Orbital and muscle involvement in multiple myeloma

Orbital and muscle involvement in multiple myeloma François Thoumazet,* MD; Angélique Donnio,* MD; Lucas Ayeboua,* MD; Alain Brebion,† MD; Abdoulaye Diedhou,‡ MD; Harold Merle,* MD ABSTRACT • RÉSUMÉ

Case report: We report 2 cases of orbital plasmacytoma in patients with known multiple myeloma. Orbital spread with secondary maxillary sinus involvement is reported in the first case. Case 2 is the first report of immunoglobulin A kappa light chain multiple myeloma involving orbital recti muscles. Computed axial tomography and magnetic resonance imaging aided the diagnosis, confirmed with histopathologic studies. Comments: Extraskeletal spread is rare and orbital involvement is exceedingly uncommon. From a review of the literature since 1972, we conclude that the immunoglobulin G type of multiple myeloma, whether lambda or kappa light chain, may be a risk factor for orbital involvement. Observation : Nous rapportons 2 cas de plasmocytome orbitaire chez des patients atteints de myélome multiple. Dans le premier cas, l’atteinte orbitaire était associée à une atteinte du sinus maxillaire. Dans le second, on signalait pour la première fois un myélome multiple à chaîne légère kappa avec immunoglobuline A affectant les muscles droits de l’orbite. La tomographie axiale informatisée et l’imagerie par résonance magnétique ont aidé à poser le diagnostic, confirmé par étude histopathologique. Commentaires : La diffusion hors du squelette est rare et l’incidence orbitaire, rarissime. Après une revue de la littérature depuis 1972, nous concluons que le type G de l’immunoglobuline du myélome multiple, à chaîne légère lambda ou kappa, peut être un facteur de risque de l’incidence orbitaire.

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ultiple myeloma is a malignant monoclonal proliferation of plasma cells that usually arises in patients after the age of 40. Secondary myelomatous orbital involvement without local bone destruction or ocular involvement is extremely rare, and muscle invasion is even more uncommon. Orbital involvement leads to systemic diagnosis in only 25% of cases, thus orbital plasmacytoma is usually the initial clinical finding in the remaining cases.1 The incidence of myeloma as an orbital tumour represents less than 1% of all orbital tumours.2 Only approximately 40 cases have been reported to date and it appears to be a bad prognostic factor.3,4 Extramedullary locations are found in less than 5% of patients with multiple myeloma, the upper respiratory tract and oropharynx being the most From *the Service d’Ophtalmologie, †the Service de Médecine Interne, and ‡the Laboratoire d’Anatomie Pathologique, Centre Hospitalier Universitaire de Fort de France, Hôpital Pierre Zobda-Quitman, Fort de France, Martinique (French West Indies), France Originally received Apr. 20, 2005. Revised Feb. 17, 2006 Accepted for publication Mar. 27, 2006 Correspondence to: Harold Merle, MD, Service d’Ophtalmologie, Centre Hospitalier Universitaire de Fort de France, Hôpital Pierre ZobdaQuitman, BP 632, 97261 Fort de France Cedex, Martinique (French West Indies), France; fax 05 96 75 84 47; [email protected] This article has been peer-reviewed. Cet article a été évalué par les pairs. Can J Ophthalmol 2006;41:733–6

Plasmacytoma—Thoumazet et al

important extraskeletal sites of metastasis.5 These reports represent few encountered cases, either by their orbital localization or their local courses. Moreover, this is the first case of immunoglobulin A (IgA) kappa light chain multiple myeloma involving orbital recti muscles. CASE

REPORTS

Case 1

A 76-year-old woman was first hospitalized with a history of progressive pain in her left leg of several months duration. Radiographic studies revealed lytic lesions in the tibia and fibula. Serum protein electrophoresis revealed a monoclonal peak of immunoglobulin G (IgG) with kappa light chain below 35 g/L. One year later, she fractured her leg and a diagnosis of multiple myeloma was made through histopathologic evaluation of an incisional biopsy, which was interpreted as plasma cell myeloma. She underwent systemic chemotherapy and external beam radiotherapy on the fracture of the pathologic bone, and subsequently the patient’s clinical status became stable. Seventeen months after diagnosis of the fracture, she was referred to the department of ophthalmology. She complained of exophthalmos, diplopia, upper and lower eyelid swelling, and an enlarging painless mass in the lower anterior temporal area of the right orbit. The examination showed chemosis and conjunctival hyperaemia with superficial punctuated keratitis. Visual acuity decreased in the right eye from 20/20 to 20/30.

