and form sheets,

the neoplasm has transformed to large B-cell lymphoma,

with a correspondingly poorer prognosis and requiring

aggressive therapy [46]. The boundary between low-grade

and high-grade MALT-lymphoma (ie, DLBCL) is poorly

defined. High mitotic rate and increased large cells (N10%)

are helpful clues, indicating that transformation to DLBCL

is occurring.

The neoplastic cells of MALT-lymphoma have a marked

tendency to invade mucosal epithelium, usually forming

lymphoepithelial lesions, each seen as a cluster of cells

within the gland lumen. However, in neoplasms with

extensive involvement, lymphoepithelial lesions may be

difficult to recognize because glands are destroyed. Immu-

nostaining for keratin can be helpful in identifying residual

epithelium invaded by tumor cells.

Reactive lymphoid follicles are common in MALT-

lymphomas, usually surrounded by neoplastic cells. In many

cases, the neoplastic cells may infiltrate or colonize the

follicles, imparting a relatively nodular pattern that can

resemble follicular lymphoma. Reactive plasma cells are

frequently associated with MALT-lymphomas. However,

these neoplasms also may exhibit true plasmacytoid differ-

entiation in up to one third of cases. In some cases, the

neoplasm appears biphasic, with sheets of cytologically

mature plasma cells and other areas of small lymphoid cells.

Dutcher bodies (eosinophilic intranuclear pseudoinclusions

of cytoplasm) are common in MALT-lymphomas with

plasmacytoid differentiation [16,46].

Extranodal marginal zone B-cell lymphomas of MALT

are B-cell tumors that are positive for monotypic immuno-

globulin light chain, pan–B-cell antigens, and BCL-2 and are

negative for IgD, CD5, CD10, and CD23 [46]. Molecular

studies typically reveal immunoglobulin heavy and light

chain gene rearrangements with TCR genes usually in the

germline configuration. Extranodal marginal zone B-cell

lymphoma of MALT can be associated with 4 specific

translocations: t(11;18)(q21;q21), t(14;18)(q32;q21),

t(3;14)(p14.1;q32), and t(1;14)(p22;q32). Most of these

translocations have been shown to be involved in activating

the downstream nuclear factor j B (NF-jB) pathway [48].

8.1. Translocations associated with MALT-lymphoma

8.1.1. t(11;18)(q21;q21)

The t(11;18) is the most frequent chromosomal transloca-

tion identified in MALT-lymphomas [49-51]. This translo-

cation has been detected most commonly in MALT-

lymphomas of the gastrointestinal tract and lung, but also

has been detected in MALT-lymphomas of head and neck. In

the t(11;18), the inhibitor of apoptosis 2 (api2) gene on

11q21 and the MALT lymphoma-associated translocation

Fig. 6. Plasmablastic lymphoma of oral mucosa. A, Diffuse infiltrate of large plasmablasts and immunoblasts with vesicular chromatin, eccentric nuclei, and

frequently prominent central nucleoli (hematoxylin and eosin, original magnification �400). B, Epstein-Barr virus was detected in the tumor cells (in situ

hybridization, EBV small-encoded RNA, original magnification �400).


(malt1) gene on chromosome 18q21 are disrupted and

recombine to form a novel api2-malt1 fusion gene on the

derivative chromosome 11. This chimeric gene encodes for

the API2-MALT1 protein that is involved in oncogenesis.

API2 belongs to a family known as inhibitor of apoptosis

proteins (IAP), which are evolutionary conserved and play a

role in regulating programmed cell death in diverse species

[52]. The api2 gene contains 3 baculovirus IAP repeat

domains, a caspase recruitment domain, and a really

interesting new gene (RING) finger domain. The common

domain of IAP family members is the baculovirus IAP repeat

motif, which plays an essential role in inhibiting apoptosis. It

is hypothesized that api2-malt1 fusion leads to increased

inhibition of apoptosis, conferring a survival advantage

independent of antigen. Malt1 is a novel gene of unknown

function, and its function appears to be required as a part of

the t(11;18).

8.1.2. t(1;14)(p22;q32)

The t(1;14)(p22;q32) is a rare translocation associated

with MALT-lymphomas, which was initially identified in a

case of MALT-lymphoma of lung [53]. The t(1;14) juxta-

poses the bcl-10 gene on chromosome 1p22 with the immu-

noglobulin heavy chain (IgH) gene on chromosome 14q32

Fig. 7. Extranodal NK/T-cell lymphoma of nasal type. A, In this case, the tumor shows extensive areas of necrosis. Viable tumor cells are seen in the upper righ

corner of the figure (hematoxylin and eosin, original magnification �200). B, As demonstrated by elastic stain, the tumor cells infiltrate and destroy blood

vessels (Verhoeff-van Gieson, original magnification �400).

