Nasal-type extranodal NK/T cell lymphoma (NK/TCL) is a rare malignancy that usually presents as a destructive midline lesion in the nasal region. The incidence of nasal-type extranodal NK/TCL has been reported to be much higher in Asia and South America than in North America and Europe. Its diagnosis mainly relies on histopathological and immunohistochemical examinations. Most patients demonstrate rapid disease progression and short survival. This report concerns a 37-year-old male with nasal-type extranodal NK/TCL showing severe facial disfigurement who was initially misdiagnosed as having Aspergillus infection. The report emphasizes the clinical manifestations and the importance of pathological diagnosis.
Nasal NK/T cell lymphoma (NK/TCL), formerly known as lethal midline granuloma, is a distinct malignancy of the human lymphoid system. Epidemiological studies have reported a remarkable racial difference in the incidence of NK/TCL. It is rare among Caucasians, but common in Asians, especially in the southern Chinese population. NK/TCL generally occurs in male adults and has a marked propensity to occur in the nasal cavity and paranasal sinuses. Other sites of involvement include skin, soft tissue, gastrointestinal tract and testis.
Evidence of Epstein-Barr virus (EBV) involvement can be detected by in situ hybridization for EBV-encoded small nuclear RNAs (EBERs) in the majority of NK/TCL cases. The prevalence of EBV seems to be related to the geographical origin of the patient and the sites involved. Angiocentric and angiodestructive growth patterns accompanied by extensive necrosis are the common and distinctive histological findings in NK/TCL. The tumour cells typically have a cytotoxic T-cell and NK-cell phenotype with expressions of cytoplasmic CD3ε, CD56 and cytotoxic molecules (such as granzyme B, TIA-1 and perforin). The misdiagnosis rate is high in clinical practice due to its rarity, the lack of well-established etiologic and genetic data, and the heterogeneity of its histopathology and clinical behaviour. This report presents an unusual case of non-EBV-associated extranodal nasal-type NK/TCL. Repeated biopsies from ulcer sites were taken in district hospitals and histopathological examinations were suggestive of infection. Hence, the patient did not receive appropriate treatment and suffered from a recurrent and progressively enlarging ulcer in the mid-facial region. The last biopsy was taken in the authors’ hospital and a final diagnosis of NK/TCL was made. The authors describe the clinical presentation and discuss the diagnostic challenge of this rare disease to highlight the importance of representative biopsy and the histopathological examination for reaching an accurate diagnosis.
A 37-year-old Chinese male who experienced a 2 year history of erythema, papule and ulcer on his face with rapid clinical progression was referred to the authors’ hospital in March 2009.
About 2 years ago, the patient was asymptomatic but noticed an erythematous papule, the size of a green bean, at the left root of his nose. Four months later, he went to the department of otorhinolaryngology (ENT) at the local hospital due to a sore throat, voice change and choking. At that time, the papule was found to expand to the tip of nose and upper lip, and a 3 mm diameter perforation in the palate was observed. A biopsy was taken from the perforation site and the histopathological examination was suggestive of Aspergillus infection. The patient refused to be treated. The skin lesion grew gradually accompanied by recurrent ulceration which underwent natural repair with scar formation and sometimes with delayed healing. Four months later, the patient was treated with dexamethasone, gentamicin, piperacillin and some traditional Chinese medicines in an unknown hospital. The ulceration became worse with a tissue defect in the upper lip, nose and nasal septum resulting in the exposure of the upper and lower teeth roots. The swelling of the skin with red discoloration made it difficult for him to open his eyes. Two months before his admission to the authors’ hospital, a diagnosis of mucormycosis was made based on a second biopsy of the ulcer on his forehead in another hospital. The treatment the patient received remained ineffective.
On admission to the authors’ hospital, a special examination of the oral and maxillofacial region revealed loss of soft tissue of the upper lip, part of the lower lip, most of the palatine lamina of maxilla, alveolar bone, gum of anterior maxilla and the soft palate. A series of laboratory tests were performed including a complete blood count, urinalysis and comprehensive metabolic panel. All the test results were in the normal range including kidney function assessment (blood, urea, nitrogen and creatinine).
The clinical differential diagnosis included fungal infection (mucormycosis), rheumatologic processes such as Wegener’s granulomatosis (WG), and malignant tumours including squamous cell carcinoma and lymphomas. To assist accurate diagnosis, serum autoantibody titres were measured. The autoantibodies included ANA (anti-nuclear antibodies), anti-dsDNA (double-stranded DNA), anti-Sm, anti-SSA (Ro), anti-SSB (La), anti-RNP, anti-Jo1, anti-Scl-70 and ANCA (anti-neutrophil cytoplasmic antibody) were all negative. Other serology tests including HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, HCV Ab, HIV Ab, anti-TB, EBV IgM and rapid syphilis serum test were also negative. The chest radiograph did not show any evidence of cardiopulmonary disease or mediastinal mass. An abdominal computed tomography (CT) scan did not reveal any abnormalities in the liver or spleen, and a renal ultrasound examination was normal. CT scanning of the head showed normal brain structure, hypertrophy of nasal mucosa in bilateral maxillary sinuses, ethmoid sinus and right sphenoid sinus, as well as lack of the nasal cavity structure.
The midfacial ulcer became larger and deeper with the involvement of bilateral cheeks and deep muscles ( Fig. 1 ). The patient received antibiotic and antifungal treatment and surgical debridement of necrotic tissue. After the effective control of inflammatory process, biopsies of the ulcer lesion from the deep part of the forehead, lower lip and muscle tissues in bilateral cheeks were performed.
The biopsied specimen obtained from the ulcer lesion showed obvious granulation tissue with abundant inflammatory infiltration, with focal and scattered atypical lymphoid cells ( Fig. 2 ). The lymphoid cells were medium in size and had clear cytoplasm and irregular nuclei with inconspicuous nucleoli. Some multinucleated large cells were also seen ( Fig. 2 B). A few atypical lymphoid cells infiltrated the vascular wall ( Fig. 2 ). Mitotic figures were easily found ( Fig. 2 B). Immunohistochemically, the atypical lymphoid cells were positive for cytoplasmic CD3ε ( Fig. 3 A ) TIA-1 ( Fig. 3 B) and partially positive for CD56 and granzyme B, while negative for CD8, CD20, PAX-5 and cytokeratin. Ki-67 labelling index was about 40%. In situ hybridization did not detect EBER1 EBV RNA. The polymerase chain reaction for T-cell receptor-gamma and -delta gene rearrangement was negative, indicating a NK/T cell origin. Special stains failed to detect fungal and bacterial organisms although biopsies of muscle tissue demonstrated the presence of fungal infection (rhizomucor, supported by fungal culture and drug sensitivity test) with aggregates of fungal mycelium and spores, as well as abundant megakaryocytes. No tumour cells were noted in biopsied muscle tissue.