Haematolymphoid tumours

Non-Hodgkin lymphoma Definition

Primary non-Hodgkin lymphomas (NHL) of the nasal cavity or paranasal sinuses are defined as lymphoid cell neoplasms in which the bulk of disease occurs in these anatomic sites.

Synonyms

Most cases described in the past as polymorphic reticulosis, malignant mid-line reticulosis, lethal midline granuloma or angiocentric immunoproliferative lesion, are now reclassifiable as extran-odal NK/T cell lymphoma of nasal-type.

Epidemiology

Malignant lymphoma is the second most common malignancy of the nasal cavity and paranasal sinuses, following squamous cell carcinoma {1013}. It accounts for 14% of all cancers in these sites {1013}.

Although many different types of NHL can occur in the nasal cavity, the most common lymphoma type is extranodal NK/T cell lymphoma of nasal-type, especially in Asian populations {5,420}. The relatively high prevalence of this lymphoma type in Asians and Latin Americans also accounts for the higher overall incidence of nasal lymphomas in these populations as compared with Caucasian populations {58,2104}. Other

Fig. 1.74 Extranodal NK/T cell lymphoma of nasal cavity in a 69-year-old patient who presented with painful nasal swelling. MRI showed tumour involvement of the left nasal cavity, left ethmoidal and maxillary sinuses.

peripheral T-cell lymphomas, such as anaplastic large cell lymphoma, can also occur in the sinonasal region.

Lymphomas presenting in the paranasal sinuses are frequently B-cell lymphomas, with diffuse large B-cell lymphoma (DLBCL) being the most common {5,551,1837}. Other B-cell lymphomas that can involve the sinonasal regions include Burkitt lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma of MALT type, and mantle cell lymphoma {5}. Please also refer to the section of non-Hodgkin lymphomas in Chapter 4 on tumours of the oral cavity and oropharynx.

NHL of the nasal cavity and paranasal sinus is primarily a disease of adults, with male predominance. Patients with extra-nodal NK/T cell lymphoma of nasal-type have a male to female ratio of 3:1, and a median age of 53 years {420}. Patients with DLBCL are generally one decade older (median age 63 years), and the male to female ratio is 1.2:1 {5,420}. Children may rarely present with NHL of the nasal cavity and the paranasal sinuses, with Burkitt lymphoma being the most common type {2808}.

Etiology

The etiology is unknown, but extranodal NK/T cell lymphoma of nasal-type is strongly associated with Epstein-Barr virus (EBV) irrespective of the ethnic background of the patients {68,376, 1107,1263,1347,2671,2828}. There is only a weak association between B-cell lymphomas in the nasal cavity and the paranasal sinuses with EBV {376,511, 2617,2740}.

Immunosuppression (e.g. post-transplant, HIV infection) is associated with an increased risk of developing NHL, including in the nasal cavity and paranasal sinuses. Although the majority of the cases in immunosuppressed patients are DLBCL {511,2068}, extranodal NK/T cell lymphoma of nasal-type has also been reported {328}. Most of the NHL that arise in the setting of immuno suppression are also EBV-related {511}. Localization

Lymphomas of the nasal cavity are often locally destructive, with obliteration of the nasal passages and maxillary sinuses. In particular, extranodal NK/T cell lymphoma can involve the adjacent alveolar bone, hard palate, orbit and nasopharynx in over half of the cases {1948}. Lymphomas of the paranasal sinuses commonly show bony destruction and local extension to adjacent structures including the orbit, palate, nasal cavity, nasopharynx, and soft tissues in the cheek and infratemporal fossa {511, 1836,1837}. Maxillary sinus is the most commonly involved paranasal sinus.

