- Email: [email protected]
Lymphoma of the tympanic membrane in acquired immunodeficiency syndrome
Auris Nasus Larynx 25 (1998) 89 – 94
Case report
Lymphoma of the tympanic membrane in acquired immunodeficiency syndrome Mark O. Goodarzi, Todd G. Broberg, Anil K. Lalwani * Di6ision of Otology, Neurotology and Skull Base Surgery, Department of Otolaryngology —Head and Neck Surgery, Rm A730, 400 Parnassus A6enue, Uni6ersity of California, San Francisco CA 94143 -0342, USA Received 10 June 1997; accepted 15 September 1997
Abstract Lymphoproliferative disease is more common in the immunocompromised host and can occur at unusual sites. Lymphomas of the temporal bone are rare. We present the first case of a large B-cell Lymphoma of the tympanic membrane in a patient with acquired immunodeficiency syndrome. The tympanic membrane is a site rich with antigen-presenting dendritic cells that may play an etiologic role in neoplastic transformation at this site. The staging, treatment and prognosis of an immunocompromised host afflicted with lymphoma is discussed. Future directions in improving survival include better therapy for the primary viral infection and less toxic therapy for the lymphoma. © 1998 Elsevier Science Ireland Ltd.
1. Introduction Human immunodeficiency virus infection and the associated acquired immunodeficiency syndrome (AIDS) are associated with significant otolaryngologic pathology, including unusual infections and neoplasms [1 – 4]. Otologic manifestations, in contrast to the ubiquitous head and neck symptoms, are less frequent. Otologic dis* Corresponding author. Tel.: + 1 415 4760757; fax: +1 415 4763591; e-mail: [email protected]
eases found with equal frequency and severity in both patients with and without AIDS include otitis externa, acute otitis media and chronic otitis media with or without cholesteatoma. These diseases presenting in AIDS, feature the same pathologic organisms, natural history and response to therapy as in people without AIDS. However, there is an increased incidence of serous otitis media, auditory brainstem abnormalities, sensorineural hearing loss and facial nerve palsy in patients with AIDS. Unusual otologic infections or neoplasms include Pneurnocystis carinii otitis
0385-8146/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 5 - 8 1 4 6 ( 9 7 ) 1 0 0 3 1 - 1
90
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
Fig. 1. Gadolinium-enhanced (A), T-2 weighted (B), and intermediateT-2 weighted (C) magnetic resonance imaging of brain demonstrating a heterogeneously enhancing lesion in the left middle ear and mastoid cavity (arrowheads).
and Kaposi’s sarcoma in this immunocompromised population. An increased incidence of neoplasia is seen in AIDS. Lymphoproliferative disease is the second most common AIDS-related malignancy following Kaposi’s sarcoma and is an AIDS-defining illness. Nearly one third of patients infected with HIV are expected to develop lymphoma. Lymphoma-related symptoms are the initial presentation in − :15% of cases leading to the diagnosis of AIDS [5,6] Lymphoma in AIDS arises at various sites in the body: : 30% present in the central nervous system (CNS), 26% in the gastrointestinal system, 25% in the bone marrow and 12% in the liver. Temporal bone is an extremely rare site of origin or involvement for lymphoma. Herein, we report the first case of
lymphoma presenting in the tympanic membrane in a patient with AIDS.