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Applanation tonometry measured 22 mm Hg in the right eye and 16 in the left. Fundoscopic examination was notable for bilateral drusen and choroidal folds in the right side. Exophthalmometry revealed a 7 mm exophthalmos in the right eye. Its mobility decreased in all fields of gaze because of mechanical limitation, even more marked in the downward gaze. Computed tomography (CT) and magnetic resonance imaging (MRI) of the orbit were performed and revealed a homogeneous, unencapsulated mass filling the inferior and temporal part of the orbit, displacing the eyeball superiorly and interiorly. This mass involved the maxillary sinus with bone destruction (Fig. 1). The initial incisional biopsy using an anterior transconjunctival orbitotomy was inconclusive; however, a second biopsy in the maxillary sinus revealed monomorphic lymphoid cells with a plasmacytoid aspect. Immunohistochemical stains were positive for monoclonal kappa light chains and epithelial membrane antigen (Fig. 2). The patient underwent external beam radiotherapy, and subsequent examinations showed decreasing symptoms. Despite systemic chemotherapy of thalidomide and dexamethasone, she died from multiple myeloma 10 months later. Case 2

A 48-year-old woman with generalized multiple myeloma presented with left eye chemosis and a palpable fixed painless mass in the upper left temporal orbit. The follow-up examination 6 days later showed bilateral exophthalmos more marked on the left side (Fig. 3) and decreasing mobility in abduction. Conjunctival chemosis on the right and conjunctival haemorrhages on the left were noticed in each temporal quadrant. Slit-lamp and fundus examination revealed superficial punctuated keratitis and blurred papillae. Best corrected visual acuity was 20/30 on the right and 20/100 on the left side. The results of the remainder of the ophthalmologic examination were unremarkable except for bilateral subcapsular cataracts. Past medical history included hypertension and infection with human T-cell lymphotropic virus type 1. Multiple myeloma with IgA kappa light chains had been diagnosed 6 years previously on the basis of 2 major criteria of the South West Oncology Group: bone marrow biopsy, which revealed a malignant plasmacytoid cell proliferation of 30%, and protein immunoelectrophoresis positive for a monoclonal peak of IgA with kappa light chains (29 g/L). Several courses of systemic chemotherapy along with autologous bone marrow transplantation failed to control her disease. A third inferior left humerus fracture 1 year earlier had been treated by orthopaedists who confirmed the bony involvement with histological analysis. On this occasion, our investigation with CT

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Fig. 1—Case 1. Orbital computed tomography scan (coronal plane) reveals a homogeneous, nonencapsulated mass filling the inferior and temporal part of the orbit and displacing the eyeball in the nasal and cranial directions. This mass involves the maxillary sinus with bony destruction.

and MRI showed 2 large masses in each lachrymal gland involving the lateral recti muscles, especially on the left, and displacing the eyeballs forward and inward. There was no bony orbital destruction (Fig. 4). Incisional biopsy was performed on the left side using an anterior transconjunctival orbitotomy, and the histopathologic examination revealed atypical monomorphic lymphoid plasma cells with a plasmacytoid aspect and eccentric nuclei, some of them binucleate and involving necrotic striated muscle (Fig. 5). Further chemotherapy was not helpful, except in the orbits, and the patient died 2 months later of generalized myelomatosis. COMMENTS

