Laboratory Studies
The following laboratory studies should be performed:
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Complete blood count (CBC) – This may reveal anemia or lymphocytopenia
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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
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Renal function tests
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Uric acid and calcium levels
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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]
CT and MRI
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)
Other Studies
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.
Histologic Findings
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).
Staging
In the Ann Arbor classification, NKTCL is staged as follows:
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Stage I - Involvement in a single lymph node region or single extralymphatic site
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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
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Stage III - Involvement of lymph node regions on both sides of diaphragm; may include spleen
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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).
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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.
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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)
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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.
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In this photomicrograph, immunohistochemical staining shows neoplastic cells to be positive for the pan T-cell antigen CD3 (positive cells have a brown tinge).
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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).
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In this photomicrograph, immunohistochemical staining shows neoplastic cells to be focally positive for granzyme B (positive cells have a brown tinge).
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In this photomicrograph, in situ hybridization for Epstein-Barr virus RNA (EBER) shows positivity in neoplastic cells (positive cells have black nuclei).