2. Case history A 38 old man with AIDS and a CD4 count of 80 presented with 3 weeks of worsening left ear pain, hearing loss and a 1 week history of left facial weakness. He denied otorrhea, vertigo and tinnitus. Otoscopy showed a rose colored mass behind the tympanic membrane. Left facial nerve function was House Brackman grade 5/6. Hilger stimulation showed facial nerve stimulation at 4 mA. Magnetic resonance imaging (MRI) of the brain with gadolinium enhancement showed opacification of the left mastoid air cells and
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
expansion of the left fossa of Rosenmueller with no evidence of intracranial pathology (Fig. 1). With a presumptive diagnosis of glomus tumor, the patient underwent an emergency left exploratory tympanotomy for excision of the tumor and decompression of the facial nerve. During elevation of the tympano-meatal flap, the medial extemal auditory canal skin adjacent to the tympanic annulus was noted to be diffusely thickened. Fleshy, nodular lesions were seen in the pars flaccida of the tympanic membrane, with a separate purple mass involving the inferior pars tense of the tympanic membrane. A frozen section of
Fig. 2. Photomicrograph demonstrating an atypical large cell infiltrate within the tympanic membrane (arrow). These atypical cells were shown to be of B-cell origin by staining with L-26, a B-cell antibody recognizing the CD20 antigen. (hematoxylin and eosin stain; original magnification × 180)
91
the nodular tympanic membrane lesions revealed intratympanic large cell lymphoma. Permanent section confirmed malignant lymphoma of the large B-cell type (Fig. 2). The mesotympanum, the facial nerve and the ossicles were nominal. On nasopharyngoscopy, a significant amount of polypoid tissue was noted in the right and left nasopharynx; multiple biopsies revealed only chronic inflammation. The biopsy defect in the tympanic membrane was grafted with temporalis fascia. Postoperatively, the facial nerve function resumed to normal within 2 days and the tympanic membrane healed without residual perforation. Oncologic evaluation and treatment of the lymphoma followed. Staging workup included computerized tomography of the pelvis and abdomen, which showed low attenuating lesions in the left kidney and anterior segment of the liver with prominent (1 cm) left cardiophrenic angle, inguinal, peripancreatic and periaortic lymph nodes and mild splenomegaly. Lumbar puncture was negative for malignancy. Two weeks postoperatively, the patient commenced chemotherapy, which consisted of three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and four cycles of intrathecal cytosine arabinoside. About 3 months after the tympanotomy, new pharyngeal masses were noted on physical exam. MRI showed an infiltrative plaque-like lesion extending along the naso and oropharynx which had progressed dramatically compared to an MRI done 2 weeks previously. Operative biopsy revealed high grade, large B-cell lymphoma. Bone marrow biopsy was also positive for lymphoma. The patient underwent two cycles of chemotherapy with mitoguazone. Within 1 month, the nasopharyngeal and oropharyngeal masses had more than tripled in size and invaded the left longus capitis muscle, prompting further therapy with ifosfamide and radiation. The patient tolerated this therapy poorly and ultimately died 8 months following the initial tympanic membrane biopsy and diagnosis of tympanic membrane lymphoma.
92
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
2.1. Comment This patient presented with facial palsy which was thought to be secondary to a tumor involving the middle ear and mastoid. However, in retrospect, the facial weakness may have been coincidental. Facial nerve palsy is seen with increased frequency in the AIDS population. Idiopathic or Bell’s palsy is the most common diagnosis of facial palsy in AIDS. Other causes include opportunistic processes such as CNS infection or tumors, progressive multifocal leukoencephalopathy and herpes zoster oticus [1,4]. Also of note, the tympanic membrane graft healed normally and remained intact throughout the patient’s postoperative course. This is remarkable given the infiltration of the tympanic membrane with neoplastic cells as well as the administration of aggressive chemotherapy for treatment of the B-cell lymphoma.