These 2 cases represent an unusual course of multiple myeloma: orbital involvement and distal bony erosion. They had tibial, fibular, and third inferior humerus fractures because of bony lytic lesions. According to the literature, in most cases the upper respiratory tract, including all of the facial sinuses, is the most commonly invaded site (82%).5 The remaining sites, the digestive tract and rarely the orbit, constitute only 18%. Three forms of the disease have been described and are used for classification: solitary extramedullary plasmacytoma (SEMP), extramedullary plasmacytoma (EMP), and secondary plasmacytoma in known multiple myeloma. SEMP comprises only 3% of plasma cell tumours, and to 2004, has only been described in the orbit in 12 patients.6,7 The criteria for this diagnosis include


Fig. 2—Case 1. Histopathologic section of the orbital tumour. A. Hematoxylin–eosin staining reveals monomorphic lymphoid cells with plasmacytoid features and eccentric nuclei. Some cells are binucleated (original magnification ×20). B. Immunoperoxidase staining reveals monoclonality for IgG kappa light chain (original magnification ×20).

Fig. 3—Case 2. Bilateral exophthalmos more marked on the left side, with conjunctival chemosis at right and conjunctival hemorrhages at left in each temporal quarter.

Fig. 5—Case 2. Histopathologic section of the orbital tumour. Histopathologic examination reveals monomorphic atypical lymphoid plasma cells with plasmacytoid features and eccentric nuclei, some binucleated. These involve heavily necrotic striated muscles (hematoxylin–eosin stain; original magnification ×20).

Fig. 4—Case 2. Axial T1-weighted magnetic resonance imaging. Shown are 2 large masses in each lachrymal gland involving the external recti muscles especially on left side, and displacing the eyeballs forward and inward. There was no bony orbital destruction.

absence of systemic disease, meaning negative lymph node assessment, skeletal survey, bone marrow biopsy, and CT scan.8 Also, plasmacytoma may signal development of multiple myeloma. On the other hand, only 10 cases of EMP have been reported to 1996,9 and with Uceda-Montanes et al’s additional case in 2000, a total

of 11 cases have been published.10 They either occur as a low-grade malignant tumour, that is, a local invasion with lymph node involvement, in 10% of cases, or develop as a multiple myeloma in 75% of cases.7,11 Orbital SEMP and EMP are histologically identical to multiple myeloma.6 This distinction is a purely clinical one. Moreover, some of the patients with SEMP developed systemic tumours over time,4 multiple myeloma occurring in 16% of cases.6,9 Also, extended follow-up and detailed postmortem studies have proven that SEMP presents as the first stage in generalized disease. Twenty-five percent of patients have immunologic irregularities, sometimes revealed by an abnormal monoCAN J OPHTHALMOL—VOL. 41, NO. 6, 2006

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clonal immunoglobulin peak in serum protein electrophoresis studies. The mean survival of patients with plasmacytoma and multiple myeloma is 192 months and 30 months, respectively.9 Thus, only long-term follow-up can definitively establish whether plasma cell infiltrates are an early manifestation of multiple myeloma, a plasma cell pseudotumour, or a localized EMP. In addition, SEMP, EMP, and secondary plasmacytoma in known multiple myeloma appear to be 3 different presentations of the same disease with different prognoses, and therefore are not 3 separated entities. Clinically, orbital plasmacytoma primarily manifests by exophthalmos (80%).4 Likewise, in this paper exophthalmos was the most common presenting complaint, followed by signs of progressing ocular indentation: marked chemosis, conjunctival haemorrhages, upper and lower eyelid swelling, diplopia, visual impairment, resistance to retropulsion, choroidal folds, and elevated ocular pressure as it classically has been described.1–3,6,9,11–13 We have also noticed a lack of pain, the presence of superficial punctuated keratitis due to exophthalmia, and decreased ocular mobility primarily due to mechanical limitation. Excluding the increased tearing reported by Nikoskelainen et al, these reports show 2 examples that combine all symptoms of orbital involvement by multiple myeloma.11 Exceptionally painful recurrent cellulitis and haematic cyst of the orbit can be presentations of the disease.9 CT and MRI gave valuable information on the extent, the bony destruction, and the localization of the tumour. In both cases, biopsy confirmed the orbital involvement by multiple myeloma. Thus, the diagnosis relies on histopathologic studies that usually reveal an atypical homogeneous and dense monomorphic plasmacytoid cell infiltration and eccentric nuclei that are often binucleated. Immunoperoxidase stains show monoclonality. In our cases, either external beam radiotherapy or systemic chemotherapy was effective. They both improved orbital symptoms even though they did not cure multiple myeloma. Contrary to our first case, EMP first appeared in the upper respiratory tract, especially the sinuses of the face, and the orbit through the orbital rim with bony destruction.7 Case 2 is the only report in the ophthalmologic literature concerning striated orbital muscle involvement in known IgA kappa light chain multiple myeloma. It is even more unusual that patients with IgA myeloma globulins have on average shorter remission and survival periods than those with an IgG peak.3 From 1972 to time of writing,4 this is only the second case of IgA immunoglobulin myeloma involving the orbit and, of 13 cases in the literature in which immunocytochemical studies were performed, the second with striated muscle

