Orbital Infiltration in a Patient with Waldenström Macroglobulinemia: Need for Multidisciplinary Aapproach and Comparison with the Literature 

Riccardo Paggi1, Francesca Mariotti1, Jessica Mencarini1,2, Silvia Bresci2, Irene Campolmi2, Filippo Bartalesi1,2, Beatrice Borchi2, Luca Nassi3, Benedetta Sordi3,4, Alessandro Maria Vannucchi4 and Alessandro Bartoloni1,2.

1 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
2 Infectious and Tropical Diseases Unit, Careggi University Hospital, Florence, Italy.
3 Hematology Unit, Careggi University Hospital, Florence, Italy.
4 Center for Innovation and Research in Myeloproliferative Neoplasms, Hematology Unit, Careggi University Hospital, University of Florence, Florence, Italy.

Correspondence to: Riccardo Paggi. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. E-mail:

Published: May 1, 2023
Received: January 31, 2023
Accepted: April 18, 2023
Mediterr J Hematol Infect Dis 2023, 15(1): e2023028 DOI 10.4084/MJHID.2023.028

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The use of specific inhibitory drugs of intracellular signalling pathways (such as BrutonKinase inhibitors) for the treatment of Waldenström's macroglobulinaemia (WM) is a recognised risk factor for Aspergillus spp. infections. The overlapping clinical manifestations of the two diseases may require the involvement of different medical specialities. We describe the clinical course of a patient with pulmonary and encephalic aspergillosis, with concomitant orbital WM involvement, a rare localisation of the disease: the case required a multidisciplinary approach to define the ocular lesions and an in-depth study of the literature, in which approximately twentycases of lymphoplasmacytic lymphoma with orbital localisation were reported.


Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma (LPL)  belonging to the category of Non-Hodgkin B Lymphomas (NHL) with an indolent course, characterized by monoclonal immunoglobulin M (IgM) protein hypersecretion.[1] The median age of diagnosis is 70 years,[2] and the disease is much more common in the white population.[3] Patients with WM can develop systemic symptoms (fever, weight loss, night sweats), symptoms related to bone marrow infiltration (e.g., anemia, leukopenia, thrombocytopenia), lymphoid tissues involvement (e.g., lymphadenopathy, hepatosplenomegaly) and IgM monoclonal proteins (e.g., hyperviscosity, peripheral neuropathy, renal disturbances).[1] Recurrent infections may also occur due to a relative decrease of other immunoglobulin classes or as a consequence of treatment-induced immunosuppression. Treatment is indicated in symptomatic patients, firstly with anti-CD20 agents (e.g., rituximab) and chemotherapy, with the possible use of drugs such as BTK (Bruton tyrosine kinase) – inhibitors (e.g., ibrutinib, acalabrutinib or zanubrutinib) or proteasome inhibitors (e.g. bortezomib).[4]
We briefly present a case description of a patient affected with WM and treated with multiple lines, including ibrutinib. The clinical history became particular after the occurrence of intraorbital lesions requiring the involvement of a multidisciplinary approach in order to establish a correct diagnosis and treatment.