3. Discussion Malignant non-Hodgkin’s lymphoma (NHL) is strongly associated with immune compromise [7]. In children with congenital immune deficiency syndromes, over half of all cancers which develop are lymphoma. Increased risk of lymphoma is also seen in patients with acquired autoimmune diseases and those who have had an organ transplant; in these patients stronger immunosuppression is associated with a higher incidence of lymphoma. AIDS is also associated with a higher incidence of NHL. It is hypothesized that deficient CD4 cell function in AIDS allows expansion of multiple Epstein – Barr virus (EBV)-immortalized neoplastic B-cell clones, from which a dominant clone gives rise to lymphoma [8]. This is supported by the fact that cells from about half of AIDS-related NHL contain EBV DNA [6]. Chronic antigenic stimulation from opportunistic infections, direct oncogenic effect of HIV and infections with other viruses (e.g. cytomegalovirus, herpes, etc.) have also been implicated in the pathogenesis of AIDS lymphoma. Similar to lymphoma arising in other immunocompromised host, the majority of AIDS-related
lymphoma present at onset as disseminated, extranodal disease. The majority of these are of B-cell origin with 80–90% of cases having high grade, immunoblastic or small non-cleaved cell histology. In contrast, only 10% of HIV-negative patients who develop NHL present with such high grade B-cell disease. Intermediate grade lymphoma is also found with increased incidence in AIDS, but low grade B-cell and T-cell lymphomas are found with the usual incidence and clinical course. Hodgkin’s disease, while not an AIDS-defining illness, afflicts patients with HIV with greater than usual virulence. It is often widespread at presentation with unfavorable histology (lymphocyte depleted or mixed cellularity) and has a dismal 1–2 year median survival [7]. AIDS-related non-Hodgkin’s lymphoma has been reported in unusual locations, including the gallbladder, orbit, temporal bone, jaw, earlobe, rectum, lung, skin, pancreas, heart, pericardium and the popliteal fossa [5,7]. The most common site of AIDS lymphoma in the head and neck include: the neck (45%), CNS (22%), mandible (12%), paranasal sinuses (10%), larynx (5%) and oropharynx (3%) [6]. Tympanic membrane, which is known to harbor lymphoid cells, has not been reported as a site of lymphoma in the immunocompromised or the immunocompetent host. The tympanic membrane is made up of three layers, an outer cuticular layer continuous with the skin of the external auditory canal, a middle fibrous layer and an inner mucosal layer of simple squamous epithelium, continuous with the epithelium lining the middle ear cavity. Early immunohistochemical studies of the human tympanic membrane concluded that this structure was relatively devoid of immune cells, particularly in comparison with the neighboring skin of the external auditory canal. In contrast, the histology of cholesteatoma or infected tympanic membranes was known to feature numerous immune cells which stained for CD1, a Langerhans cell marker [9]. Such studies led to the idea that Langerhans cells from the external auditory canal migrate through the tympanic membrane to reach the middle ear in pathological processes such as cholesteatoma or otitis media. Hussl et al. [10] challenged this hypothesis in their study of twelve
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
normal tympanic membranes. In addition to antibody against CDT, they also stained for HLA – DR and LAG; the former highlights antigen-presenting cells bearing MHC class II molecules and the latter is specific for the Birbeck granules characteristic of Langerhans cells. Staining for HLA–DR only revealed a dense network of cells with dendritic morphology in all normal tympanic membranes. Electron microscopy of two membranes also revealed dendritic cells, which appeared similar to Langerhans cells, except that they lacked Birbeck granules. This suggested the presence of a population of dendritic cells with different immunohistochemical properties from typical epidermal Langerhans cells. Further support for this idea came when dendritic cells cultured from these tympanic membranes also stained positively for HLA – DR and displayed strong stimulatory capacity for resting Tlymphocytes in an oxidative mitogenesis assay. These data suggest that there exists a population of functional antigen-presenting dendritic cells in the tympanic membrane which is phenotypically distinct from epidermal Langerhans cells. It is very likely that these cells, when presented with