Volume 1, Issue 1 , Pages 22-26, March 2006
Posttransplantation lymphoproliferative disorder of the paranasal sinuses in a child
Article Outline
Summary
Posttransplantation lymphoproliferative disorder (PTLD) represents an often fatal complication of chronic immunosuppression following solid organ or bone marrow transplantation. PTLD in the head and neck is uncommon and generally involves lymphoproliferation in Waldeyer's ring, cervical lymphadenopathy, or both. This unusual case of PTLD involving the paranasal sinuses in a child illustrates the difficulty in distinguishing PTLD from invasive fungal sinusitis. Promptly establishing the correct diagnosis via biopsy is critical to the successful management of such a patient.
Keywords: Posttransplantation lymphoproliferative disorder, T-cell, Paranasal sinuses, Child
1. Introduction
Posttransplantation lymphoproliferative disorder (PTLD) is a complication of chronic immunosuppression in organ transplant recipients that has been recognized since the early 1970s. It occurs in approximately 2% of all transplant recipients, though the incidence is generally higher in bone marrow transplant patients (5–30%). The overall mortality rate is approximately 30%, and may be as high as 80% in patients who require chemotherapy [1].
Extranodal involvement most frequently affects the gastrointestinal tract, central nervous system, and allografted organs. Historically, head and neck involvement has been felt to be rare, usually presenting as a focal submucosal mass within Waldeyer's ring, or as cervical lymphadenopathy [2]. However, a recent review of pediatric lung transplant patients suggests that sinonasal PTLD may be more common than previously thought, particularly among patients with a history of cystic fibrosis [3].
Here, we present an unusual case of PTLD involving the paranasal sinuses and orbits in a child following renal transplantation.
2. Case report
A six-year-old boy was transferred from an outside inpatient facility to Lucile Packard Children's Hospital (LPCH) in January 2005 with severe right-sided periorbital cellulitis, pansinusitis, left lower lobe pneumonia, and diffuse cervical lymphadenopathy with a dominant 4
cm lymph node in level V of the right neck.
Past medical history was significant for a living related renal transplant nearly 4 years prior to presentation. Before transplantation, the boy was diagnosed with end stage renal disease as a result of obstructive uropathy and severe hydronephrosis secondary to posterior urethral valves. There was no history of diabetes mellitus.
The patient was diagnosed with PTLD, including pulmonary involvement, approximately 1 year following transplantation. He was subsequently treated with rituximab with an excellent response, completing treatment 3 years before the present symptom complex. The boy remained on chronic immunosuprresive therapy with tacrolimus and oral prednisolone.
Approximately 18 months prior to presentation, the boy began to report sinonasal complaints including nasal congestion, intermittent fevers, and a pressure sensation in the face. These symptoms persisted despite medical therapy and adenoidectomy. Two months prior to presentation, the patient underwent bilateral anterior ethmoidectomies and maxillary antrostomies. He experienced symptom relief for 2 weeks before the nasal congestion, fevers, and pressure sensation returned.
Approximately 3 weeks prior to admission, the boy developed right-sided periorbital cellulitis in the setting of pansinusitis. Functional endoscopic sinus surgery with bilateral revision maxillary antrostomies and completion ethmoidectomies was performed. At this point, maxillary sinus cultures demonstrated Streptococcus pneumoniae, Candida albicans, and Beauvaria species. Histopathology did not demonstrate fungal invasion. The patient was treated with fluconazole, ambisome, and ampicillin/sulbactam based upon a presumptive diagnosis of fungal sinusitis; however, there was no improvement in his condition. Several more transnasal debridement procedures as well as right external ethmoidectomy with incision and drainage of a right subperiosteal fluid collection were performed. Tissue specimens from these procedures all failed to show any evidence of fungal invasion. The patient's clinical condition still failed to improve, at which point he was transferred to LPCH.