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involvement. There was mention of neither muscle involvement for the first orbital myeloma, nor an IgA peak for the first muscle involvement described. In fact, this is the first documented case that brings together IgA myeloma involving orbital recti muscles. Although IgG type is the most common immunoglobulin secreted in these diseases, it is normally seen with greater frequency in orbital or ocular involvement compared with the percentage of IgG found in secretory multiple myeloma. There is no significant difference between the lambda and kappa light chain subtypes. Thus IgG type, whether lambda or kappa light chain, appears to be a risk factor for orbital involvement in multiple myeloma. REFERENCES 1. Fay AM, Leib ML, Fountain KS. Multiple myeloma involving the orbit. Ophthalmol Plast Reconstr Surg 1998;14:67–71. 2. Kottler UB, Cursiefen C, Holbach LM. Orbital involvement in multiple myeloma: first sign of insufficient chemotherapy. Ophthalmologica 2003;217:76–8. 3. Mewis-Levin L, Garcia CA, Olson JD. Plasma cell myeloma of the orbit. Ann Ophthalmol 1981;13:477–81. 4. Rodman HI, Font RL. Orbital involvement in multiple myeloma. Review of literature and report of three cases. Arch Ophthalmol 1972;87:30–5. 5. Etienne G, Grenouillet M, Ghiringhelli C, et al. Pulmonary plasmacytoma: about two new cases and review of literature [in French]. Rev Med Int 2004;25:591–5. 6. Ezra E, Mannor G, Wright JE, Rose GE. Inadequately irradiated solitary extramedullary plasmacytoma of the orbit requiring exenteration. Am J Ophthalmol 1995;120:803–5. 7. Balayre S, Gicquel JJ, Mercie M, Dighiero P. Orbital extension of sinus plasmacytoma secondarily transforming into multiple myeloma: a case study [in French]. J Fr Ophtalmol 2004;27:67–71. 8. Adkins JW, Shields JA, Shields CL, Eagle RC Jr, Flanagan JC, Campanella PC. Plasmacytoma of the eye and orbit. Int Ophthalmol 1996–97;20:339–43. 9. Rappaport K, Liesegang TJ, Menke DH, Cservionke LF. Plasmacytoma manifesting as recurrent cellulitis and hematic cyst of the orbit. Am J Ophthalmol 1996;122:595–7. 10. Uceda-Montanes A, Blanco G, Saornil MA, Gonzales C, Sarasa JL, Cuevas J. Extramedullary plasmacytoma of the orbit. Acta Ophthalmol Scand 2000;78:601–3. 11. Nikoskelainen E, Dellaporta A, Rice T, Egbert B, Lane B. Orbital involvement by plasmacytoma. Report of two cases. Acta Ophthalmol (Copenh) 1976;54:755–61. 12. Benjamin I, Taylor H, Spindle J. Orbital and conjunctival involvement in multiple myeloma. Report of a case. Am J Clin Pathol 1975;63:811–7. 13. Gonul E, Izci Y, Sefali M, Erdogan E, Timurkaynak E. Orbital manifestation of multiple myeloma: case report. Minim Invasive Neurosurg 2001;44:172–4. Key words: multiple myeloma, plasmacytoma, orbital tumour, immunoglobulin A