foreign antigens, are responsible for recruiting lymphocytes into the area during pathologic processes. Their role in the generation of a tympanic membrane lymphoma remains to be investigated. Otolaryngologists must be especially aware of AIDS lymphoma since it also commonly presents at the parotid, mouth, or orbit. Whereas lymphoma limited to lymph nodes occurs in the majority of non-HIV lymphoma, the majority of AIDS patients with lymphoma present with extranodal disease and systemic ‘B’ symptoms such as fever, drenching night sweats, and weight loss. Unfortunately, these symptoms are also typical of many opportunistic infections, thus confounding diagnosis. Moreover, initial symptoms may be more subtle, including personality changes, apparent periodontal abscess, or, as in our patient, facial palsy. Primary CNS lymphoma, which occurs in the most severely immunosuppressed AIDS patients, may present with headache, cranial nerve palsy, seizures, hemiparesis, altered mental status or personality change. Of interest,
93
when systemic AIDS lymphoma involves the CNS, it does so by infiltration of the leptomeninges and may present as headache, cranial nerve neuropathy, chin numbness, neck stiffness or be asymptomatic [7]. Efficient diagnosis and accurate staging is essential for such an aggressive and usually widespread neoplasm. Workup should include total body CT (including chest, abdomen, pelvis, brain) and gallium-67 scanning for staging purposes. Bone marrow biopsy should be performed because of the high incidence of marrow involvement (25%) and for prognostication. Lumbar puncture is performed routinely because there is a 20% chance of incidental asymptomatic leptomeningeal involvement with AIDS lymphoma [7]. For this reason, intrathecal chemotherapy is instilled at the time of diagnostic lumbar puncture as therapy/prophylaxis of meningeal disease. Commonly used chemotherapeutic agents include cytosine arabinoside or methotrexate. Symptoms or initial imaging studies may necessitate further studies such as a bone scan. MRI with gadolinium is used to image lymphoma at the skull base because primary CNS lymphoma can be confused with CNS toxoplasmosis on head CT, since both appear as ring-enhancing lesions [11]. Treatment of AIDS lymphoma presents the problem of administration of chemotherapy and radiation to patients already immune deficient. Furthermore, dose intensive combination chemotherapy regimens found to be effective in treatment of NHL in patients without HIV have had suboptirnal results in AIDS patients. Better complete response rates and survival with intensive regimens have been achieved in patients who do not have any of the negative prognostic factors [12]. Unfortunately, such patients are a minority in the group of patients with AIDS-associated lymphoma. Factors correlating with poor prognosis in AIDS lymphoma are impaired performance status, bone marrow involvement, history of AIDS prior to diagnosis of lymphoma, low CD4 count and incomplete response to therapy [7,13]. Research is now focusing on the use of less toxic therapy such as growth factors, alone or in combination with low dose chemotherapy. Radiation therapy is useful in treating more localized dis-
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
94
ease, particularly head and neck lymphomas where symptom relief may be more rapidly achieved than with chemotherapy alone. In most series, the mean survival has ranged from 4 – 7 months; without treatment, mean survival is only 1 month [14,15].
4. Summary Lymphomas are more common and occur at unusual sites in the immunocompromised patient. The first case of large B-cell lymphoma of the tympanic membrane is presented. The antigenpresenting dendritic cells within the tympanic membrane may be involved in the etiology of AIDS associated lymphoma at this site. Commonly presenting as widespread, extranodal high grade disease, AIDS lymphoma remains difficult to treat and has a poor prognosis. Since it presents at many sites of the head and neck, the otolaryngologist must maintain a high index of suspicion for lymphoma in patients with AIDS or HIV risk factors. In the latter case, the otolaryngologist is likely to prolong patients’ lives and promote public health by making the diagnosis of AIDS in a timely fashion.
References [1] Lalwani AK, Sooy CD. Otologic and neurotologic manifestations of acquired immunodeficiency syndrome. Otolaryngol Clin North Am 1992;25:1183–97. [2] Morris MS, Prasad S. Otologic disease in the acquired immunodeficiency syndrome. Ear Nose Throat J 1990;69:451 – 3.
.