Case Presentation

Clinical history. The patient was a 71 years-old male, affected with symptomatic WM since 2000, previously treated with a CHOP-like chemotherapy followed by rituximab consolidation in 2001. In 2006 he received rituximab and chlorambucil for a first relapse; in 2011, for a second relapse, he underwent treatment with rituximab, fludarabine, and cyclophosphamide and in 2017 with rituximab and bendamustine for a subsequent recurrence. For chronic obstructive pulmonary disease (COPD) exacerbations, the patients experienced several hospitalizations since 2018 and started intravenous immunoglobulin support for secondary, symptomatic hypogammaglobulinemia. The patient was also receiving entecavir for chronic HBV infection. Due to the increase of IgM protein, the presence of anemia, and the emergence of abdominal lymphadenopathies, ibrutinib was started in June 2019: a complete bone marrow (BM) evaluation was performed before starting the treatment, showing 80% of clonal lymphoplasmacytic BM infiltration. Multiparameter flow cytometry demonstrated a characteristic WM phenotype: CD19+, CD22+, CD79b+, FMC7+, IgM+, monoclonal kappa (k) light chain surface expression. MYD88 gene mutation was tested as well, resulting positive for MYD88L265P mutation.
A partial response was then obtained, with the resolution of anemia, lymphadenopathy reduction, and decreased IgM monoclonal protein. In October 2020, the patient was admitted for symptomatic COVID-19 pneumonia, treated with remdesivir with rapid improvement.
Diagnosis of invasive aspergillosis
. In December 2020, invasive pulmonary aspergillosis (IA) was diagnosed, according to sputum samples positive for Aspergillus flavus and A. fumigatus, bronchoalveolar lavage (BAL) Aspergillus spp. positive polymerase chain reaction (PCR) detected by polymerase chain reaction (PCR), BAL-sample's galactomannan optical density index of 1.71, and chest high-resolution CT findings consistent with the disease. Antifungal therapy with isavuconazole was started in January 2021, improving the pulmonary lesions. Considering the diagnosis, ibrutinib treatment was briefly interrupted and restarted at a lower dose, considering the pharmacological interaction with isavuconazole.
In March 2021, he was admitted to a peripheral hospital for an epileptic crisis. A brainstem contrast-enhanced (CE) magnetic resonance (MR) was performed, showing a 12 mm nodular lesion in the left parietal lobe, weakly enhanced in T1-weighted (T1W) sequences and hypointense in T2-weighted (T2W) sequences, with ring enhancement, and a similar 4 mm finding in the right lobe. Additionally, the patient experienced a likely ischemic stroke.
Ibrutinib was suspended for cerebral IA suspect, a lumbar puncture was executed (microbiological samples resulted in negatives), and a cerebral biopsy of the bigger lesion was performed after a month, with evidence of fungal hyphae and spores and positive Aspergillus spp. PCR, confirming the encephalic fungal localization.
Laboratoristic progression of Waldenström macroglobulinemia
. In May 2021, he was admitted to our hospital for hepatic toxicity related to isavuconazole, and antifungal therapy was switched firstly to liposomal B amphotericin, then to voriconazole. Brain C.E. MR in May 2021 was substantially unchanged. In August 2021, the stability of the radiological brain picture and improving lung imaging were confirmed with an additional CT examination.
During the same period, considering the evidence of atypical lymphocytes in blood smear and the serum levels of IgM 29.4 g/L (normal values 0.4-2.3), BM biopsy (BMB) was performed, with evidence of lymphoid interstitial infiltrate of 70-80% of cellularity, plasmacytoid elements and monoclonal expression of k light chain and M heavy chain: considering the absence of symptoms related to WM and the concomitant IA, the patient did not start any treatment for WM.
Orbital infiltration - Initial work-up
. In September 2021, the patient was admitted for fever. For the evidence of a slight lymphocytosis, a peripheral blood flow cytometry was performed and showed the presence of a mature B lymphocyte population (CD19+, CD22+, IgM+ CD23 -/+ and clonal expression of k light chain). During hospitalization, the patient complained of bilateral conjunctivitis: at the examination, bilateral nodules were palpable under the eyebrow arch without pain, vision deficit, diplopia, or corneal involvement. Orbit CT (Figure 1) evidenced bilateral increased lacrimal glands (20x10 mm). Several (> 10) small and hyperdense nodularities (from 2 to 15 mm) were detected bilaterally in the eyelid's soft tissues and intra- and extra-conical endo-orbital areas. Nodular lesions were confirmed with an orbit CE MR (Figure 1), iso/hypointense in T1W sequences, and hypointense in T2W, with contrast enhancement. Similar findings were described in both maxillary sinuses and ethmoidal lamina papyracea. The Serum IgM level was 46 g/L (normal value: 0.4-2.3).

Figure 1
Figure 1. Orbit CT (a), T1-weighted magnetic resonance  (b), contrast enhanced T1-weighted magnetic resonance (c), T2-weighted magnetic resonance (d) showing bilateral  enlargement of lacrimal  glands  and intra-orbital nodules (October 2021)

Differential Diagnosis. Orbital masses in the adult can occur in a wide range of diseases, including infections (e.g., Staphylococcus spp., Mycobacterium tuberculosis, Aspergillus spp.), inflammatory diseases (e.g., IgG4-related sclerosing disease, systemic amyloidosis), vascular lesions (e.g., venous and arteriovenous malformations), benign (e.g. schwannoma, neurofibroma) and malignant tumors (e.g., B-cell lymphoma, metastasis).[5] Lacrimal gland lesions account for approximately 10% of all biopsied orbital masses: the most common causes are inflammatory (as IgG-4-related disease) or lymphoproliferative disorders, with potential bilateral involvement.[6,7]
Considering the subacute onset of the manifestation (4 months since the last brain MR) and that intraorbital lesions are uncommon but possible in both IA and WM, we focused on the differential diagnosis between these two pathological entities. Orbital presentation's main differences are described in Table 1.

