A Case Report of Gelatinous Transformation of Bone Marrow Following Lymphoma and a Novel, Potential Treatment

doi:10.21203/rs.3.rs-3342813/v1

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Case Report

A Case Report of Gelatinous Transformation of Bone Marrow Following Lymphoma and a Novel, Potential Treatment

https://doi.org/10.21203/rs.3.rs-3342813/v1

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Background

Gelatinous transformation of bone marrow (GTBM) is a rare hematologic condition in which hematopoietic cells in the bone marrow are replaced by extracellular gelatinous substances, often resulting in cytopenias. The true incidence of this condition is presently unknown, as the current body of literature primarily consists of case reports. However, an analysis of a large bone marrow registry suggests that this is a highly rare entity even amongst a population requiring bone marrow biopsy.

Case Presentation:

We hereby present a case of a 24-year-old man with a history of diffuse-large B-cell lymphoma (DLBCL) and an associated 45-kilogram weight loss who was found to have GTBM. The extent of his cytopenias resulted in a prolonged hospitalization with numerous complications, eventually leading to experimental treatment with allogeneic stem cell transplantation (ASCT).

Conclusions

To our knowledge, this is the first reported case of GTBM in which ASCT was employed as a potential treatment modality. While our patient did have clinical improvement following ASCT, the permanence of these results is presently unclear. Furthermore, it is uncertain if the ASCT was truly causative of the stabilization of the patient. Given this, we are currently unable to advocate for ASCT as a treatment for GTBM. We suggest that clinicians consider GTBM as a diagnostic possibility in patients with refractory cytopenias.

Gelatinous transformation of bone marrow

pancytopenia

stem cell transplant

lymphoma

Gelatinous transformation of bone marrow (GTBM) is an exceptionally rare condition whereby hematopoietic cells in the bone marrow are replaced by extracellular gelatinous substances similar to mucopolysaccharides(1). As such, the main manifestation of this disease is often severe cytopenias. The condition was first described in patients with anorexia nervosa in 1930 but has now been documented in a multitude of disease states including celiac disease, congestive heart failure and acquired immunodeficiency syndrome (AIDS) (2, 3). The true incidence of the disease is presently unknown, however retrospective analysis of a large bone marrow registry (n = 80,000) only documented the finding in 0.2% of the analyzed specimens(3). Case reports of the condition have rapidly increased in the past few decades, perhaps indicating a growing awareness of the disease (2). Today, malignancy and malnutrition are recognized as the most common etiologies of GTBM (3). While GTBM was initially described in cases of solid tumour cancers, case reports have now documented the pathology in various hematologic conditions such as multiple myeloma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia and myelofibrosis(4–9).

Mortality and treatment approaches are ill-defined with respect to GTBM, however it appears that the pathologic bone marrow changes are reversible in some patients. Case reports, for instance, have documented resolution of GTBM following treatment of the underlying disease, balanced nutrition, and support with hematopoietic growth factors(10–12). We hereby present a case of a 24-year-old man with a history of diffuse-large B-cell lymphoma (DLBCL) who was found to have GTBM, which we attempted to treat with allogeneic stem cell transplantation (ASCT).

A 24-year-old male from rural Saskatchewan presented to care at the Royal University Hospital in Saskatoon, Saskatchewan, Canada after a yearlong history of fever, chills and a 45-kilogram weight loss. His comorbidities were notable for type 1 diabetes and psoriasis. His initial investigations in December 2021 were significant for a profound bicytopenia [Hemoglobin 55 g/L (ref: 135–180 g/L); Platelets 10 x 10e9/L (ref: 150–400 x 10e9/L)]. Additionally, he was found to have a mild lymphocytosis and an absolute neutrophil count of 0.05 (ref 1.50–7.50 x10e9/L). A pan-computed tomograpgy (CT) scan demonstrated widespread lymphadenopathy through the neck, mediastinum, as well as the retroperitoneum and periportal regions. A bone marrow biopsy and aspirate, as well as a core lymph node biopsy were subsequently arranged, revealing diffuse large-B cell lymphoma (DLBCL) and markedly decreased trilineage hematopoeisis. Fluorescence in-situ hybridization was negative for MYC, BCL-2 and BCL-6.

Due to the patient’s ongoing transfusion requirements, he was admitted to the oncology ward to begin chemotherapy. He received his first cycle of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the end of December 2021. The patient completed his sixth course of R-CHOP chemotherapy in July 2022 with a follow-up positron-emitted tomography (PET) scan revealing a complete response to chemotherapy (Deauville Stage 3). Despite a successful treatment regimen, the patient had multiple requirements for ongoing hospital admission.