[3] Kohan D, Rothstein SG, Cohen NL. Otologic disease in patients with acquired immunodeficiency syndrome. Ann Otol Rhinol Laryngol 1988;97:636 – 40. [4] Linstrom CJ, Pincus RL, Leavitt EB, et al. Otologic neurotologic manifestations of HIV-related disease. Otolaryngol Head Neck Surg 1993;108:680 – 7. [5] Kieserman SP, Finn DG. Non-Hodgkin’s lymphoma of the external auditory canal in an HIV-positive patient. J Laryngol Otol 1995;109:751 – 4. [6] Finn DG. Lymphoma of the head and neck and acquired immunodeficiency syndrome: Clinical investigation and immunohistochemical study. Laryngoscope 1995;105:1 – 18. [7] Levine AM. AIDS-associated malignant lymphoma. Med Clin North Am 1992;76:253 – 68. [8] Levine AM. Acquired immunodeficiency syndrome-related lymphoma. Blood 1992;80:8 – 20. [9] Van Dijk CM, Visser CE, Veldman JE. Spatial distribution of Langerhans’ cells and T-lymphocyte subpopulations in human tympanic membrane and aural cholesteatoma. Virchows Arch B 1986;52:143 – 52. [10] Hussl B, Egg G, Romani N, et al. Dendritic cells in the normal human tympanic membrane. Ann Otol Rhinol Laryngol 1995;104:803 – 7. [11] Gill PS, Levine AM, Meyer PR, et al. Primary central nervous system lymphoma in homosexual men. Clinical, immunologic and pathologic features. Am J Med 1985;78:742 – 8. [12] Bermudez MA, Grant KM, Rodvien R, et al. NonHodgkin’s lymphoma in a population with or at risk for acquired immunodeficiency syndrome: Indications for intensive chemotherapy. Am J Med 1989;86:71 – 6. [13] Ziegler JL, Beckstead JA, Volberding PA, et al. NonHodgkin’s lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 1984;311:565 – 70. [14] Levine AM, Sullivan-Halley J, Pike MC, et al. HIV-related lymphoma: Prognostic factors predictive for survival. Cancer 1991;68:2466 – 72. [15] Kaplan LD, Abrams DI, Feigal E, et al. AIDS-associated non-Hodgkin’s lymphoma in San Francisco. J Am Med Assoc 1989;261:719 – 24.
.
Case report
Lymphoma of the tympanic membrane in acquired immunodeficiency syndrome Mark O. Goodarzi, Todd G. Broberg, Anil K. Lalwani * Di6ision of Otology, Neurotology and Skull Base Surgery, Department of Otolaryngology —Head and Neck Surgery, Rm A730, 400 Parnassus A6enue, Uni6ersity of California, San Francisco CA 94143 -0342, USA Received 10 June 1997; accepted 15 September 1997
Abstract Lymphoproliferative disease is more common in the immunocompromised host and can occur at unusual sites. Lymphomas of the temporal bone are rare. We present the first case of a large B-cell Lymphoma of the tympanic membrane in a patient with acquired immunodeficiency syndrome. The tympanic membrane is a site rich with antigen-presenting dendritic cells that may play an etiologic role in neoplastic transformation at this site. The staging, treatment and prognosis of an immunocompromised host afflicted with lymphoma is discussed. Future directions in improving survival include better therapy for the primary viral infection and less toxic therapy for the lymphoma. © 1998 Elsevier Science Ireland Ltd.
1. Introduction Human immunodeficiency virus infection and the associated acquired immunodeficiency syndrome (AIDS) are associated with significant otolaryngologic pathology, including unusual infections and neoplasms [1 – 4]. Otologic manifestations, in contrast to the ubiquitous head and neck symptoms, are less frequent. Otologic dis* Corresponding author. Tel.: + 1 415 4760757; fax: +1 415 4763591; e-mail: [email protected]
eases found with equal frequency and severity in both patients with and without AIDS include otitis externa, acute otitis media and chronic otitis media with or without cholesteatoma. These diseases presenting in AIDS, feature the same pathologic organisms, natural history and response to therapy as in people without AIDS. However, there is an increased incidence of serous otitis media, auditory brainstem abnormalities, sensorineural hearing loss and facial nerve palsy in patients with AIDS. Unusual otologic infections or neoplasms include Pneurnocystis carinii otitis
0385-8146/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 3 8 5 - 8 1 4 6 ( 9 7 ) 1 0 0 3 1 - 1
90
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
Fig. 1. Gadolinium-enhanced (A), T-2 weighted (B), and intermediateT-2 weighted (C) magnetic resonance imaging of brain demonstrating a heterogeneously enhancing lesion in the left middle ear and mastoid cavity (arrowheads).
and Kaposi’s sarcoma in this immunocompromised population. An increased incidence of neoplasia is seen in AIDS. Lymphoproliferative disease is the second most common AIDS-related malignancy following Kaposi’s sarcoma and is an AIDS-defining illness. Nearly one third of patients infected with HIV are expected to develop lymphoma. Lymphoma-related symptoms are the initial presentation in − :15% of cases leading to the diagnosis of AIDS [5,6] Lymphoma in AIDS arises at various sites in the body: : 30% present in the central nervous system (CNS), 26% in the gastrointestinal system, 25% in the bone marrow and 12% in the liver. Temporal bone is an extremely rare site of origin or involvement for lymphoma. Herein, we report the first case of
lymphoma presenting in the tympanic membrane in a patient with AIDS.