Table 1
Table 1. Clinical, radiological and therapeutic differences between orbital involvement of Waldenström macroglobulinemia and invasive aspergillosis.

Further Examinations
. Considering IA pulmonary picture improvement and encephalic lesions stability after eight months of antifungal therapy (Figure 2) and the evidence of WM progression at BMB with peripheral blood involvement, after a multidisciplinary discussion, treatment with bortezomib (a proteasome inhibitor) was started in October 2021. At the same time, voriconazole was suspended, and the patient started posaconazole prophylaxis. According to ophthalmological and neuro-radiological evaluation, the patient was discharged with a scheduled clinical and radiological follow-up. He initially reported conjunctival chemosis reduction with decreased swelling, especially of the right eye. Five cycles of bortezomib were administered until February 2022. The patient was admitted in March 2022 for COPD exacerbation, presenting worsening bilateral orbital edema (Figure 3): decreasing pulmonary aspergillosis lesions were confirmed at CT exam, in line with negative serum beta-D-glucan ad galactomannan, with no evidence of IA encephalic radiologic worsening. However, MR examination evidenced increased dimensions of known orbital lesions (Figure 4), with a worsening picture of erosive foci in subcutaneous, maxillary, and ethmoidal areas, diffused also in left frontal and sphenoidal sinuses, mastoid and ethmoidal cells, bilaterally in nasal turbinates.

Figure 2 Figure 2. Timeline of events from December 2020, evidencing radiological, histological and laboratory findings. Below the timeline are evidenced chemotherapy.

Figure 3 Figure 3.  Evidence of bilateral orbital oedema and subcutaneus palpebral nodules at the clinical examination, April 2022.

Figure 4 Figure 4. Progression of lacrimal glands and intra-orbital nodules enlargement, contrast enhanced T1-weighted magnetic resonance , comparison between October 2021, April 2022 and June 2022. 

Final Diagnosis. Considering the worsening clinical picture, according to maxillofacial surgeons, palpebral and maxillary biopsies were performed. The latter sample evidenced a picture consistent with LPL (lymphoid proliferation with plasma cells expressing IgM). Additional therapeutic cycles with bortezomib were not performed because of the increased infection risk and the progressively worsening performance status. IgM levels were reduced to 22.4 g/L (normal values 0.4-2.3).
Orbital infiltration was confirmed as a progressive WM involvement; interestingly, only eighteen cases in the literature from 1967 to nowadays report similar findings (Table 2). Lacrimal gland involvement is reported in only seven cases.[8-14]

Table 2
Table 2. Cases of Waldenström macroglobulinemia orbital involvement described in literature. Cases of orbital invasion in Bing-Neel syndrome, case reports written in French and Japanese languages were excluded.

 In June 2022, intraorbital and maxillofacial diffusion worsened (Figure 4), involving nasal bones and extending to the left infratemporal fossa and alveolar processes through the ipsilateral maxillary sinus. Palliative radiotherapy was performed in June and July 2022. The patient experienced an additional COPD exacerbation needing hospitalization in July 2022 with concurrent pancytopenia (red blood cells 3.04x1012/L, white blood cell 1.18x109/L, neutrophils 0.86x109/L, platelets 51x109/L). Serological markers of fungal infection were persistently negative; an antimicrobial regimen and recombinant human granulocyte colony-stimulating factor (Filgrastim) were introduced. The patient was discharged after one week and died in August 2022.


