NK-Cell Lymphomas of the Head and Neck

Extranodal NKTCL manifests in the nasal cavity. Patients with this type tend to have earlier disease (stage I). However, later-stage presentations are observed, and the stage at presentation has an impact on the survival rate. Nasal NKTCLs are almost always (>95% of cases) associated with Epstein-Barr virus (EBV), irrespective of the ethnicity of the patient. The exact mechanism of malignant transformation via EBV has not been clearly elucidated.[8, 9, 10]

Extranodal nasal-type NKTCL demonstrates a predilection for the nasopharynx (see the image below), palate, skin, soft tissues, orbit, gastrointestinal (GI) tract, and testes. Secondary lymph nodes may be involved in some cases; a disseminated leukemic picture is even possible. Lymphomas that manifest outside of the nose have a strong association with EBV in Asian patients, but this strong association is not present in whites.

Coronal (left) and axial (right) CT scans of the sinus reveal severe pansinusitis with abnormal nasopharyngeal thickening, right facial edema and right temporal bone opacification.

The pattern of involvement of the extranasal sites has been hypothesized to be related to the marker CD56. CD56 represents the neural cell adhesion molecule (NCAM) that has been shown to have homophilic binding properties. With the skin, GI tract, and testes expressing the CD56 marker in large amounts, the neoplastic cells travel to these areas and set up foci of disease. The skin is the most common site of dissemination in NKTCL.

Risk factors for NKTCL are as follows:

• Inherited immunodeficiencies – Klinefelter syndrome, Chédiak-Higashi syndrome, ataxia telangiectasia syndrome, Wiskott-Aldrich syndrome, and common variable immunodeficiency disease

• Acquired immunodeficiency diseases – Iatrogenic immunosuppression, HIV-1 infection, and acquired hypogammaglobulinemia

• Autoimmune disease – Sjögren syndrome, celiac sprue, rheumatoid arthritis, and systemic lupus erythematosus

• Chemical or drug exposures – Phenytoin, dioxin, phenoxyl herbicides, irradiation, and prior chemotherapy or radiotherapy

• Association with infectious agents – EBV, human T-cell leukemia/lymphoma virus-I, and ataxia telangiectasia syndrome

NKTCL is very rare in whites; its prevalence is significantly higher in people of Asian descent. In Western populations, the prevalence of nasal lymphomas is estimated at 0.17-1.5% of all NHLs, 45% of which are thought to be NK-/T-cell in origin. Worldwide, NKTCL has a low prevalence, but it is much more prevalent in Asia, Mexico, and Central and South America.[11, 12, 13] Reported rates of nasal lymphoma in Hong Kong and South America range from 2.6% to 8% of all NHLs, of which 45% are thought to represent NKTCL.

Patients with NKTCL commonly present in their sixth decade of life, which is almost a decade younger than the age at which people with B-cell neoplasms present. However, the disease has been seen in both geriatric and pediatric populations.[14, 4] Men are more commonly affected with the disease than women, with a male-to-female ratio of almost 3:1.[14, 4, 12]

Using the Surveillance, Epidemiology, and End Results (SEER) Program database, Kommalapati et al determined that between 2001 and 2014, the US incidence of nasal NKTCL doubled, from 0.4 to 0.8 per 1,000,000 individuals. The incidence in Hispanic patients was significantly higher than that in non-Hispanic patients.[15]

A retrospective Brazilian study, by de Arruda JAA, of oral and oropharyngeal lymphomas found that mature T- and NK-cell neoplasms were the second most common group of these lymphomas (the most common being mature B-cell neoplasms [87.2%]). Moreover, extranodal NKTCLs made up the most frequent subtype of these neoplasms.[16]

Compared with other subtypes of lymphoma found in the head and neck region, NKTCL carries a much higher mortality and responds less well to traditional chemotherapy and radiotherapy regimens.[17] Overall, median survival time is reported as 12.5 months (although the aforementioned study by Kommalapati et al reported the median overall survival time for nasal NKTCL to be 20 months, with this period varying significantly with the disease’s primary site and NKTCL’s stage at diagnosis[15] ). Survival time for patients who present with a disseminated leukemic picture is reported to be less than 6 months. A complete response to primary treatment is reported in 56% of patients. Overall, the 2-year survival rate is 45%, and the 2-year disease-free survival (DFS) rate is reported at 31%.