2. Case history A 38 old man with AIDS and a CD4 count of 80 presented with 3 weeks of worsening left ear pain, hearing loss and a 1 week history of left facial weakness. He denied otorrhea, vertigo and tinnitus. Otoscopy showed a rose colored mass behind the tympanic membrane. Left facial nerve function was House Brackman grade 5/6. Hilger stimulation showed facial nerve stimulation at 4 mA. Magnetic resonance imaging (MRI) of the brain with gadolinium enhancement showed opacification of the left mastoid air cells and
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
expansion of the left fossa of Rosenmueller with no evidence of intracranial pathology (Fig. 1). With a presumptive diagnosis of glomus tumor, the patient underwent an emergency left exploratory tympanotomy for excision of the tumor and decompression of the facial nerve. During elevation of the tympano-meatal flap, the medial extemal auditory canal skin adjacent to the tympanic annulus was noted to be diffusely thickened. Fleshy, nodular lesions were seen in the pars flaccida of the tympanic membrane, with a separate purple mass involving the inferior pars tense of the tympanic membrane. A frozen section of
Fig. 2. Photomicrograph demonstrating an atypical large cell infiltrate within the tympanic membrane (arrow). These atypical cells were shown to be of B-cell origin by staining with L-26, a B-cell antibody recognizing the CD20 antigen. (hematoxylin and eosin stain; original magnification × 180)
91
the nodular tympanic membrane lesions revealed intratympanic large cell lymphoma. Permanent section confirmed malignant lymphoma of the large B-cell type (Fig. 2). The mesotympanum, the facial nerve and the ossicles were nominal. On nasopharyngoscopy, a significant amount of polypoid tissue was noted in the right and left nasopharynx; multiple biopsies revealed only chronic inflammation. The biopsy defect in the tympanic membrane was grafted with temporalis fascia. Postoperatively, the facial nerve function resumed to normal within 2 days and the tympanic membrane healed without residual perforation. Oncologic evaluation and treatment of the lymphoma followed. Staging workup included computerized tomography of the pelvis and abdomen, which showed low attenuating lesions in the left kidney and anterior segment of the liver with prominent (1 cm) left cardiophrenic angle, inguinal, peripancreatic and periaortic lymph nodes and mild splenomegaly. Lumbar puncture was negative for malignancy. Two weeks postoperatively, the patient commenced chemotherapy, which consisted of three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and four cycles of intrathecal cytosine arabinoside. About 3 months after the tympanotomy, new pharyngeal masses were noted on physical exam. MRI showed an infiltrative plaque-like lesion extending along the naso and oropharynx which had progressed dramatically compared to an MRI done 2 weeks previously. Operative biopsy revealed high grade, large B-cell lymphoma. Bone marrow biopsy was also positive for lymphoma. The patient underwent two cycles of chemotherapy with mitoguazone. Within 1 month, the nasopharyngeal and oropharyngeal masses had more than tripled in size and invaded the left longus capitis muscle, prompting further therapy with ifosfamide and radiation. The patient tolerated this therapy poorly and ultimately died 8 months following the initial tympanic membrane biopsy and diagnosis of tympanic membrane lymphoma.
92
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
2.1. Comment This patient presented with facial palsy which was thought to be secondary to a tumor involving the middle ear and mastoid. However, in retrospect, the facial weakness may have been coincidental. Facial nerve palsy is seen with increased frequency in the AIDS population. Idiopathic or Bell’s palsy is the most common diagnosis of facial palsy in AIDS. Other causes include opportunistic processes such as CNS infection or tumors, progressive multifocal leukoencephalopathy and herpes zoster oticus [1,4]. Also of note, the tympanic membrane graft healed normally and remained intact throughout the patient’s postoperative course. This is remarkable given the infiltration of the tympanic membrane with neoplastic cells as well as the administration of aggressive chemotherapy for treatment of the B-cell lymphoma.
