Dr.HARIKA REGANI

Dr.Ankita aishwarya, Dr. SANTOSH G. HONAVAR, Dr.HARIKA REGANI

Semi Finals

Abstract

This article describes orbital plasmacytoma and its management including documentation of the youngest case in the literature as per our best knowledge.This is a retrospective observational and interventional case series of six patients from 2013 to 2019. Male to female ratio was 4:2 and 5(83.3%) were unilateral and 1(16.7%) was bilateral. The range age at the time of diagnosis was 20-74 years.3(50%) had association with Multiple Myeloma and 3(50%) were solitary plasmacytoma.Incisional biopsy was done in all (100%) patients. EBRT was given in 5

patients and in 1 patient Chemotherapy with Bone marrow transplantation was done. At a

mean follow up of 13.6 months, 100% of patients had good visual acuity.1(16.6%) showed

excellent response, 2 (33.3%) showed good response, 2(33.3%) showed partial

response and 1(16.6%) had a poor response. Early diagnosis with a multidisciplinary approach increases the chances of vision salvage and provide a decent quality of life to the patient.

Full Text

Key words: Orbital Plasmacytoma, Multiple Myeloma, CD138, Plasma cells
Abstract:

Purpose: Multiple myeloma (MM) is the second most common haematological malignancy, usually affecting patients more than 40 years of age. Extramedullary plasmacytoma is a rare manifestation of multiple myeloma and may be associated with poor visual and clinical outcomes. This article describes the clinical, pathological , radiological diagnosis and management in these patients.

Methods: This is a retrospective observational and interventional case series of six patients of Orbital Plasmacytoma from 2013 to 2019 at a tertiary eye care centre in India. Medical records were reviewed for patient information including demographics, clinical features, radiological features , pathological features and the course of management.

Results: Male to female ratio was 2:1. Mean age at the time of diagnosis was 55.5 years ( Range:20-74 years). The presentation was unilateral in five(83.3%) and bilateral in one(16.7%)patient. Three patients (60%)presented with acute onset of diplopia and proptosis. Radiologically all the lesions (100%) were in anterior orbit involving both inferior and superior quadrant equally(50%). Three patients (50%) had an association with Multiple Myeloma and three (50%) were solitary plasmacytoma. Incisional biopsy was done in all the patients (100%) to confirm the diagnosis. External bean radiotherapy (EBRT) was given in four patients (Pre incisional biopsy EBRT was done in 2(33.3%) and post incisional biopsy EBRT was done in  2(33.3%)  patients. Chemotherapy with Bone marrow transplantation was done in one patient. At a mean follow up of 13.6 months, all the patients (100%) had good visual acuity.

Conclusions: Early diagnosis with a multidisciplinary approach fairly increases the chances of vision salvage and provides a decent quality of life to the patient.

Introduction

Plasmacytomas constitute 5-10% of all plasma cell neoplasms and only 1% of orbital tumors. Orbital Plasmacytoma is an uncommon presentation of multiple myeloma and in more than half of the cases, it is only discovered after diagnosis of multiple myeloma. Multiple myeloma is a tumor of malignant plasma cells that is considered as the second most common hematologic malignancy.^[1]  Plasmacytomas without multiple myeloma have been classified by the International Myeloma Working group in 2003 into three groups. [a] Solitary Plasmacytoma of bone when there is single bone lesion, [b] Solitary Extramedullary plasmacytoma when there is single soft tissue lesion), [c] Multiple Solitary Plasmacytoma when there are Multiple sites of disease in bone, soft tissue or both. Extramedullary involvement with multiple myeloma is generally a manifestation of advanced disease.^[2]  It occurs in 3% cases of  multiple myeloma which are also called as secondary plasmacytoma. There is a female preponderance of 3:1.^[4]We discuss the clinicoradiological evaluation, pathological confirmation and the management in our cases of Orbital plasmacytoma. 

Methods:

This is a retrospective observational and interventional case series of five patients from 2013 to 2019 at a tertiary eye care centre in India. Medical records were reviewed for patient information including demographics, clinical features, radiologic features , pathologic features and management strategy.

