Angiogenic non-Hodgkin T/natural killer (NK)-cell lymphoma: report of three cases.

Abstract

Angiogenic T/natural killer (NK)-cell lymphoma is a non-Hodgkin lymphoma characterized by necrosis and vascular destruction that is strongly associated with Epstein-Barr virus and AIDS. Early diagnosis is essential to improve the chances of patient survival, but severe local inflammatory infiltrate impairs histologic diagnosis by obscuring neoplastic cells. The most common markers are CD2, CD56, cytoplasmic CD3, and CD43 EBV. We describe 3 cases of angiogenic T/NK-cell lymphoma that show the diverse presentation of the same disease. Patient 1 was HIV positive and had nasal obstruction, facial edema, and ulceration of the nasal mucosa. Patient 2 had fever, a sore throat, and weight loss. Patient 3 had facial edema, fever, proptosis, and rapid development of neurologic alterations. Several biopsies were needed for histologic confirmation in these patients, despite positivity for the CD3 and CD56 markers.

Introduction

Approximately 3 to 5% of malignant neoplasias are lymphomas, and 60% of those are non-Hodgkin lymphomas. (1) Among patients with AIDS, the incidence of non-Hodgkin lymphoma is 4 to 10%. (1) Lymphomas are divided into B-cell, T-cell, and natural killer (NK)-cell types. (2) Evidence of the presence of Epstein-Barr virus (EBV) is found in almost all T-cell lymphomas. (2-7) Lymphomas that express a T/NK phenotype usually have an angiogenic growth pattern, characterized by necrosis and vascular destruction. (3) These lesions occur most often in the nasal fossae but also can involve skin, soft tissues, testicles, upper airways, and the gastrointestinal tract. (1,3,6) Non-Hodgkin lymphoma in patients with AIDS commonly involves the central nervous system, gastrointestinal tract, bone marrow and, more rarely, the nasal fossae. (1)

Nasal angiogenic T/NK-cell lymphomas are rare in the United States and Europe but are more common in Asia and regions of South and Central America. (1-6) In Asia they represent up to 7% of all non-Hodgkin lymphomas, (4) compared with only 0.2 to 2% in the United States and Europe. In Brazil the incidence is unknown, but these tumors mainly affect males (male-to-female ratio, 9:4) of the white race (92%) at an average age of 49 years. Among Brazilians, sinonasal lymphomas occur most frequently (56%), followed by lymphomas of the palate (7 to 28%), nasopharynx (2 to 3%), and oropharynx (1 to 4%). (2)

In the worldwide population, the mean age at presentation of angiogenic lymphomas is approximately 50 years. (5) The most common signs are nasal obstruction with posterior discharge, intranasal mass, facial edema, epistaxis, and palate lesion (table). (1) Angiogenic T/NK-cell lymphomas are rare in children, with a predominance of those formed by B cells. (8) In most cases, they involve boys at a mean age of 5 years, and diagnosis is established early in only 15% of cases. (8) The most common signs in children are facial and cervical edema, epistaxis, and proptosis, and the most common primary sites are the maxillary sinus and palatine tonsils. (8)

In general, the lesions are destructive and often cause ulceration of the mucosa. (5) Histologic examination reveals lesions with an exuberant inflammatory infiltrate, which impairs diagnosis because of difficulty in visualizing neoplastic cells. (5) Cytologic characteristics are varied; small, medium, large, and hyperchromatic cells maybe present. (5) Histochemistry usually reveals positivity for CD2, CD56, cytoplasmic CD3, CD45RO, and CD43 EBV. (2,4-7) The 5-year survival rate is 40%. (1)

We report 3 clinical cases seen in our service that demonstrate the diversity of presentation, diagnostic difficulty, and evolution of the disease.

Case reports

Patient 1. A 28-year-old HIV-positive man was seen in the otorhinolaryngology service of our institution reporting a 5-month history of an ulcerated nose lesion associated with pain, local edema, cacosmia, posterior nasal discharge, nasal obstruction, and purulent rhinorrhea. He reported worsening of symptoms 15 days earlier, with fever, hyperemia, and palpebral edema on the left. He had been taking several antibiotics and had been using ketoconazole for 1 month with no improvement. He denied previous diseases.

On physical examination, the patient had edema and left palpebral hyperemia, with preserved ocular motility. Anterior rhinoscopy revealed an ulcerated lesion with raised borders in the left ala nasi and a wide anterior perforation of the nasal septum. Oroscopy revealed no lesions. Nasal endoscopy showed osteocartilaginous destruction of the nasal septum, a partially destroyed left nasal turbinate, and the presence of fibrosis throughout the nasal fossae. The endoscope could not be passed on the right, and the passage in the cavum on the left was narrow.