3. Discussion Malignant non-Hodgkin’s lymphoma (NHL) is strongly associated with immune compromise [7]. In children with congenital immune deficiency syndromes, over half of all cancers which develop are lymphoma. Increased risk of lymphoma is also seen in patients with acquired autoimmune diseases and those who have had an organ transplant; in these patients stronger immunosuppression is associated with a higher incidence of lymphoma. AIDS is also associated with a higher incidence of NHL. It is hypothesized that deficient CD4 cell function in AIDS allows expansion of multiple Epstein – Barr virus (EBV)-immortalized neoplastic B-cell clones, from which a dominant clone gives rise to lymphoma [8]. This is supported by the fact that cells from about half of AIDS-related NHL contain EBV DNA [6]. Chronic antigenic stimulation from opportunistic infections, direct oncogenic effect of HIV and infections with other viruses (e.g. cytomegalovirus, herpes, etc.) have also been implicated in the pathogenesis of AIDS lymphoma. Similar to lymphoma arising in other immunocompromised host, the majority of AIDS-related
lymphoma present at onset as disseminated, extranodal disease. The majority of these are of B-cell origin with 80–90% of cases having high grade, immunoblastic or small non-cleaved cell histology. In contrast, only 10% of HIV-negative patients who develop NHL present with such high grade B-cell disease. Intermediate grade lymphoma is also found with increased incidence in AIDS, but low grade B-cell and T-cell lymphomas are found with the usual incidence and clinical course. Hodgkin’s disease, while not an AIDS-defining illness, afflicts patients with HIV with greater than usual virulence. It is often widespread at presentation with unfavorable histology (lymphocyte depleted or mixed cellularity) and has a dismal 1–2 year median survival [7]. AIDS-related non-Hodgkin’s lymphoma has been reported in unusual locations, including the gallbladder, orbit, temporal bone, jaw, earlobe, rectum, lung, skin, pancreas, heart, pericardium and the popliteal fossa [5,7]. The most common site of AIDS lymphoma in the head and neck include: the neck (45%), CNS (22%), mandible (12%), paranasal sinuses (10%), larynx (5%) and oropharynx (3%) [6]. Tympanic membrane, which is known to harbor lymphoid cells, has not been reported as a site of lymphoma in the immunocompromised or the immunocompetent host. The tympanic membrane is made up of three layers, an outer cuticular layer continuous with the skin of the external auditory canal, a middle fibrous layer and an inner mucosal layer of simple squamous epithelium, continuous with the epithelium lining the middle ear cavity. Early immunohistochemical studies of the human tympanic membrane concluded that this structure was relatively devoid of immune cells, particularly in comparison with the neighboring skin of the external auditory canal. In contrast, the histology of cholesteatoma or infected tympanic membranes was known to feature numerous immune cells which stained for CD1, a Langerhans cell marker [9]. Such studies led to the idea that Langerhans cells from the external auditory canal migrate through the tympanic membrane to reach the middle ear in pathological processes such as cholesteatoma or otitis media. Hussl et al. [10] challenged this hypothesis in their study of twelve
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
normal tympanic membranes. In addition to antibody against CDT, they also stained for HLA – DR and LAG; the former highlights antigen-presenting cells bearing MHC class II molecules and the latter is specific for the Birbeck granules characteristic of Langerhans cells. Staining for HLA–DR only revealed a dense network of cells with dendritic morphology in all normal tympanic membranes. Electron microscopy of two membranes also revealed dendritic cells, which appeared similar to Langerhans cells, except that they lacked Birbeck granules. This suggested the presence of a population of dendritic cells with different immunohistochemical properties from typical epidermal Langerhans cells. Further support for this idea came when dendritic cells cultured from these tympanic membranes also stained positively for HLA – DR and displayed strong stimulatory capacity for resting Tlymphocytes in an oxidative mitogenesis assay. These data suggest that there exists a population of functional antigen-presenting dendritic cells in the tympanic membrane which is phenotypically distinct from epidermal Langerhans cells. It is very likely that these cells, when presented with foreign antigens, are