[54]. The bcl-10 gene on the derivative chromosome 14

comes under the control of the IgH gene enhancers resulting

in BCL-10 overexpression. The bcl-10 gene has 4 exons and

encodes a protein of 233 amino acids, with a group of

residues that form a caspase recruitment domain similar to

api2. Wild-type BCL-10 weakly promotes apoptosis and

activates NF-jB. The t(1;14) truncates the bcl-10 gene, and

as a result, truncated BCL-10 loses its proapoptotic function

but retains its ability to activate NF-jB.

8.1.3. t(14;18)(q32;q21)

The t(14;18)(q32;q21) seems to occur most frequently in

MALT lymphomas of the liver, ocular adnexa, and skin

(14%), although other sites can be involved [55]. In this

translocation, themalt1 gene is juxtaposed with the IgH gene

at 14q32, resulting in malt1 overexpression [56,57]. High

cytoplasmic expression of both MALT1 and BCL-10

characterize MALT-lymphomas carrying this translocation

[55]. The t(11;18) and t(14;18) appear to be mutually

exclusive in MALT-lymphomas.

8.1.4. t(3;14)(p14.1;q32)

The t(3;14)(p14.1;q32) involves the IgH and forkhead box

protein P1 (foxp1) genes and has been found in 10% of

t


MALT-lymphomas, most often arising in the thyroid, ocular

adnexae/orbit, and skin [58]. In this translocation, the foxp1

gene is juxtaposed with the IgH gene at 14q32, resulting in

foxp1 overexpression. Most t(3;14) positive MALT-lympho-

mas also harbor additional genetic abnormalities, such as

trisomy 3. foxp1 is a member of the foxp subfamily (foxp 1-4)

of transcription factors and has been shown to act as a

transcriptional repressor [59]. The mechanisms by which

foxp1 overexpression contributes to the tumorigenesis are

currently unclear.

8.2. Reactive versus MALT-lymphoma

The distinction between a reactive lymphoid infiltrate

and MALT-lymphoma can be difficult. In general, the larger

the infiltrate, the greater the likelihood of lymphoma. Clear

evidence of cytological atypia and Dutcher bodies, if

numerous, support lymphoma [16,46]. A relatively mono-

morphous lymphoid population is also more likely to be

lymphoma. However, this distinction may not be possible in

some cases without ancillary studies. Many pathologists

believe that MALT-lymphoma is present if a monotypic

B-cell population is detected using immunophenotypic

methods. The presence of monoclonal immunoglobulin

gene rearrangements without immunophenotypic evidence

of monoclonality is more controversial [60,61]. Particularly

when using polymerase chain reaction–based methods,

small monoclonal B-cell populations or chromosomal

abnormalities may be present in lesions that histologically

and immunohistochemically do not meet the criteria for a

malignant process. The term lesion of uncertain malignant

potential has been suggested by others for these lesions

[29]. In our opinion, detection of a MALT-lymphoma–

associated chromosomal translocation supports the diagno-

sis of MALT-lymphoma.

9. Plasmablastic lymphoma

Delecluse et al [62] described an AIDS-associated

B-lineage neoplasm with plasmacytic differentiation,

typically presenting in the oral cavity, and proposed that

this constituted a new subtype of DLBCL, for which they

coined the term plasmablastic lymphoma. Plasmablastic

lymphoma is considered a variant of DLBCL in the

World Health Organization classification of lymphoid

neoplasms [63].

Plasmablastic lymphoma is an aggressive neoplasm that

originates in the mucosa of the oral cavity, often involves

the gingiva, and may infiltrate the adjacent bone. In most of

the patients, the tumor is confined to the oral cavity at the

time of diagnosis, but the tumor can spread to distant sites

during the clinical course of the disease.

Morphologically, plasmablastic lymphomas are charac-

terized by a monotonous proliferation of plasmablasts and/

or immunoblasts with relatively few morphological features

of mature plasmacytic differentiation (Fig. 6) [64]. Apopto-

tic bodies, mitotic figures, and confluent areas of necrosis

are numerous. Plasmablastic lymphomas have a postgermi-

nal center B-cell/plasma cell phenotype. They express

MUM1/IRF4, CD38, and CD138/syndecan-1 but are

frequently negative for CD20 and PAX5/BSAP [64].

Epstein-Barr virus is frequently positive (Fig. 6), and human

herpes virus 8 does not appear to be associated with this

lymphoma subtype. This immunophenotype is unlike most

cases of DLBCL, raising the possibility that plasmablastic

lymphoma is better considered as an aggressive plasma cell

neoplasm [64].