[FIGURE 1 OMITTED]

The patient was admitted to the hospital on the day of his visit for evaluation and intravenous antibiotic therapy (ceftriaxone and clindamycin). Complementary tests revealed a shift to the left without leukocytosis (WBC count, 7,900; neutrophil bands, 28%; neutrophil segments, 48%; lymphocytes, 18%; monocytes, 6%). Positive serologic findings for HIV were also present. Computed tomography (CT) revealed preseptal cellulitis, destruction of the anterior septum and the left ala nasi, and lateral dislocation of the right inferior turbinate with mucosal thickening of the maxillary and ethmoid sinuses on the right (figure 1).

Reaching a diagnosis of angiogenic T/NK-cell non-Hodgkin lymphoma in this patient required 3 biopsies: 1 in the adenoid region and 2 in the ulcerated region of the nasal fossa. Histologic sections showed extensive areas of necrosis and coagulation, containing areas of proliferation of cells of a neoplastic nature. The cells had a lymphoid aspect and rounded and hyperchromatic nuclei and were arranged in nests with clearly visible tropism for the vessel wall (figure 2, A). Histochemistry testing revealed positivity for CD3 and CD56 and negativity for CD20 (figure 2, B).

[FIGURE 2 OMITTED]

The patient underwent CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin [vincristine], prednisone) chemotherapybut experienced febrile neutropenia at the end of the third cycle and died.

Patient 2. A 30-year-old man was seen in the otorhinolaryngology service of our institution reporting fever, sore throat, dry cough, odynophagia, and weight loss of 4 kg over the preceding 4 months. Exacerbation of his symptoms had occurred during the previous 11 days. He had taken several antibiotics with no improvement of symptoms.

Anterior rhinoscopyrevealed anterior septal deviation to the right with purulent secretion in the nasal fossae; postnasal purulent discharge; hyperemic tonsils; whitish, nonbleeding plaque adhering to the mucosa and covering the entire oropharynx; and four mobile, parenchymatous, painless, submandibular ganglia measuring 1 cm in diameter. Nasal endoscopy showed an anterior septal crista on the right and a deviation in area IV on the left, hypertrophic turbinates, hyperemic mucosa, and purulent secretion in a sphenoid recess on the right.

[FIGURE 3 OMITTED]

The patient was admitted on the day of his visit for evaluation and intravenous antibiotic treatment with clindamycin. Complementary examinations revealed only a deviation to the left without leukocytosis (WBC count, 6,900; neutrophil bands, 26%; neutrophil segments, 54%; lymphocytes, 10%; monocytes, 10%). CT showed bilateral maxillary mucosal thickening and bilateral ethmoid and left frontal thickening (figure 3).

Even after 14 days of antibiotic therapy, the patient's clinical signs and symptoms worsened. In this case, 4 biopsies--2 of the adenoid region, 1 of the tonsil, and 1 of a cervical ganglion--were required to reach a diagnosis of angiogenic T/NK-cell non-Hodgkin lymphoma, which was made after the last 2 biopsies. Histochemistry testing showed positivity for CD3 and CD56 (figure 4) and negativity for CD20.

The patient underwent 6 cycles of CHOP chemotherapy followed by radiotherapy, which resulted in full regression of signs and symptoms.

Patient 3. An 11-year-old boy presenting with unilateral amaurosis was seen in the otorhinolaryngology service of our institution. He had a 2-month history of acute right maxillary sinusitis and right orbital cellulitis.

The patient had been hospitalized and medicated in another service for 15 days, but signs and symptoms had not resolved. There, he had first received IV oxacillin (700 mg every 6 hours for 3 days) and then IV ceftriaxone (twice daily for 15 days) plus IV clindamycin (three times daily for 15 days) plus IV dexamethasone (four times per day, with a progressive reduction over a period of 15 days). He had also undergone right ethmoid-sphenomaxillary sinusectomy by microscopy, with resection of a friable fragment of the lamina papyracea and without drainage of purulent secretion.

[FIGURE 4 OMITTED]

The boy was hospitalized and given routine antibiotic therapy. He underwent ophthalmologic and otorhinologic exploration of the right orbit and facial sinuses, and material was collected and submitted for pathologic analysis. Two days later, biopsy specimens of the medial rectus and conjunctiva of the right eye were obtained. No fungal or bacterial microorganisms were found, and results of a lumbar puncture were normal.

