June 2014

A 71 year-old man with a nasal mass

Dr. Lu, Dr. Howell, Dr. Vos

Overview

71-year-old male with history of meningioma and prostate adenocarcinoma presents with left eye swelling, nasal congestion, and a left nasal mass. An MRI shows a very large left nasal mass that obstructs the left maxillary sinus. The mass obliterates the left nasolacrimal duct and extends through a disrupted nasal bone into the soft tissues around the left orbit and the nasal bridge.

Gross Description

The patient underwent biopsy of the left nasal mass. H & E stained sections shows a dense infiltrate or intermediate to large atypical cells (Figure 1A-D). Focal sinonasal mucosa is present (Figure 1B and 1C).  The atypical cells are characterized by ovoid to irregular nuclei, small nucleoli and abundant pale cytoplasm (Figures 1C and 1D). Mitotic figures are easily identified and numerous small lymphocytes are scattered in the background. In addition, focal areas of geographic necrosis and angiocentric growth are present (not shown).

By immunohistochemistry, the atypical infiltrate is positive for CD3 (Figure 2A) and TIA-1 (Figure 2C); in addition, the infiltrate is positive for CD2, CD56, Bcl-2 and CD43 (not shown). The infiltrate is negative for CD4, CD8, CD5, CD7 and cyclin D1 (not shown). CD30 highlights a small subset of larger cells (not shown). Scattered small CD4+ and CD8+ T-cells are present in the background. CD20 highlights rare B-cells (Figure 2B). CD21 and CD23 show no evidence of dendritic meshwork and no germinal centers are identified by CD10 or bcl-6 (not shown). Scattered plasma cells were noted by CD138 stain; they are polyclonal by light chain in-situ hybridization stains (not shown). The infiltrate is positive for EBER by in-situ hybridization (Figure 2D). Additionally, Ki-67 highlighted approximately 50% of atypical infiltrate (Figure 2E). Flow cytometry was non-contributory due to insufficient cellularity.

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Figure 1: H & E stained sections of the nasal mass at 100x (A), 200x (B), 400x (C) and 1000x (D) magnification.
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Figure 2: The atypical infiltrate is positive for CD3 (A); Scattered B-cells are identified by CD20 (B). The infiltrate is additionally positive for TIA1 (C). The infiltrate is positive for EBER by in situ hybridization (D). Ki-67 highlights many of the atypical cells within the infiltrate (E, approximately 50% overall).

Diagnosis

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Answer

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Discussion

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) has been previously diagnosised as lethal midline granuloma and as angiocentric T-cell lymphoma. ENKTCL is a lymphoproliferative disorder composed of T-cells/NK-cells with prominent angio-invasion and tissue necrosis. Clinically, it is characterized by destruction of the nasal cavity by an ulcerated mass. The mass often involves the nasopharynx and paranasal sinuses and can extend to the orbit, oral cavity, palate and oropharynx.[1,2,3] Extranasal sites of involvement have been reported; these most often involve skin, soft tissue, gastrointestinal tract and testis.[1,2] ENKTCL is rare, but has a predilection for adult males from Asia (China, Japan, Korea) and Central/South America (Mexico and Peru).[3] In these locations, it accounts for 5-10% of non-Hodgkin lymphomas.[3]

The etiologic attributions to ENKTCL include genetic abnormalities, hypersensitivity to mosquito bites (HMB), and viral factors.[1,3] The most frequently observed cytogenetic abnormalities are del(6)(q21q25) and i(6)(p10).[2] Other genetic abnormalities implicated in ENKTCL include: mutations in the p53 gene, ras oncogene, and Fas gene, downregulation of class I HLA antigen, deletion within chromosome 6q, defects of p15, p16, and p14 tumor suppressor genes, and excess methylation of p73.[1,3]

Furthermore, a relationship between Epstein-Barr virus (EBV) and ENKTCL has been established. The presence of EBV, almost always of subtype A, can be frequently found in clonal populations with type II latency pattern.[2] These clonal cells express multiple EBV viral antigens including: EBV nuclear antigen 1 (EBNA-1), latent membrane protein 2 (LMP2), and latent membrane protein 1 (LMP1) with a 30-base pair deletion.[1,3] The association with EBV allows disease activity to be monitored through the measurement of circulating EBV DNA.[2] A marked increase in the viral copy number is a poor prognostic indicator and is associated with limited responsiveness to therapy and poor survival.[2]

Hypersensitivity to mosquito bites (HMB) is a rare condition which manifests with intense local cutaneous reactions and fever along with lymphadenopathy and hepatosplenomegaly after a challenge of mosquito bites.[1,3] It has been observed that patients with HMB frequently have chronic active infection with EBV.[1,3] These patients often develop lymphoproliferative disorders. [1,3] Hemophagocytic lymphohistiocytosis and NK-cell lymphomas are two such entities; these frequently result in death.[1,3] A common pathogenesis is proposed for HMB, EBV infection, and NK-cell leukemia/lymphoma as a result of these observations.[1,3]

Histopathologically, ENKTCL is composed of a diffuse proliferation of variably sized atypical lymphocytes with oval to irregular nuclei, indistinct nucleoli and moderate to voluminous cytoplasm. Brisk mitotic activity is observed. The extensive mucosal ulceration overlying this lesion sometimes results in pseudoepitheliomatous hyperplasia. The atypical lymphocytes tend to grow in an angiocentric and angiodestructive pattern that eventually results in geographic and coagulative necrosis with surrounding granulomas.[2]

Immunophenotypically, the cells in ENKTCL lack detectable expression of most T-cell markers, such as CD3, CD4, CD5, CD7, CD8, TCRβ and TCRδ. However, the ε chain of the CD3 molecule is frequently positive, in addition to CD2, CD56, and cytotoxic proteins like TIA-1 and perforin. EBV positivity is often demonstrated by in situ hybridization.[2]

The prognosis of extranodal T/NK cell lymphoma, nasal type, is variable; however, systemic chemotherapy remains the treatment of choice.[1,2,3] In addition to high circulatin levels of EBV DNA, additional negative prognostic factors include: advanced disease stage, invasion of bone or skin, and presence of EBV-positive malignant cells involving the bone marrow.

References

  • Al-Hakeem DA, Fedele S, Carlos R, Porter S. Extranodal NK/T-cell lymphoma, nasal type. Oral Oncology. 2007. 43: 4-14.
  • Swerdlow HS, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2008:285-288.
  • Metgud RS, Doshi JJ, Gaurkhede S, Dongre R, Karle R. Extranodal NK/T-cell lymphoma, nasal type (angiocentric T-cell lymphoma): A review about the terminology. J Oral Maxillofac Pathol. 2011. 15: 96-100.