The case denotes the diagnostic and therapeutic complexity of a patient affected by WM progression, a pathology requiring a multidisciplinary approach[4,15,16] in the context of a pulmonary and encephalic IA.
Disseminate or extrapulmonary IA is commonly associated with hematopoietic cell/solid organ transplantation and hematologic malignant therapy:[17] in particular, association with Bruton-kinase inhibitor (e.g., ibrutinib) is well described,[18-20] with encephalic involvement commonly reported.[19]
The most common Aspergillus spp. ocular manifestation is endophthalmitis, while the typical orbital aspergillosis is characterized by unilateral painful, red eye with proptosis,[21] usually starting from paranasal sinuses.[22] The involvement of lacrimal sack has been rarely described in the literature.[21]
In WM, the most common ocular manifestation (present in up to 34% of cases)[23] is hyperviscosity syndrome associated with funduscopic abnormalities, characterized by characteristically tortuous "sausage link"-like retinal veins. Tumor infiltration of the orbital and periorbital tissues, involving retro-orbital lymphoid tissue and lacrimal glands, rarely occurs.[24] If it happens, it is described as bilateral masses [8,15,25,26], in some cases with palpebral edema,[9,26] nodular palpebral involvement,[10] and proptosis.[25] Bilateral swelling of lacrimal glands is an extremely rare presentation of WM and has been described only in a few cases in the literature, [8-14,27] as well as bone involvement.[28] Orbital infiltration can be present also in Bing-Neel syndrome, a WM malignant form of the central nervous system, but usually with a more extended involvement.[29,30] Radiologically, LPL lesions are usually mildly hypointense in T1W and T2W MR imaging,[24,28,31] probably for the high density of tumor cells and low interstitial water content.[31] Lesions, shown in T1W sequences, are also characterized by homogeneous CE.[24,28,31]Treatment for WM orbital involvement is not well defined, and in published case reports, chemotherapy alone[10,14,28] or combined with local radiotherapy[8,15,24] was used, with a reduction of symptoms, intraorbital masses, and blood IgM levels. In our case, although the reduction of IgM level (22.4 vs. 46 g/L), symptoms persisted, and orbital and maxillofacial foci gradually increased in size


We reported a case of orbital WM with lacrimal glands involvement, rarely described in the available literature. Differential diagnosis between WM and IA was particularly difficult considering the two pathologies' systemic nature and overlapping clinical features. A correct diagnosis was reached only thanks to a multidisciplinary approach.