10. Extramedullary plasmacytoma

Plasmacytomas are monoclonal neoplastic proliferations

of plasma cells. Approximately 80% of all plasmacytomas

occur in the head and neck region, and plasmacytomas

represent 4% of all nonepithelial tumors of the nasal cavity,

paranasal sinuses, and nasopharynx [65]. Plasmacytoma

occurs most commonly in men and, in most cases, presents

in patients older than 40 years, with the sixth decade of life

being the most common age of occurrence. The nasopharynx,

nose, sinus, and tonsil are the most common primary sites,

although virtually any head and neck site may be a primary

site of involvement [66]. Plasmacytoma located in the thyroid

gland also occurs rarely and is reported to be associated with

germinal center formation and with changes of lymphocytic

thyroiditis and fibrosis [67].

Morphologically, plasmacytomas may be well, moder-

ately, or poorly differentiated. Well-differentiated tumors

may be difficult to distinguish from reactive proliferations

and are composed of a uniform population of mature-

appearing plasma cells with round eccentric nuclei and

clumped peripheral nuclear chromatin. Nucleoli are absent

or inconspicuous in these cases, and a cytoplasmic

perinuclear hof is usually present. Poorly differentiated

plasmacytomas may be composed of cells that are not

obviously of plasma cell origin with large pleomorphic

nuclei. The nuclear chromatin is more fine and immature,

and prominent nucleoli are present and often multiple. The

characteristic perinuclear hof of mature plasma cells is

usually absent. Moderately differentiated tumors have

intermediate features.

Although plasmacytomas are B-cell neoplasms, they

usually lose many of the cell surface antigens that are

typical of B cells, such as CD19, CD20, and CD22. In

addition, immunoglobulin light and heavy chains are

frequently not present on the cell surface of these tumors,

and clonality cannot be assessed in many cases by routine

flow cytometric cell surface immunophenotyping. How-

ever, clonality can be determined by flow cytometry

performed after cell permeabilization to assess cytoplasmic

immunoglobulin. In addition, cytoplasmic immunoglobulin

is easily detectable by routine paraffin-section immuno-

histochemistry. Plasma cells also express CD38 and

CD138. Evidence of Epstein-Barr virus is not present in

most cases.


11. Extranodal NK/T-cell lymphoma of nasal type

These tumors represent less than 1% of all lymphomas in

Western countries but are more common in Asia and in

Native Americans of Central and South America, suggest-

ing a racial predisposition [68]. A number of names have

been used to describe these tumors in the past, including

lethal midline granuloma, polymorphic reticulosis, midline

malignant reticulosis, angiocentric immunoproliferative

lesion, and angiocentric lymphoma [68,69]. It is now

believed that most of these tumors are of NK-cell origin,

with a small subset of tumors being of T-cell lineage, hence,

the current name.

Clinically, extranodal NK/T-cell lymphomas of nasal

type have a propensity for involving extranodal sites, most

commonly, the nasal cavity, nasopharynx, and palate, and

are usually localized at time of diagnosis [68]. However,

these tumors can involve other extranodal sites, and relapses

commonly involve extranodal sites [70]. Lymph node and

bone marrow are involved rarely. These neoplasms may be

associated with a hemophagocytic syndrome [71].

Histologically, extranodal NK/T-cell lymphomas of nasal

type are composed of a mixture of atypical lymphoid

cells that can exhibit a wide cytological spectrum, admixed

with reactive lymphocytes, plasma cells, and histiocytes

[68,72,73]. Eosinophils and neutrophils are rare or absent.

In the early stages of disease, relatively few neoplastic cells

are present, and these cells may be of small size. As a result,

biopsy specimens obtained at an early stage of disease can

be misinterpreted as a benign process. Over time, these

neoplasms accrue greater numbers of large atypical cells,

and the diagnosis is more easily established. These neo-

plasms have a propensity for invading and destroying blood

vessels (Fig. 7), but angiocentricity is not a universal feature

present in 60% to 70% of cases [68].

Immunophenotypic studies of extranodal NK/T-cell

lymphomas of nasal type have shown that most neoplasms

express the NK-cell–associated antigen CD56 and NK/

T-cell–associated antigens such as CD2, CD7, and CD8

[68,70,74]. These tumors also express cytoplasmic CD3, but

are negative for T-cell–specific antigens such as surface

CD3, CD5, and T-cell receptors as well as the NK markers

CD16 and CD57. The neoplastic cells commonly express

T-cell intracellular antigen-1 (TIA-1), perforin, Fas, and Fas

ligand [75]. Tumors with large cell cytology often have p53

gene mutations [76].

Molecular studies of extranodal NK/T-cell lymphomas of

nasal type have demonstrated an absence of T-cell receptor

and immunoglobulin gene rearrangements in most cases

studied [73,74]. Epstein-Barr virus has been identified in the

tumor cells and is present in monoclonal form, indicating

that the virus is present before clonal expansion [73,74,77]

c-kit gene mutations have been detected in 70% of tumors in

China [78]. Recent comparative genomic hybridization

studies of these tumors have shown common chromosomal

losses at 1p, 12q, and 17p and gains at 2q, 10q, and 13q [79].

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Extranodal lymphomas of the head and neck

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