Firstly, the patient had refractory cytopenias requiring almost daily support with transfusion products and hematopoietic agents such as granulocyte colony stimulating factor (G-CSF). From December 2021 to September 2022, the patient required over 140 units of packed red blood cells and 100 units of adult-dose platelets. His persistent neutropenia unfortunately precipitated several nosocomial infections which further complicated his course. He was treated for prolonged febrile neutropenia for which a dental abscess was ultimately believed to be the culprit source, hepatosplenic candidiasis, COVID pneumonia and a vancomycin-resistant enterococcal line infection.

In August 2022, a possible explanation for the patient’s cytopenias came into view. A repeat bone marrow biopsy and aspirate was performed to elucidate a potential explanation for the patient’s delayed recovery post-chemotherapy. The results were suggestive of persistent gelatinous transformation of the bone marrow (GTBM) which had previously been documented from a bone marrow biopsy in February 2022 (Fig. 1). While the expected course of GTBM has not been well-explored, the recrudescence of the patient’s disease was thought to be peculiar as the patient’s lymphoma and associated malnutrition had been treated. Given the patient’s young age, the consequences of his cytopenias and separation from his home community, a strong impetus to ameliorate his refractory GTBM developed.

Figure 1: A bone marrow biopsy of the patient performed in February 2022 demonstrating gelatinous transformation of bone marrow (GTBM). The bone marrow is markedly hypocellular with no definite evidence of hematopoeisis. Gelatinous transformation was seen universally in all bone marrow fragments.

In September 2022, the patient was approached for allogeneic stem cell transplant (ASCT) as a potential treatment for his GTBM. To our knowledge, this modality has never been utilized exclusively for the treatment of GTBM. He underwent a conditioning regimen and was transplanted later in the month (Table 1). The patient tolerated transplantation well, however he had persistent neutropenia. Eventually, he experienced some recovery following support with G-CSF. His chimerism showed less than ten percent donor cells, indicating transplant failure. Nonetheless, the patient experienced enough recovery in his cell counts to be safely discharged from hospital in November, after nearly a year of hospitalization.

Table 1

*Transplant Characteristics*
Conditioning Regimen	FluCyATG
Donor Type	Matched Unrelated Donor (12/12)
ABO (donor/recipient)	O positive/O positive
CMV (donor/recipient)	positive/negative
EBV (donor/recipient)	positive/negative
VZV recipient	positive
HSV recipient	positive
Initial Chimerism	< 10%
GVHD prophylaxis	*Tacrolimus, MMF, ATG

Table 1: Allogeneic transplant characteristics. Abbreviations: FluCyATG: Fludarabine, cyclophosphamide and antithymocyte globulin. CMV: cytomegalovirus. EBV: Epstein-Barr Virus. VZV: Varicella-Zoster Virus. HSV: Herpes Simplex Virus. GVHD: Graft Versus Host Disease. MMF: Mycophenolate mofetil.

As of the time of this writing, this patient has not required re-admission to hospital and is no longer transfusion-dependent. However, he has required three donor lymphocyte infusions to assist with engraftment. Given his ongoing leukopenia, he receives no prophylactic immunosuppression to prevent graft-versus host disease (GVHD). Fortunately, he has not had any symptoms consistent with GVHD at this point. His most recent PET scan in April 2023 showed continued remission of his lymphoma. He has close follow-up arranged via our institution’s cancer centre and has returned to his home community which is far away from a tertiary centre in Saskatchewan.

There is a great deal of uncertainty surrounding this case. Firstly, it is unclear as to the exact etiology of GTBM in this patient. Major hypotheses include lymphoma, weight loss or perhaps R-CHOP chemotherapy itself. A study conducted in a cohort of patients with anorexia and GTBM demonstrated a correlation between histologic burden of disease and amount of weight loss (13). Perhaps this indicates that cachexia, malnutrition and malabsorption are the true drivers of GTBM, even in the context of hematologic malignancies. Additionally, the persistence of GTBM in our patient following treatment of lymphoma and improvement in nutrition is not well understood. Numerous case studies, for instance, have documented resolution of GTBM with treatment of the underlying cause, alongside nutritional and transfusion support where necessary (10–12, 14, 15).

At this point, we are uncertain if resolution of GTBM has occurred in our patient. Certainly, his hematopoiesis has improved from when he was an inpatient at our institution and requiring near daily transfusion support. However, he still has marked, albeit stable, pancytopenia (Hemoglobin 80 g/L; Platelets 7x 10e9; Absolute Neutrophil Count 0.6 x 10e9/L at last follow-up). Nonetheless, there are reports that histologic burden of disease poorly correlates with severity of cytopenias (13). The patient has not been subjected to repeat bone marrow biopsy post-ASCT, as this would be unlikely to alter clinical management, especially given the fact that there are currently no specific treatments described for GTBM. While ASCT may have been the factor which stabilized our patient and enabled him to be weaned off transfusion support, a much deeper understanding of the disease process is required before we can advocate for this approach to be widely used in the context of refractory GTBM.