Results:

Three patients (60%) were diagnosed with orbital plasmacytoma and two (40%) were diagnosed with conjunctival and orbital plasmacytoma. Male to female ratio was 2:1 (M=4,F=2) with a mean age of 51.8 years (range 20–70 years) at the time of presentation. Four were unilateral (80%) and one was bilateral (20%). Mean onset of symptoms was 14.1 days. All patients (100%) underwent incisional biopsy. EBRT was given in four patients (Pre incisional biopsy EBRT was done in 2(50%) which was given earlier for systemic MM and 2(50%) post incisional biopsy EBRT) .Three (60%) patients in this study were diagnosed with orbital plasmacytoma as a manifestation of multiple myeloma and two (40%) were having solitary plasmacytoma. Incisional biopsies showed CD138 positivity in all patients. Two(40%) patients were treated with a combination of chemotherapy and bone marrow transplantation; whereas, three (60%) patients were treated with EBRT alone. One patient did not follow the treatment advice and was not investigated further after incisional biopsy. Among the treated ones, One patient (20%) showed excellent response to treatment, one (20%) showed good response to treatment (had <10% plasma cells in Bone marrow aspiration) , Two (40%) showed partial response (had >50% plasma cells in Bone marrow aspiration) and one (20%) had poor response (had 80% plasma cells in Bone marrow aspiration).  6 cases of Orbital plasmacytoma are discussed here in detail.

Case 1

A 51 year old female presented to us with swelling of Right Eye (RE) lower lid since 20 days associated with loss of sensation of teeth on right side. Her Best corrected visual acuity (BCVA) was 6/6 in Both eyes (BE). Her ocular movements were full and free and there was no associated proptosis. RE had a ptosis of 2mm. On palpation there was firm , tender lesion along right inferior orbital rim but posterior margin was not palpable. Retrobulbar resistance was present. CT scan showed punched out lesions of skull , mass involving maxillary sinus and temporal fossa which was suggestive of plasmacytoma associated with Multiple Myeloma(MM). Incision biopsy was done. Histopathology report showed tumor cells of plasmacytoid appearance, punched out appearance of tumor cells, plasmablasts suggestive of plasmacytoma.(Figure 1) Immunohistochemistry (IHC) was positive for CD138 and lambda light chain restriction. Ki67 labelling index was 30-40%. Bone marrow biopsy showed <10% plasma cells. Urinary Bence jones protein was negative. Calcium was normal.  Serum protein electrophoresis showed elevated gamma globulins and M-Band (25.1%) in gamma region. Based on clinical , radiological and histopathological reports diagnosis of Extramedullary plasmacytoma with Multiple Myeloma was made. Patient was started on chemotherapy (Bortezomib, Doxorubicin and Dexamethasone) for four cycles with allogenic bone marrow transplantation. ost treatment, her BCVA was 6/6 in BE. There was no mass felt on palpation and no orbital mass was seen (Figure 2). Patient showed very good response to therapy.

Case 2

A 70 year male presented to us with swelling in the left eye since 15 days. His Best Corrected Visual Acuity was 6/6P in RE and 6/9P in LE. Ocular movements of Left eye (LE)  were restricted in all gazes except inferiorly and the patient had significant diplopia. There was proptosis of 5mm by Hertle’s Exophthalmometry and hypoglobus of 2mm. MRI Orbit with contrast was done which showed a well defined soft tissue mass of approximately 30x30x15mm   in superolateral aspect of the left orbit which was isointense on T1 and T2 and is causing destruction of the adjoining left frontal bone in roof of the left orbit with intracranial extension in left frontal lobe. CECT Orbits confirmed the erosion of adjacent roof and lateral wall of left orbit and left frontal bone compressing the superior surface of the left globe and abutting the superior rectus. A multilevel incisional biopsy was done which showed poorly cohesive plasmacytoid cells, bi to multinucleate cells with marked nuclear atypia and specky necrosis. IHC was positive for CD138 with Ki67 labelling index of 60-70% suggestive of Orbital Plasmacytoma. PET CT scan showed increased uptake in the left orbit with foci of increased uptake in left humeral neck and D4 transverse process. Biopsy of left humeral head lesion also showed features of plasmacytoma. A systemic evaluation for multiple myeloma was negative. Bone marrow biopsy showed <10% plasma cells. The final diagnosis of Multifocal Plasmacytoma of Bone was made. Patient was given EBRT to left orbit, left humeral head and D4 vertebrae. 6 months later, there was no palpable mass clinically, the intracranial component has resolved and good bone remodelling was seen. The patient was monitored for signs of multiple myeloma. After 1 year of radiation, the bone remodelling has further increased. Intralesional steroid injection was given for the residual lesion in the sphenoid wing. There is a significant increase in the bone growth after 6 months of intralesional injection. There is no activity seen on PET Bone scan so the patient is advised for a regular follow up of 6 monthly for 3 years and then annual follow up to investigate for multiple myeloma. It has been 2 years since the time of presentation and he is doing very well. (Figure 4).