Subsequently, aphthoid oral ulcers on the palate, upper and lower lips, medial canthus of the left eye, and parietal region of the scalp developed. Concomitantly, the development of mild spastic tetraplegia, bilateral amaurosis, and areas of meningeal thickening and right frontal hypodensity was detected by CT. Biopsy of the palate revealed a necrotizing inflammatory process. Biopsy specimens were obtained of the lateral rectus, medial rectus, medial wall bone, mucosa of the maxillary sinus, and medial orbital fat. The diagnosis was lymphoblastic lymphoma of T immunophenotype. A bone marrow puncture revealed no signs of neoplasia.

After 42 days of hospitalization, the patient had 2 episodes of tonic-clonic convulsions, followed by a reduced level of consciousness. He died on the 54th day of hospitalization.

Discussion

Angiogenic lymphoma is a rare disease that has attracted the attention of large medical centers, mainly after the advent of AIDS. Still, establishing a diagnosis and attaining histopathologic confirmation are difficult. In our service, we saw 3 clinical cases of the disease and each had different characteristics.

Patient 1 experienced nasal obstruction, posterior discharge, facial edema, and areas of mucosal ulceration with nasal osteocartilage destruction. This patient was HIV positive in addition to having non-Hodgkin lymphoma, a singular situation since nasal involvement is uncommon in HIV-infected patients. Patient 2 had an atypical presentation, lacking the most common signs and symptoms of the disease. The rhinopharynx and nasopharynx were involved, which is uncommon in this disease, and palpable cervical lymph nodes were present. In patient 3 we saw the typical picture of this disease in children, with characteristic signs such as facial edema and proptosis, late diagnosis, and involvement of the maxillary sinus, orbit, and skull.

Obtaining a histologic diagnosis was difficult in all 3 cases. Several biopsies were required because of the severe local inflammatory infiltrate and the presence of large areas of necrosis that impaired visualization of neoplastic cells. Rapid, precise diagnosis of angiogenic lymphoma is critical despite these challenges, because the sooner treatment is started, the better the chances of patient survival.

References

(1.) Quraishi MS, Bessell EM, Clark D, et al. Non-Hodgkin's lymphoma of the sinonasal tract. Laryngoscope 2000;110(9):1489-92.

(2.) Altemani A, Barbosa AC, Kulka M, et al. Characteristics of nasal T/NK-cell lymphoma among Brazilians. Neoplasma 2002;49(1):55-60.

(3.) Chan JK, Jaffe ES, Ralfkiaer E. Extranodal NK/T-cell lymphoma, nasal type. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. WHO Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC;2001:204-7.

(4.) Gaal K, Sun NC, Hernandez AM, Arber DA. Sinonasal NK/T-cell lymphomas in the United States. Am J Surg Pathol 2000;24 (11): 1511-17.

(5.) Cleary KR, Batsakis JG. Sinonasal lymphomas. Ann Otol Rhinol Laryngol 1994; 103 (11) :911-14.

(6.) Jaffe ES, Chan JK, Su IJ, et al. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas: Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20(1):103-11.

(7.) Mourad WA, Ahktar M, Khalil SH, et al. Sinonasal T-celllymphomas: A clinicopathologic study of a possibly distinct entity. Ann Saudi Med 1999;19(6):484-9.

(8.) Wollner N, Mandell L, Filippa D, et al. Primary nasal-paranasal oropharyngeallymphoma in the pediatric age group. Cancer 1990;65 (6):1438-44.

Rubens A. Martins-Filho, MD; Ricardo C. Demarco, MD; Fabiana C.P. Valera, MD; Catarina Shaletich, MD; Paulo R. Felix, MD; Giovana B. Badiale, MD; Wilma T. Anselmo-Lima, MD, PhD

From the Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, University Hospital (Dr. Martins-Filho, Dr. Demarco, Dr. Valera, Dr. Anselmo-Lima), and the Department of Pathology (Dr. Shaletich, Dr. Fe1ix, Dr. Badiale), Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

Corresponding author: Wilma T. Anselmo-Lima, MD, Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, Faculty of Medicine of Ribeirao Preto, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil. E-mail: mcecilia@hcrp. fmrp.usp.br

Table. Most common signs of angiogenic T/NK-cell non-Hodgkin
lymphoma (nasal type)

Sign                          % of patients

Nasal obstruction                 50.0
Intranasal mass                   41.6
Facial edema                      37.5
Unilateral epistaxis              33.3
Palate lesion                     33.3
Visual disorders                  29.1
Proptosis                         20.8
Unilateral serous otitis          20.8
Trigeminal nerve deficiency       12.5
Epiphora                           8.3