A retrospective study by Su et al of 101 patients with extranodal NKTCL indicated that age 60 years or greater and the presence of Ann Arbor stage III/IV disease are independent risk factors for poor progression-free and overall survival. Median periods of progression-free and overall survival in the advanced-stage patients were 2.3 and 4.8 months, respectively.[18]

The poor survival rates and low rates of response to treatment in NKTCL are theorized to be secondary to the CD56 cell marker and the presence of a multidrug resistance (P-glycoprotein–positive) phenotype. CD56 is thought to facilitate tumor cell dissemination by virtue of its binding properties.

A study by Zhang et al indicated that higher levels of myeloid-derived suppressor cells (MDSCs), specifically, HLA-DR-CD33+CD11b+ MDSCs and CD14+ monocytic MDSCs, independently predict poor disease-free and overall survival in patients with extranodal NKTL. The MDSCs were found to suppress T-cell proliferation in these patients.[19]

On the other hand, a literature review by Chen et al indicated that the prognosis in extranodal NKTCL tends to be better when CD30, a tumor necrosis factor receptor superfamily member, is expressed. The investigators reported that CD30 expression is associated with a 41% relative decrease in hazard of death.[20]

NKTCLs have a higher local relapse rate (21.4%) than do either T-cell lymphomas presenting in the nasopharynx (5%) or B-cell lymphomas presenting in the nasopharynx (0%). Fewer recurrences in the cervical nodes are reported for NKTCLs (2.4%) than are reported for T-cell (10%) and B-cell (14.3%) malignancies.

Hemophagocytic syndrome, associated with fever, marked pancytopenia, hemophagocytic histiocytes in the bone marrow, and rapid liver function deterioration, is a devastating complication of NHL. This syndrome appears to be much more common in NKTCLs.

In a study involving 69 patients with early stage extranodal nasal-type NKTCL (58 with stage I and 11 with stage II) who received primary radiotherapy, high pretreatment Epstein-Barr virus (EBV)–DNA concentrations were associated with B symptoms, elevated lactic dehydrogenase (LDH) levels and a high International Prognostic Index score.[21] The investigators suggested that circulating EBV-DNA levels could serve both as a valuable biomarker of tumor load for accurate classification of early stage disease and as a prognostic factor.

Similarly, a literature review by Liu et al indicated that in patients with NKTCL, circulating EBV-DNA concentrations predict patient survival and treatment response. The investigators reported that overall and progression-free survival are poorer in individuals with both a high pretreatment EBV-DNA level and a detectable posttreatment concentration. Moreover, an apparent association was found between a high pretreatment level and a decreased treatment response.[22]

General manifestations of natural killer (NK)/T-cell lymphoma (NKTCL) include the following:

• Weight loss

• Fever

• Fatigue

• Night sweats

• Bone pain

Fewer than 20% of patients have B symptoms on presentation.

Head and neck manifestations include the following:

• Facial pain and swelling

• Diplopia

• Decreased visual acuity

• Orbital swelling

• Nasal obstruction

• Nasal septal perforation

• Purulent nasal discharge

• Refractory sinusitis

• Epistaxis

• Impaired hearing

• Palatal ulceration

• Odynophagia

• Dysphagia

• Velopharyngeal incompetence (VPI)

• Trismus

• Halitosis

• Otalgia

• Facial swelling

• Dyspnea

• Hoarseness

Pulmonary manifestations include the following:

• Cough

• Breathing restriction

Gastrointestinal (GI) manifestations include the following:

• Pain

• Abdominal fullness

• Early satiety

• Perforation

• Hemorrhage

Testicular pain may also be reported, as may nonhealing sores on the skin.