Case 3

A 61 year male who was a known case of multiple myeloma presented to us with complaints of double vision in LE  since 15 days. Palliative radiotherapy to spine has been given to him elsewhere. BCVA was 6/6P in BE. Ocular movements were restricted in LE superior and lateral gazes with diplopia. There was proptosis of 8mm by Hertles Exophthalmometry. There was  diffuse red superior bulbar conjunctival infiltrate involving superior epibulbar, superior fornix, tarsal conjunctiva and lacrimal gland. CT scan orbit showed ill defined lesion eroding superior and temporal aspect of left orbit. Incisional biopsy was done . Histopathology showed sheets of plasmablasts and plasma cells. Mitoses average 8/10 HPF (Figure 5). Bone marrow biopsy showed >50% plasma cells. Serum electrophoresis showed monoclonal band positivity. Serum IgG and lambda light chains was raised. Based on above findings diagnosis of Extramedullary plasmacytoma with Multiple Myeloma was made. Patient underwent Localized radiotherapy to left orbit. There was partial response to treatment.

Case 4

A 57 year male who was known case of Left submandibular node plasmacytoma and right ethmoidal sinus myeloma status post chemotherapy and radiotherapy presented to us with watering and swelling of LE. BCVA was 6/6 P in BE . In LE there was restriction of ocular motility in upgaze associated with diplopia. There was proptosis of 6mm by Hertles Exophthalmometry. CT Scan orbit showed lesion involving left frontal bone and ethmoidal sinus with extensive bony erosion. Incisional biopsy was done . Histopatholgy report showed poorly cohesive plasmacytoid cells (Figure 6).IHC showed CD138 positive. Serum electrophoresis showed M-Band in Gamma region with raised kappa light chain. Based on above findings diagnosis of Extramedullary plasmacytoma with Multiple Myeloma was made. Patient underwent Localized radiotherapy to left orbit. There was partial response to treatment.

Case 5:

A 20 year male noticed swelling in inferior orbit 18 days back. BCVA was 6/6 in BE. Ocular motility was full and free. On palpation there was non mobile mass palpated in inferior orbit attached to the floor of orbit with mild warmth and tenderness which was confirmed on CT scan orbit. Chemosis was present in inferior tarsal conjunctiva. Incisional biopsy was done which was suggestive of solitary orbital plasmacytoma (Figure 7). Bone marrow biopsy showed >80% plasma cells. A thorough systemic evaluation for plasma cell dyscrasia was negative. Bone marrow transplantation was done but patient succumbed  within one year of treatment. There was poor response to treatment.

Case 6:

A 74 year female presented to us with swelling above the left eyebrow since 1 month. On examination her BCVA was 6/9 in RE and 6/12P in LE. Extraocular movements were limited in upgaze and there is a hypoglobus of 3mm and associated diplopia.There was proptosis of 4mm in LE by Hertles exophthalmometry. There was temporal fossa fullness with firm , non-tender, non-mobile, non-compressible mass in superotemporal quadrant. CT scan showed a mass which had triradiate lesion of size 34.7×23.8×28.3mm. Provisional diagnosis of LE proptosis to rule out plasmacytoma, meningioma, eosinophilic granuloma and osteogenic sarcoma was made. She underwent multilevel transseptal incisional biopsy which showed patternless proliferation of plasmacytoid cells. IHC was CD 138 positive, monoclonal cells with kappa light chains only and Ki 67 labelling index of 30-35%. These were suggestive of extraskeletal plasmacytoma. The patient denied any form of further evaluation and treatment but is currently doing well.

