Nasal natural killer cell lymphoma presenting as lethal midline granuloma
Authors: Yamazaki Masashi , Kakuta Mie , Takimoto Reiko , Murayama Noriko , Takamori Kenji 
Published: March 2003

A 65‐year‐old man was admitted to hospital on November 26, 1998 with multiple tumors and ulcers on his lower extremities. The patient had been suffering from deafness since childhood. Nine months before admission, his right breast became swollen. Multiple tumors appeared on his legs and increased in number and size, some of them becoming ulcerated. During the same period, the patient began to experience nasal occlusion and worsening of his deafness. Although his sister had already died as a result of leukemia, a definite diagnosis and details of her clinical course were unknown. Physical examination revealed multiple tumors and ulcers on the bilateral lower extremities (Fig. 1) and right breast. There were advanced ulcerated tumors in the patient's nasal cavity. Magnetic resonance imaging showed that the nasal cavity was obstructed by neoplasms (Fig. 2). A gallium scintigram of the whole body revealed that the neoplasms were localized to the nasal cavity, the right breast, and the lower extremities. Metastasis to internal organs or bone marrow was not found. Laboratory examinations showed the following values. The white cell count was 5000/mm3 (4000–8000/mm3 ) with 72.6% neutrophils (45–60%), 18.2% lymphocytes (25–45%), 7.0% monocytes (4.0–7.0%), 0.5% eosinophils (1.0–5.0%), and 0.4% basophils (0–1.0%). The erythrocyte sedimentation rate was 76 mm/h (< 10 mm/h). The C‐reactive protein was 4.8 mg/dL (< 0.3 mg/dL). Aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were 38 U/L (13–33 U/L), 41 U/L (8–42 U/L), and 552 U/L (119–229 U/L), respectively. A test for antibodies to the adult T‐cell leukemia virus associated antigen was negative. The titers of antibodies to Epstein–Barr virus capsid antigen (EBVCA) immunoglobulin G (IgG) and EB‐determined nuclear antigen (EBNA) were 2500 (< 10) and 20 (< 10), respectively. An audiogram showed a severe conductive deafness.

One of the ulcerated tumors of the lower extremities

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The nasal cavity was filled with neoplasms (magnetic resonance imaging). Arrowheads indicate tumor mass in the nasal cavity

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All of the biopsy specimens taken from the lower extremities, breast, and nasal cavity revealed the same histologic feature consisting of atypical, small‐ to medium‐sized lymphocytes with irregularly shaped nuclei (Fig. 3a). An electron micrograph showed dense core granules in the cytoplasm (Fig. 3b). Angiocentric or angiodestructive invasion was not found. According to the fluorescein activated cell sorter (FACS), the tumor cells were CD2 (receptor of leukocyte function associated antigen) and CD56 (neural cell adhesion molecule) positive, whereas CD3 (T‐cell receptor associated molecules), CD4 (which binds to major histocompatibility complex (MHC) class II), CD6, CD7, CD8 (which binds to MHC class I), as T‐cell markers, CD10 (neural endopeptidase), CD19 (B4), CD20 (B1, Bp35), as B‐cell markers, and CD13, CD14, CD33, CD41, as the markers for myeloid cells, were negative. Neither β nor γ chain rearrangement of T‐cell receptors was detected in southern blotting. Using the specific primers (sense 5′‐TCGTCGTCCAGCAAGAAGAG‐3′ and antisense 5′‐CAACTTGAGGCAGCCTAATCC‐3′) for the EBV genome, the predicted polymerase chain reaction (PCR) product was detected using DNA extracted from the tumor cells.

(a)  Atypical, small‐ to medium‐sized lymphocytes with irregularly shaped nuclei (hematoxylin and eosin staining; original magnification, × 314). (b)  Dense core granules in the cytoplasm of atypical lymphocytes (electron micrograph; original magnification, × 25,000)

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After the disease had been diagnosed as nasal natural killer (NK) cell lymphoma (stage IV of Ann Arbor classification), the patient was treated with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) twice in December 1998 and January 1999. As a result, the tumor size in the extremities and breast diminished, while audiogram tests showed a concomitant improvement in the patient's deafness. Nonetheless, the patient began to exhibit incomplete right hemiplasia and left facial palsy, which advanced in spite of treatment. Because the neural abnormality was thought to be due to the invasion of nasal tumor cells into the central nervous system and the peripheral facial nerve, radiation therapy was prescribed for the nasal cavity. This was not effective even when the total amount of radiation was increased to 26 Gy using a linear accelerator (linac). The patient died due to respiratory failure in February 1999.