responsible for recruiting lymphocytes into the area during pathologic processes. Their role in the generation of a tympanic membrane lymphoma remains to be investigated. Otolaryngologists must be especially aware of AIDS lymphoma since it also commonly presents at the parotid, mouth, or orbit. Whereas lymphoma limited to lymph nodes occurs in the majority of non-HIV lymphoma, the majority of AIDS patients with lymphoma present with extranodal disease and systemic ‘B’ symptoms such as fever, drenching night sweats, and weight loss. Unfortunately, these symptoms are also typical of many opportunistic infections, thus confounding diagnosis. Moreover, initial symptoms may be more subtle, including personality changes, apparent periodontal abscess, or, as in our patient, facial palsy. Primary CNS lymphoma, which occurs in the most severely immunosuppressed AIDS patients, may present with headache, cranial nerve palsy, seizures, hemiparesis, altered mental status or personality change. Of interest,
93
when systemic AIDS lymphoma involves the CNS, it does so by infiltration of the leptomeninges and may present as headache, cranial nerve neuropathy, chin numbness, neck stiffness or be asymptomatic [7]. Efficient diagnosis and accurate staging is essential for such an aggressive and usually widespread neoplasm. Workup should include total body CT (including chest, abdomen, pelvis, brain) and gallium-67 scanning for staging purposes. Bone marrow biopsy should be performed because of the high incidence of marrow involvement (25%) and for prognostication. Lumbar puncture is performed routinely because there is a 20% chance of incidental asymptomatic leptomeningeal involvement with AIDS lymphoma [7]. For this reason, intrathecal chemotherapy is instilled at the time of diagnostic lumbar puncture as therapy/prophylaxis of meningeal disease. Commonly used chemotherapeutic agents include cytosine arabinoside or methotrexate. Symptoms or initial imaging studies may necessitate further studies such as a bone scan. MRI with gadolinium is used to image lymphoma at the skull base because primary CNS lymphoma can be confused with CNS toxoplasmosis on head CT, since both appear as ring-enhancing lesions [11]. Treatment of AIDS lymphoma presents the problem of administration of chemotherapy and radiation to patients already immune deficient. Furthermore, dose intensive combination chemotherapy regimens found to be effective in treatment of NHL in patients without HIV have had suboptirnal results in AIDS patients. Better complete response rates and survival with intensive regimens have been achieved in patients who do not have any of the negative prognostic factors [12]. Unfortunately, such patients are a minority in the group of patients with AIDS-associated lymphoma. Factors correlating with poor prognosis in AIDS lymphoma are impaired performance status, bone marrow involvement, history of AIDS prior to diagnosis of lymphoma, low CD4 count and incomplete response to therapy [7,13]. Research is now focusing on the use of less toxic therapy such as growth factors, alone or in combination with low dose chemotherapy. Radiation therapy is useful in treating more localized dis-
M.O. Goodarzi et al. / Auris Nasus Larynx 25 (1998) 89–94
94
ease, particularly head and neck lymphomas where symptom relief may be more rapidly achieved than with chemotherapy alone. In most series, the mean survival has ranged from 4 – 7 months; without treatment, mean survival is only 1 month [14,15].
4. Summary Lymphomas are more common and occur at unusual sites in the immunocompromised patient. The first case of large B-cell lymphoma of the tympanic membrane is presented. The antigenpresenting dendritic cells within the tympanic membrane may be involved in the etiology of AIDS associated lymphoma at this site. Commonly presenting as widespread, extranodal high grade disease, AIDS lymphoma remains difficult to treat and has a poor prognosis. Since it presents at many sites of the head and neck, the otolaryngologist must maintain a high index of suspicion for lymphoma in patients with AIDS or HIV risk factors. In the latter case, the otolaryngologist is likely to prolong patients’ lives and promote public health by making the diagnosis of AIDS in a timely fashion.
References [1] Lalwani AK, Sooy CD. Otologic and neurotologic manifestations of acquired immunodeficiency syndrome. Otolaryngol Clin North Am 1992;25:1183–97. [2] Morris MS, Prasad S. Otologic disease in the acquired immunodeficiency syndrome. Ear Nose Throat J 1990;69:451 – 3.
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