Discussion

According to the International Myeloma Working Group, the diagnosis of multiple myeloma should fulfill the following criteria: clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma plus any one of the following myeloma defining events: end organ damage (hypercalcemia, renal insufficiency, anaemia, bone lesions), or any one or more of the following biomarkers of malignancy, a clonal bone marrow plasma cell percentage ≥ 60%, an involved: uninvolved serum free light chain ratio of ≥ 100, or >1 focal lesions by MRI .^[11]  The criteria for the diagnosis of SEP include negative lymph node assessment, skeletal survey, bone marrow biopsy, and computed tomography.^[3] Bonavolonta et al reported plasmacytoma had a prevalence of 3% patients and accounted for <1% of total orbital lesions. ^[12] The cases reported here represent a variety of eye and adnexal locations of plasmacytomas. We found two cases involving conjunctiva, one case involving lacrimal gland, one involving maxillary sinus and another involving ethmoidal sinus along with orbital lesion.  In our case series there was male preponderance of 4:1 which was different from the study done by Wang et al in 2018 where they had a female preponderance of 3:2. ^[13] This difference may be because of the study population. In our series mean age of diagnosis was 51.8 years which was different from study done by Terenzi et al in 2012 which showed mean age of 70 years at diagnosis and only 3.4% of cases are diagnosed between 35 – 44 years of age.^[5] This difference may be because of difference in sample size and range of age group of sample. In our series most of the patients presented with diplopia and proptosis which was acute or subacute in onset with good visual acuity. This was in contrast to study done by Wang et al in 2018 where patients presented with proptosis and decrease in vision which was insidious in onset. ^[13] The differences in demographic details with  our study  may be due to the sample size, the range of age group and the relatively early presentation to us much before the involvement of the optic nerve. Four cases were unilateral (80%) and one was bilateral (20%). In Cases 1, 3 and 4 the orbital plasmacytomas presented in conjunction with evidence of systemic multiple myeloma . Case 2 and 4 had Extramedullary Plasmacytoma. Case 2,3 and 5 are associated with adnexal involvement. Case 1 and 4 are associated with paranasal sinus involvement. Case 5 of 20 year male is the youngest reported case of solitary orbital plasmacytoma to the best of our knowledge. Darbari et al in 1972 reported youngest case of plasmacytoma at 30 years of age. ^[16] Reported cases of orbital plasmacytoma predominantly originate in the superotemporal quadrant of the orbit.^[4] Our series support this finding, with three out of five cases of orbital plasmacytoma occurring in superior quadrant.The most common type of heavy chain found in MM are IgG and IgA.^[15,16] This correlates with our finding where most common type of heavy chain was IgG (60%). In our case series we found two cases (40%) had lamba chains, two (40%) cases had kappa chains and one (10%) did not have any light chains. This is in contrast to Burkat et al in 2009 who wrote Kappa and lambda light chains were  present in a significant number of patients, but neither were more likely to involve the orbit. ^[4]  In our series all SEP were arising from paranasal sinuses .This matches with the study done by Webb et al in 1962 where they mentioned that solitary extramedullary plasmacytoma (SEP) are often found in the upper respiratory tract, and possess the ability to invade the orbit from the surrounding sinuses.^[17,18] Multiple myeloma is generally treated with systemic chemotherapy and autologous stem cell transplantation where appropriate.^[19-21]

Key features of the previous reported cases are summarised in Table 1.

Conclusion:

We have observed in our study that patients with bone marrow biopsy having ≤10% plasma cells had good response to treatment , those with ≤50% showed partial response to treatment and those with ≥80% showed poor response to treatment. Further study on their correlation will definitely help in prognosticating and managing  these patients.

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Table 1: Clinical Summary of cases

Patient	Age at Presentation (years)	Sex	Prior Treatment	Quadrant Involvement	Associated with MM	Treatment given	Response to treatment
Case 1	51	F	Nil	Inferior	No	BMT+Chemo	Good
Case 2	70	M	Nil	Superotemporal	No	EBRT	Good
Case 3	61	M	RT	Superior with conjunctival and LG involvement	Yes	Local EBRT	Partial
Case 4	57	M	RT	Medial and Superomedial	Yes	EBRT	Partial
Case 5	20	M	Nil	Inferotemporal with conjunctival involvement	No	BMT	Poor