Clinical features

Patients may present with nasal obstruction, epistaxis, nasal discharge, pain and nasal swelling or facial swelling. Locally advanced cases can cause destruction of midline facial structures. The nasal septum or palate may be perforated. Extension to the orbits can lead to prop-tosis and visual disturbance. Regional lymph node involvement may occur in some patients. Occasional patients have systemic symptoms including fever and weight loss. Haemophagocytic syndrome with pancytopenia occurs at presentation in a minority of patients with extranodal NK/T cell lymphoma of nasaltype {420,2533}.

Fig. 1.75 CT scan of nasal NK/T cell lymphoma. The tumour involves the nasal cavity mainly on the left side, with extension to the medial part of the left maxillary sinus and the left ethmoidal sinuses.
Fig. 1.76 Nasal NK/T cell lymphoma. A In this example, the mucosa is intact and expanded by a diffuse infiltrate of lymphoma cells. B The mucosal lymphoid infiltrate is destructive, resulting in separation and loss of mucosal glands.
Segregation Lymph Nodes Mucosa
I t \, (4. ■ ■■

Fig. 1.77 Nasal NK/T cell lymphoma. A This case shows marked pseudoepitheliomatous hyperplasia, mimicking squamous cell carcinoma. B Note angiocentric and angiodestructive growth.

Tumour spread and staging

The majority (80%) of patients with extra-nodal NK/T cell lymphoma of nasal-type have localized disease at presentation (Stage IE/IIE) {420,1500,1505}. Bone marrow involvement at presentation is uncommon {2810}. Although extranodal NK/T cell lymphoma often shows localized disease at presentation, spread to other sites (such as skin, gastrointestinal tract, liver, lymph node, testis) during the course of disease is common. Most of the patients (75%) with DLBCL of the nasal cavity and the paranasal sinuses present with low clinical stage (IE/IIE) {420,511}. In contrast to extranodal NK/T cell lymphoma, cervical lymph node involvement is more frequent at presentation (60%), and the common sites of relapse are lymph node, liver and lung {420}.

Extranodal NK/T cell lymphoma ICD-O code 9719/3

Extranodal NK/T cell lymphoma of nasal-

type is characterized by a diffuse lym-phomatous infiltrate expanding the nasal or paranasal sinus mucosa, with wide separation and destruction of the mucos-al glands, which may undergo a peculiar clear cell change. Extensive coagulative necrosis and frequent apoptotic bodies are very common, as are ulceration, angiocentricity, angiodestruction and fib-rinoid deposits in vessel walls. The lymphoma cells vary in size in different cases, ranging from small through medium-sized to large. Some nuclei have an irregular outline, while others can be round or oval. The cells have a moderate amount of pale cytoplasm, and cytoplasmic azurophilic granules can be identified in Giemsa-stained touch preparations. Some cases are associated with a rich inflammatory infiltrate, consisting of small lymphocytes, histiocytes, plasma cells and eosinophils. Occasionally pseudoepitheliomatous hyperplasia of the overlying squamous epithelium may occur, mimicking well differentiated squamous cell carcinoma.

Immunoprofile and genetics

The lymphoma most commonly exhibits an NK-cell immunophenotype of CD2+, surface CD3(Leu4)-, cytoplasmic CD3+, CD56+ {1196}. CD43 and CD45RO are commonly positive, but other T-cell markers (including CD5) and NK-cell markers (CD16, CD57) are usually negative. The tumours commonly exhibit a cytotoxic phenotype with expression of perforin, TIA1, and granzyme B {662,1773,1878, 1935}. Fas (CD95) and Fas ligand expression are frequent, and may account for the extensive necrosis {1877,1935}. Expression of the various NK cell receptors is variable. P-glycopro-tein/MDR1 is often expressed (90%), and may explain the poor response to chemotherapy {2838}. The T-cell receptor genes are often in germline configuration {1196}. Practically all cases (>95%) are associated with EBV {68,376,1 107,1263,1347,2671,2828}. The virus is best demonstrated in the tumour cells by in situ hybridization for EBER (EBV-encoded early RNAs) {376}. The EBV is in clonal episomal form, pro-