Upon arrival, physical examination demonstrated severe edema, erythema, and induration of the right orbit. Sensation was decreased in the distribution of the maxillary division of the right trigeminal nerve. Cranial nerves were otherwise intact. In particular, extraocular muscle function, papillary light reflexes, and visual acuity were equal bilaterally. There was no photophobia. Breath sounds were diminished over the left lower lobe. Oxygen saturation was 92–95% on room air.
At this point, all antimicrobials as well as the patient's immunosuppressive medications were continued. A sinonasal CT with contrast as well as a contrast CT of the chest and abdomen were obtained. The sinonasal study demonstrated soft tissue edema and stranding in the right cheek, and an expansile pansinusitis with involvement of the right inferior and medial orbit. The bony detail of the paranasal sinuses had a remarkably washed out appearance (Fig. 1). The chest study demonstrated subcarinal and precarinal lymphadenopathy with scarring versus atelectasis in the left lower lung.
Fig. 1.
Coronal CT demonstrating washed out appearance with bony erosion involving bilateral maxillary and ethmoid sinuses as well as bilateral laminae papyracea.
The patient was taken to the operating room for bronchoscopy with bronchoalveolar lavage, right cervical lymph node biopsy, and an examination under anesthesia of the nose and sinuses with biopsy. The working differential diagnosis at this point was subacute invasive fungal sinusitis versus PTLD.
Bronchoscopy demonstrated small, white globular collections in both mainstem bronchi. These were collected and sent for evaluation by both the microbiology and pathology departments. No organisms or malignan T-cells were identified.
On examination of the nose and sinuses, the boy was noted to have massive hypertrophy of all sinonasal mucosa with severe nasal airway obstruction. The mucosa was quite friable, and bled with even the least bit of trauma. Thus, attempts at a transnasal procedure were abandoned. A right Caldwell-Luc was performed. The maxillary division of CN V was noted to be intact. The bone of the anterior wall of the maxillary sinus was eroded and weak. Upon entering the sinus, a tan, friable mass filled the majority of the sinus and extended up toward the orbit. The orbital floor was also noted to be eroded and weak. Generous biopsies of this tissue were taken.
Incidentally, right cervical node biopsy demonstrated tissue very similar to what was encountered in the right maxillary sinus. Again, no nervous invasion was noted in the neck. Histopathology and culture failed to reveal any fungal elements or invasion.
Histologic examination of the right cervical lymph node showed an atypical population of large mononuclear cells with pleomorphic nuclei, open chromatin, and irregular nuclear membrane contours with increased mitotic activity. Immunohistochemical stains were negative for CD20 and CD79A, but strongly positive for CD3 (Fig. 2). In addition, in situ hybridization was positive for Epstein Barr Virus (EBV), leading to a diagnosis of EBV-positive T-cell lymphoma consistent with PTLD. The right maxillary sinus tissue was found to contain scattered clusters of similar atypical lymphoid cells associated with extensive necrotic tissue, consistent with T-cell lymphoma of the maxillary sinus as well (Fig. 3).
Fig. 2.
High power view of lymph node specimen with immunostain strongly positive for CD3.
Fig. 3.
Low power view of maxillary sinus specimen demonstrating necrosis and atypical lymphoid cells (Hematoxylin and Eosin).
All immunosuppressive medications were discontinued and intravenous ganciclovir was initiated once a preliminary diagnosis of PTLD was obtained. In addition, the patient received IVIG in response to low IgG levels. Significant improvement in the patient's periorbital edema and erythema was noted immediately with the discontinuation of immunosuppression. In addition, sensation in the distribution of the maxillary division of CN V returned.
When the diagnosis of EBV-positive T-cell lymphoma was reached, the patient was begun on a multiagent chemotherapy regimen (CHOP). As a result, his nasal symptoms as well as his periorbital edema resolved. Of note, the patient's respiratory status also improved significantly following the initiation of chemotherapy.