Case reports of GTBM are steadily increasing and it is now considered to be a rare consequence of a multitude of disease states, thereby indicating that this condition has been previously under-recognized. Further exploration of the pathogenesis and epidemiology of GTBM is likely needed to unveil new treatment options for this rare disease. At this moment, we recommend that clinicians give some consideration to this diagnosis and strive for aggressive amelioration of the underlying cause.

GTBM: gelatinous transformation of bone marrow. DLBCL: diffuse large b-cell lymphoma. ASCT: allogeneic stem cell transplantation. AIDS: acquired immunodeficiency syndrome. CT: computed tomography. R-CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. PET: positron-emitted tomography. G-CSF: granulocyte colony stimulating factor. FluCyATG: Fludarabine, cyclophosphamide and antithymocyte globulin. CMV: cytomegalovirus. EBV: Epstein-Barr Virus. VZV: Varicella-Zoster Virus. HSV: Herpes Simplex Virus. MMF: Mycophenolate mofetil.

Ethics approval and consent to participate: Written and informed consent was obtained directly from the patient. Ethics approval was granted via our local ethics review board.

Consent for publication: Informed consent for publication of these materials was obtained from the patient.

Availability of data and materials: Not applicable.

Competing Interests: The authors declare that they have no competing interests.

Funding: Not applicable.

Author Contributions: LH was responsible for literature review and was a major contributor in writing the manuscript. EW prepared images of the bone marrow biopsy and was consulted for details pertaining to the associated pathology of the condition. MB identified the case, provided clinical context, and edited the final manuscript. All authors have read and approved the final manuscript.

Acknowledgements: Not applicable

Barbin FF, Oliveira CC. Gelatinous transformation of bone marrow. Autops Case Rep. 2017;7(2):5–8.
Shergill KK, Shergill GS, Pillai HJ. Gelatinous transformation of bone marrow: rare or underdiagnosed? Autops Case Rep. 2017;7(4):8–17.
Böhm J. Gelatinous Transformation of the Bone Marrow. Am J Surg Pathol. 2000;24(1):56.
Mathew M, Mathews I, Manohar C, Rao S. Gelatinous transformation of bone marrow following chemotherapy for myeloma. Indian J Pathol Microbiol. 2001;44(1):53–4.
Arranz R, Gil-Fernandez JJ, Acevedo A, Tomas JF, Alegre A, Fernandez-Ranada JM. Gelatinous degeneration presenting as a preleukaemic syndrome. J Clin Pathol. 1996;49(6):512–4.
Ifrah N, Saint-Andre JP, de Gentile L, Foussard C, Chevailler A, Flandrin G, et al. Gelatinous Transformation of the Bone Marrow: Manifestation of an Acute Leukemia? Acta Haematol. 1989;82(3):165–8.
Das S, Mishra P, Kar R, Basu D. Gelatinous Marrow Transformation: A Series of 11 Cases from a Tertiary Care Centre in South India. Turkish Journal of Hematology. 2014;31(2):175–9.
Hong FS, Mitchell CA, Zantomio D. Gelatinous transformation of the bone marrow as a late morphological change in imatinib mesylate treated chronic myeloid leukaemia. Pathology. 2010;42(1):84–5.
Böhm J, Schmitt-Gräff A. Gelatinous bone marrow transformation in a case of idiopathic myelofibrosis: a morphological paradox. Pathol Res Pract. 2000;196(11):775–9.
Mant MJ, Faragher BS. The Haematology of Anorexia Nervosa. Br J Haematol. 1972;23(6):737–49.
Miguelañez Matute L, van Noord D, Rayman N, Guillen SS. Gelatinous bone marrow transformation due to extensive weight loss in median arcuate ligament syndrome. BMJ Case Rep. 2022;15(1):e246916.
Charania RS, Kern WF, Charkrabarty S, Holter J. Successful management of gelatinous transformation of the bone marrow in anorexia nervosa with hematopoietic growth factors. International Journal of Eating Disorders. 2011;44(5):469–72.
Abella E, Feliu E, Granada I, Millá F, Oriol A, Ribera JM, et al. Bone Marrow Changes in Anorexia Nervosa Are Correlated With the Amount of Weight Loss and Not With Other Clinical Findings. Am J Clin Pathol. 2002;118(4):582–8.
Steinberg SE, Nasraway S, Peterson L. Reversal of Severe Serous Atrophy of the Bone Marrow in Anorexia Nervosa. Journal of Parenteral and Enteral Nutrition. 1987;11(4):422–3.
Orlandi E, Boselli P, Covezzi R, Bonaccorsi G, Guaraldi GP. Reversal of bone marrow hypoplasia in anorexia nervosa: Case report. International Journal of Eating Disorders. 2000;27(4):480–2.

No competing interests reported.

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A Case Report of Gelatinous Transformation of Bone Marrow Following Lymphoma and a Novel, Potential Treatment

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