SHMEm

Fig. 1.78 Nasal NK/T cell lymphoma: the cytological spectrum. A Predominantly small cells that are slightly larger than small lymphocytes. Most cells show mild nuclear foldings. B Predominantly large cells. There are many intermingled apoptotic bodies. C This example is predominated by small lymphoid cells. The admixture of plasma cells may give the impression of a reactive inflammatory process (so-called polymorphic reticulosis). Note presence of mitotic figures.

viding additional evidence of the clonal nature of the lesion {1107,1693}. Some cases are CD56 negative, but are still classified as extranodal NK/T cell lymphoma provided they express T-cell markers and cytotoxic markers, and are EBV positive. These cases may show clonally rearranged T-cell receptor genes and may represent a neoplasm of cyto-toxic T-lymphocytes {426}. T-cell lymphomas which lack cytotoxic markers or evidence of EBV infection are diagnosed as peripheral T-cell lymphoma unspecified. Lymphoblastic lymphoma of probable NK-cell lineage (or so-called blastic NK-cell lymphoma) with expression of CD56 and TdT and no EBV association has also been described in the nasal cavity, but this is an entity distinct from the extranodal NK/T cell lymphoma of nasal-type {1352,1838}.

Differential diagnosis

Since the tumour cells of extranodal NK/T cell lymphoma can be masked by a prominent inflammatory infiltrate, the lesion can be mistaken as an infective, inflammatory or granulomatous lesion (including Wegener granulomatosis). It is not uncommon that a definitive diagnosis can only be reached after repeated biopsies. While Wegener granulomatosis sim ilarly presents with destructive nasal lesion, simultaneous pulmonary involvement may be present. There is serologic positivity for cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA), and the main histologic findings are chronic inflammation with microabscesses and histiocytic infiltrate, in the absence of atypical lymphoid cells. In those examples of extranodal NK/T cell lymphomas dominated by small cells with minimal atypia, a definitive diagnosis can be difficult to make. An angio-centric infiltrate with expansion of the mucosa and mucosal gland destruction, coupled with prominent necrosis, should raise suspicion for the diagnosis of extranodal NK/T cell lymphoma. Confirmation of the diagnosis can be made by demonstrating sheets of CD3+, CD56+ and EBER+ cells.

Some non-lymphoid CD56+ small round cell tumours (e.g. olfactory neuroblastoma, Ewing sarcoma/primitive neuroec-todermal tumour, rhabdomyosarcoma) also enter in the differential diagnoses. However, these can be easily excluded by appropriate immunohistochemical stains {1532}.

Diffuse large B-cell lymphoma ICD-O code 9680/3

In DLBCL of the nasal cavity or paranasal sinuses, the mucosa shows dense, diffuse and interstitial infiltration by large or medium-sized lymphoid cells. There may or may not be ulceration and necrosis. Occasional cases show angioinvasion. The tumour cells may resemble centroblasts or immunoblasts, or have a non-specific blastoid appearance. The nuclei are round, multilobated or irregularly folded, with multiple small membrane-bound nucleoli or single central prominent nucleolus. The tumour cells express pan-B markers (e.g. CD20, CD79a). Extramedullary myeloid sarcoma, plasmacytoma, undifferentiated carcinoma and amelanotic melanoma may resemble DLBCL, but these entities can be readily distinguished by appropriate immunohistochemical stains.

Histogenesis

Most cases of extranodal NK/T cell lymphoma of nasal-type are activated NK-cell neoplasms, while some appear to be neoplasms of cytotoxic T-cells {425}. DLBCL are mature B-cell neoplasms at either the germinal centre or post-germinal centre stage of differentiation.

Somatic genetics

A number of cytogenetic abnormalities

Table 1.4 Non-Hodgkin lymphomas in the nasal cavity or paranasal sinuses: differences in distribution according to cell lineage.

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