  1. Mazzucchelli M, Frustaci AM, Deodato M, et al (2018) Waldenstrom's Macroglobulinemia: An Update. Mediterr J Hematol Infect Dis 10:e2018004. PMid:29326801 PMCid:PMC5760071
  2. Castillo JJ, Olszewski AJ, Kanan S, et al (2015) Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database. Br J Haematol 169:81-89. PMid:25521528
  3. Benjamin M, Reddy S, Brawley OW (2003) Myeloma and race: a review of the literature. Cancer Metastasis Rev 22:87-93. PMid:12716040
  4. Kastritis E, Leblond V, Dimopoulos MA, et al (2018) Waldenström's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv41-iv50. PMid:29982402
  5. Bs P, Mi V, A A, et al (2016) Orbital tumours and tumour-like lesions: exploring the armamentarium of multiparametric imaging. Insights Imaging 7. PMid:26518678 PMCid:PMC4729705
  6. Kim JS, Liss J (2021) Masses of the Lacrimal Gland: Evaluation and Treatment. J Neurol Surg Part B Skull Base 82:100. PMid:33777623 PMCid:PMC7987400
  7. Teo L, Seah LL, Choo CT, et al (2013) A survey of the histopathology of lacrimal gland lesions in a tertiary referral centre. Orbit Amst Neth 32:1-7. PMid:23387446
  8. Krishnan K, Adams PT (2009) Bilateral orbital tumors and lacrimal gland involvement in Waldenström's macroglobulinemia. Eur J Haematol 55:205-206. PMid:7672095
  9. Vangsted A, Mikkelsen LH, Jørgensen JS, Heegaard S (2020) Lymphoplasmacytic lymphoma infiltrating both lacrimal glands in a patient with Waldenström's macroglobulinemia. Am J Ophthalmol Case Rep 17:100597. PMid:32016162 PMCid:PMC6992929  
  10. Adiga S, Mehta A, Singh U, et al (2022) Waldenström Macroglobulinemia of the orbit: A diagnostic challenge. Eur J Ophthalmol 32:NP246-NP250. PMid:33183084
  11. Little JM (1967) Waldenström's macroglobulinemia in the lacrimal gland. Trans - Am Acad Ophthalmol Otolaryngol Am Acad Ophthalmol Otolaryngol 71:875-879
  12. Hafezi F, Moesen I, Carels G, et al (2010) [Waldenstrom's macroglobulinaemia of the lacrimal gland in a patient with sarcoidosis]. Ophthalmol Z Dtsch Ophthalmol Ges 107:60-63. PMid:19669149
  13. Schechterman L, Tyler SJ (1970) Waldenström's macroglobulinemia. Localization in ileum and lacrimal glands. N Y State J Med 70:2025-2029
  14. Leone G, Parisi V, Rebecchi A, et al (1996) Multiple ocular impairment in a patient affected by Waldenström's macroglobulinaemia. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol 234:533-535. PMid:8858361
  15. Guerin C, Normile C, Quinn J, et al (2022) Orbital involvement in Waldenstrom macroglobulinaemia: a multidisciplinary approach. Ir J Med Sci 1971 - 191:2229-2230. PMid:34762279
  16. Kapoor P, Ansell SM, Fonseca R, et al (2017) Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol 3:1257-1265. PMid:28056114 PMCid:PMC5556979
  17. Patterson TF, Thompson GR, Denning DW, et al (2016) Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 63:e1-e60. PMid:27365388 PMCid:PMC4967602  
  18. Fürstenau M, Simon F, Cornely OA, et al (2020) Invasive Aspergillosis in Patients Treated With Ibrutinib. HemaSphere 4:e309. PMid:32309779 PMCid:PMC7162080
  19. Ghez D, Calleja A, Protin C, et al (2018) Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood 131:1955-1959. PMid:29437588
  20. Maus MV, Lionakis MS (2020) Infections associated with the new "nibs and mabs" and cellular therapies. Curr Opin Infect Dis 33:281-289. PMid:32657964 PMCid:PMC7367497
  21. Levin LA, Avery R, Shore JW, et al (1996) The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol 41:142-154. PMid:8890440
  22. Khoo SH, Denning DW (1994) Invasive aspergillosis in patients with AIDS. Clin Infect Dis Off Publ Infect Dis Soc Am 19 Suppl 1:S41-48. PMid:7948570
  23. García-Sanz R, Montoto S, Torrequebrada A, et al (2001) Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol 115:575-582. PMid:11736938
  24. Ranchod TM, Mansour TN, Fogt F, Gausas RE (2008) Waldenström macroglobulinemia of the orbit. Ophthal Plast Reconstr Surg 24:76-77. PMid:18209658
  25. Kumar S, Das S, Goyal JL, et al (2007) Bilateral orbital tumor formation and isolated facial palsy in Waldenstrom's macroglobulinemia. Int Ophthalmol 26:235-237. PMid:17356930
  26. Verdú J, Andrés R, Sánchez-Majano JL, Fernández JA (2011) Bilateral ocular involvement as a presentation of Waldenström's macroglobulinemia. Med Oncol Northwood Lond Engl 28:1624-1625. PMid:20697839
  27. Blatrix C, Fine JM, Yeme D, Lambin P (1973) [Tumoral forms of Waldenstrom's macroglobulinemia. Apropos of a case involving 2 localisations, orbital and hepatic]. Sem Hopitaux Organe Fonde Par Assoc Enseign Med Hopitaux Paris 49:2847-2851
  28. Karimi S, Wong RJ, Holodny AI (2006) Skull Base, Orbital, and Perineural Involvement in Waldenström's Macroglobulinemia. J Otolaryngol 35:68. PMid:16527022
  29. Varettoni M, Defrancesco I, Diamanti L, et al (2017) Bing-Neel Syndrome: Illustrative Cases and Comprehensive Review of the Literature. Mediterr J Hematol Infect Dis 9:e2017061. PMid:29181138 PMCid:PMC5667529  
  30. Stacy RC, Jakobiec FA, Hochberg FH, et al (2010) Orbital involvement in Bing-Neel syndrome. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc 30:255-259. PMid:20548243
  31. Ettl AR, Birbamer GG, Philipp W (1992) Orbital Involvement in Waldenström's Macroglobulinemia: Ultrasound, Computed Tomography and Magnetic Resonance Findings. Ophthalmologica 205:40-45. PMid:1436990
  32. Giarelli L, Melato M, Falconieri G (1982) Eye involvement in Waldenströms's macroglobulinaemia. Ophthalmol J Int Ophtalmol Int J Ophthalmol Z Augenheilkd 185:214-219. PMid:6815601
  33. Moulis H, Mamus SW (1989) Isolated trochlear nerve palsy in a patient with Waldenström's macroglobulinemia: complete recovery with combination therapy. Neurology 39:1399. PMid:2507958
  34. Lossos A, Averbuch-Heller L, Reches A, Abramsky O (1990) Complete unilateral ophthalmoplegia as the presenting manifestation of Waldenström's macroglobulinemia. Neurology 40:1801-1802. PMid:2122277
  35. Hellman JB, Harocopos GJ, Lin LK (2018) Waldenstrom macroglobulinemia involving the superior rectus muscle. Am J Ophthalmol Case Rep 10:304-306. PMid:29780960 PMCid:PMC5956744