Unfortunately, despite an initial response to chemotherapy, the patient experienced progression of disease most notably in the left (contralateral) orbit. This was heralded approximately 2.5 months after his initial presentation to LPCH by epiphora and chemosis. Repeat biopsy of his left orbital mass confirmed T-cell lymphoma. The patient subsequently underwent external beam radiation to his head and neck for palliation. Approximately 6 months after presentation to LPCH, he died from complications related to his PTLD. Disease was found to involve his lungs, abdomen, skull base, sinuses, and bone marrow by that time.
3. Discussion
Until recently, the diagnosis of PTLD of the nose or paranasal sinuses has been extremely rare. Only two other cases were encountered upon review of the English literature. One case involved a 53-year-old man following lung transplant with EBV-associated B-cell lymphoma of the sphenoid and posterior ethmoids involving unilateral cranial nerves II, III, V, and VI [2]. He had a complete response with rituximab. The second case involved a 27-year-old man following living related renal transplant with EBV-associated NK-cell lymphoma of the left nasal cavity and ethmoid air cells [4]. He had a complete response with combination chemotherapy.
However, a recent review of 246 pediatric lung transplant patients found that the paranasal sinuses were the most common site of involvement for PTLD in the head and neck. Five cases of sinonasal PTLD occurred in this population over a 13-year period. All five patients were female, and all five had cystic fibrosis with a history of nasal polyposis. Only two of the five had monoclonal disease requiring treatment with chemotherapy or radiotherapy. Interestingly, both of these patients had disseminated disease [3].
Cranial nerve involvement in an immunosuppressed child is an ominous sign that should heighten one's suspicion for either malignancy or invasive fungal disease. In one small case series, all three reports of intraorbital involvement had positive cranial nerve findings, including one case of numbness in the distribution of the maxillary division of CN V [1]. Of the two individual sinonasal case reports reviewed in the literature, one demonstrated involvement of CN II, III, V, and VI, while the cranial nerve status of the other case was not reported [2], [4]. In particular, involvement of the maxillary division of CN V is a subtle sign that, when detected, should prompt imaging and sinonasal biopsy.
Interestingly, in both of these cases, as well as in the present case, the patients had similar findings at the time of biopsy: a pale mass. In addition, all three patients, as well as all of the patients in the lung transplantation study had favorable responses to treatment once the appropriate diagnosis was made by biopsy.
In adult patients, magnetic resonance (MR) is considered the imaging modality of choice because of its ability to distinguish neoplasm, sinonasal secretions, and inflammatory disease within the paranasal sinuses. MR also provides an advantage with respect to identifying intracranial extension [2].
However, MR, even in cooperative children, necessitates sedation or general anesthesia. While MR may be able to distinguish soft tissue from fluid in the sinuses, a definitive diagnosis of PTLD still requires biopsy. In contrast, helical computed tomography (CT) is a much more rapid study with a lesser requirement for sedation or general anesthesia. In addition, screening for other sites of involvement by PTLD generally requires CT of the head, chest, and abdomen. CT also provides excellent bony anatomic detail of the paranasal sinuses, which is critical in preoperative planning for transnasal procedures. A CT is also required if one plans to use image-guidance at the time of surgery—a desirable option when distortion of the sinonasal anatomy is significant as in the case presented.
Though the treatment for invasive fungal sinusitis differs quite markedly from the treatment for PTLD of the paranasal sinuses, the intervention needed for diagnosis is the same: sinonasal biopsy. In the case of invasive fungal sinusitis, one must see fungal elements within the mucosa, submucosa, or bone. In the case of PTLD, tissue must meet at least two of the following three criteria: disruption of underlying tissue architecture by a lymphoproliferative process, presence of monoclonal or oligoclonal populations of lymphoid cells as determined by cellular or viral markers, and/or EBV infection of many cells [2], [5].
Of note, Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is another diagnosis that should be considered in cases of cervical lymphadenopathy and obstructive sinonasal disease, particularly in children 10 years of age or younger. This disease is a rare, non-hereditary, idiopathic, benign histiocytic proliferative disorder characterized by painless bilateral cervical lymphadenopathy, fever, leukocytosis, and polyclonal gammopathy. This granulomatous process may respond to systemic corticosteroids. There is no known predilection among the post-transplant population [6], [7].