General findings on physical examination include the following:

• Ulcerations involving the skin

• Pallor

Head and neck findings include the following:

• Cranial neuropathies

• Visual impairment

• Orbital mass

• Proptosis

• Facial swelling and erythema (midline facial features)

• Serous otitis media

• Ulcerations of the palate, tonsil, nasopharynx, and larynx

• Nasal mass

• Neck mass

Pulmonary findings include the following:

• Cough

• Restricted breathing

GI findings include the following:

• Hepatosplenomegaly

• Abdominal mass

A testicular mass may be detected

The following laboratory studies should be performed:

• Complete blood count (CBC) – This may reveal anemia or lymphocytopenia

• Liver function tests, including assessment of lactic dehydrogenase (LDH) levels – Elevated LDH levels have been associated with poorer prognoses; these levels should be checked in every patient

• Renal function tests

• Uric acid and calcium levels

• Epstein-Barr virus (EBV) titers

Recommendations for the evaluation of T-cell lymphomas, developed by Vega et al under the auspices of the American Registry of Pathology, included suggestions regarding the optimal workup for extranodal NKTCL of the nasal and extranasal type. According to the recommendations, a T- and NK-cell marker panel, in situ hybridization for EBV-encoded RNA (EBER), and cytotoxic markers are most useful in the workup.[23]

Imaging studies are obtained to determine the full extent of disease for staging purposes. Computed tomography (CT) scanning of the neck, chest, abdomen, and pelvis is indicated. Neck CT scanning is important for detecting skull base erosion and intracranial extension.[4, 5] Magnetic resonance imaging (MRI) of the head (see the image below) is performed in cases of suspected skull base invasion and intracranial extension.[4, 5]

MRI revealed a low, non enhancing T1 signal in the right maxillary, ethmoid and sphenoid sinuses. (left) A high and inhomogeneous T2 signal suggested tumor involvement and destruction of the middle and inferior turbinates. (right)

Flexible nasopharyngoscopy with direct laryngoscopy should be performed to characterize the extent of the lesion.

Biopsy of the primary site should be done to characterize the morphology and to allow genetic studies (eg, for EBV) and immunohistochemical studies. Multiple large biopsy specimens should be obtained to provide adequate tissue for diagnosis. Repeat biopsy may be necessary if too much necrosis is present. Bone marrow biopsy may be done to assess for disseminated disease.

Lumbar puncture may be performed to determine whether intrathecal chemotherapy is indicated.

The histologic features of NK/T-cell lymphoma (NKTCL) are similar at all sites of presentation. Morphologically, these malignancies demonstrate a broad cytologic spectrum. Atypical cells that are small, medium-sized, or large may be observed. Most commonly, cells are medium-sized, with irregular nuclei, granular chromatin, small nucleoli, and pale-to-clear cytoplasm (see the image below).

High-power photomicrograph of a nasopharyngeal mass that was diagnosed as natural killer (NK)–/T-cell lymphoma, nasal type. In this section stained with hematoxylin and eosin, a diffuse infiltrate of variably sized cells with irregularly shaped nuclei that contain coarsely granular chromatin is visible. In other areas of this tumor, necrosis and angiocentrism could be appreciated.

An inflammatory cell infiltrate may be observed, most commonly with small-cell tumors. The infiltrate can include lymphocytes, plasma cells, histiocytes, and eosinophils; this explains the common use of the term polymorphic reticulosis in earlier classifications of these malignancies.

Atypical malignant cells possess moderately pale cytoplasm with azurophilic granules. Necrosis is almost always present, along with evidence of angioinvasion, which indicates a vascular pathogenesis (hence the use of the term angiocentric lymphoma in previous classifications). Florid pseudoepitheliomatous hyperplasia may also be present and may lead to a mistaken diagnosis of squamous cell carcinoma.[14, 24, 25, 6, 26]

Immunophenotypical tests demonstrate characteristic patterns for NKTCLs. The most commonly present cell markers are CD2+, cytoplasmic CD3e+, and CD56+. Other markers that may be present are CD7, CD30, CD43, CD45RO, HLA-DR, interleukin (IL)-2 receptor, Fas (CD95), and Fas ligand. Several markers are known to be associated with NK cells and T cells but are not found in NKTCLS, such as surface CD3, CD4, CD5, CD8, TCRg, TCRd, CD16, CD20, and CD57.[27, 28, 5, 29, 24]

On immunohistochemical testing, the findings of surface CD3-, cytoplasmic CD3e+, and CD56+ differentiate NKTCL from peripheral T-cell lymphoma (see the images below).

In this photomicrograph, immunohistochemical staining shows neoplastic cells to be positive for the pan T-cell antigen CD3 (positive cells have a brown tinge).

In this photomicrograph, immunohistochemical staining shows neoplastic cells to be positive for the natural killer (NK)–cell antigen CD56 (positive cells have a brown tinge).