In contrast, PTLD should be considered when organ rejection or opportunistic infection is suspected in a transplant recipient on immunosuppression.
Approximately 90% of cases of PTLD lymphoma are of B-cell origin [8], [9]. Chemotherapy is sometimes effective treatment option, but is best avoided due to the risk of further immunosupppression and side effects in patients who are already severely ill. In the subset of patients who require chemotherapy for treatment, mortality has been reported to be as high as 80%. The present case illustrates how difficult the treatment of T-cell PTLD can be. Though the patient in the present case demonstrated an excellent response to combination chemotherapy initially, he ultimately succumbed to his disease. Rituximab, a monoclonal antibody preparation directed at B-cell surface antigens, has proven to be very effective and well tolerated. The drug results in complete remission in at least 64% of cases. However, this agent is not effective in cases of T-cell PTLD [1], [2], [4].
Herrmann's study suggests that preexisting nasal polyposis in patients with cystic fibrosis may be a risk factor for the development of sinonasal PTLD. However, the patient in the present case did not have a prior history of nasal polyposis, nor did he have a history of cystic fibrosis. Interestingly, both of the patients with monoclonal sinonasal PTLD in Herrmann's study, as well as the patient in the present case had disseminated disease and worsening nasal airway obstruction. Of the other two case reports of sinonasal PTLD mentioned, only the case involving NK-cell lymphoma was not associated with disseminated disease. This suggests that the paranasal sinuses are one site among many that must be monitored for involvement by PTLD, that sinonasal monoclonal involvement may indicate systemic disease, and that nasal airway obstruction is an important early sign that should prompt sinonasal biopsy in any post-transplant patient on immunosuppression.
4. Conclusion
Both PTLD and invasive fungal sinusitis should be suspected in post-transplant patients on chronic immunosuppression who demonstrate cranial nerve deficits. Because the two disease entities present so similarly but necessitate very different treatments, diagnosis should be clarified promptly by sinonasal biopsy. Obtaining a CT scan in children with sinonasal PTLD is vital because it is rapid, requires less sedation, readily allows for screening of disseminated lymphoproliferative disease, and can be useful in anticipation of image-guided surgery. However, MRI, or a combination of MRI and CT, may also be appropriate. Patients with monoclonal PTLD of the paranasal sinuses seem likely to have systemic disease. When appropriately diagnosed, patients with PTLD benefit from treatment.
References
- Orbital presentation of posttransplantation lymphoproliferative disorder. Ophthalmology. 2002;109:2351–2355
- . Posttransplantation lymphoproliferative disorder of the paranasal sinuses mimicking invasive fungal sinusitis: case report. AJNR. 2002;23:855–857
- . Sinonasal posttransplant lymphoproliferative disorder in pediatric lung transplant patients. Otolaryngol. Head Neck Surg. 2005;133:38–41
- Nasal natural killer cell lymphoma in a post-renal transplant patient. Transplantation. 2000;69:1501–1503
- Epstein-Barr Virus-induced posttransplant lymphoproliferative disorders. ASTS/AS TEBV-TLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation. 1999;68:1517–1525
- . Rosai-Dorfman disease manifesting as relapsing uveitis and subconjunctival masses. Chang Gung Med. J. 2002;25:621–625
- . Relapsing bilateral uveitis and papilledema in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Eur. J. Opthalmol. 1995;5:59–62
- . Cancers complicating organ transplantation. N. Engl. J. Med. 1990;323:1767–1769
- Lymphoproliferative disorders after organ transplantation: a report of 24 cases observed in a single center. J. Clin. Oncol. 1995;13:961–968
PII: S1871-4048(05)00011-0
doi:10.1016/j.pedex.2005.11.005
© 2005 Elsevier Ireland Ltd. All rights reserved.
Volume 1, Issue 1 , Pages 22-26, March 2006