In this photomicrograph, immunohistochemical staining shows neoplastic cells to be focally positive for granzyme B (positive cells have a brown tinge).

Genetic tests find EBV in most tumor cells (see the image below). The virus is present in a clonal episomal form. In most cases, T-cell receptor and immunoglobulin genes are in germline configurations. Various genetic abnormalities have been identified in patients with NKTCLs, but no specific chromosomal translocations have been identified.[5, 28]

In this photomicrograph, in situ hybridization for Epstein-Barr virus RNA (EBER) shows positivity in neoplastic cells (positive cells have black nuclei).

In the Ann Arbor classification, NKTCL is staged as follows:

• Stage I - Involvement in a single lymph node region or single extralymphatic site

• Stage II - Involvement of 2 or more lymph node regions on the same side of diaphragm, localized contiguous involvement of only one extralymphatic site and lymph node region

• Stage III - Involvement of lymph node regions on both sides of diaphragm; may include spleen

• Stage IV - Disseminated involvement of one or more extralymphatic organs with or without lymph node involvement

When added to any of these stage numbers, the letter E denotes extralymphatic sites, and the letter B indicates the presence of B symptoms (ie, fever, night sweats, or weight loss).

Because NK/T-cell lymphoma (NKTCL) of the head and neck is an extremely rare malignancy, a standard treatment protocol has not yet been delineated. Treatment planning should include consultations with hematologists, oncologists, and radiation oncologists.[5, 25, 6, 28, 30, 7, 31, 32, 33, 34, 35]

Early stage, localized disease may be treated with local radiotherapy; however, monotherapy may result in high rates of local and distant recurrence (up to 49%).[6, 7] Currently recommended treatment includes CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in conjunction with radiotherapy. The combination of treatments has yielded 5-year survival rates ranging from 20% to 80%. Unfortunately, disease progression commonly occurs despite treatment.[5, 25, 6, 28, 7, 31]

NKTCLs of the head and neck are associated with a high relapse rate, as well as a high degree of resistance to standard therapy. For these patients, alternative strategies have been investigated with some success. High-dose chemotherapy with or without total-body irradiation, followed by autologous stem cell rescue, has been used for patients with relapsing disease. In addition, treatments using the SMILE protocol (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) show promise, but adverse effects, including significant myelotoxicity, suggest that more research is needed to further develop this promising protocol.[32, 33, 34]

Takahara et al achieved good results with a treatment regimen for early stage nasal NKTL that included radiotherapy combined with infusion, through the superficial temporal artery, of ifosfamide, carboplatin, methotrexate, peplomycin, and etoposide. The study’s 12 patients achieved and maintained complete remission (observation period 39-111 mo), with copies of serum Epstein-Barr virus DNA dropping to undetectable levels in each patient.[36]

Surgical management of patients with NKTCL is limited to biopsy, stabilization of the airway if necessary, or debulking of disease.

Recent studies evaluating hematopoietic stem cell transplantation in patients with high-risk or refractory NKTCL show promise in select patients, but larger studies still need to be completed.[37] The presence of EBV in tumor cells may also prove to be an independent predictor of response to this and other therapies.[38]

Because of the relatively high mortality, low response rate, and high relapse rate after definitive treatment, patients should be regularly monitored by an otolaryngologist. The use of flexible nasopharyngoscopy is particularly important because of the high local recurrence rate for head and neck NKTCL.

Cancer chemotherapy is based on an understanding of tumor cell growth and on how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S), the premitotic phase (phase G2), and, finally, mitotic cell division (phase M).

Cell division rates vary for different tumors. Most common cancers grow slowly in comparison with normal tissues, and the growth rate may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells, and it is the rationale for current cyclic dosage schedules.

Today, most patients are treated with the chemotherapy regimen known as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in conjunction with radiotherapy.

Class Summary

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle–specific, whereas others (eg, alkylating agents, anthracyclines, and cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

Cyclophosphamide

Cyclophosphamide alkylates and cross-links DNA.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline. Its multiple mechanisms of action involve DNA intercalation, topoisomerase-mediated DNA strand breakage, and oxidative damage due to free radical production.

Vincristine (Vincasar PFS)

Vincristine inhibits microtubule formation in the mitotic spindle, causing metaphase arrest.

Prednisone

Prednisone is an immunosuppressant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity.