Bone Marrow Biopsy for the Initial Staging of Patients With Lymphoma: Too Soon to Toss the Trephine

December 15, 2013

Although the prospect is tempting, we do not believe there are sufficient grounds at this time to abandon bone marrow biopsy in patients with lymphoma. It still provides robust prognostic information, and in the majority of patients it remains an indispensable staging tool.

Recent studies showing excellent sensitivity of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT for detecting marrow involvement in patients with Hodgkin lymphoma (HL)[1-3] and diffuse large B-cell lymphoma (DLBCL)[4] have led some to claim that bone marrow biopsy (BMB) is obsolete. The argument is that the low number of patients “upstaged” by positive BMB no longer justifies the pain, anxiety, and risk of complications.

Although invasive, BMB is quite safe if performed by an experienced operator; the risks of major bleeding (1:4,000, and largely restricted to patients with myeloproliferative neoplasms) and death (1:50,000) are low.[5] Patient anxiety can be allayed with good communication to establish trust and rapport, while pain can be minimized using generous local anesthesia, the offer of sedation, and analgesia.[6] A single trephine (length ≥ 20mm with analysis of multiple levels and appropriate immunohistochemistry) obviates the need for bilateral biopsies and maximizes the diagnostic yield.[7]

In patients with HL, the sensitivity of PET-CT for detecting bone marrow involvement is high, exceeding that of BMB, but the characteristics of patients identified by each procedure do not overlap completely. In the series of 454 patients assessed by El-Galaly et al, the reported sensitivity of PET-CT was 95%, compared with 31% for BMB.[1] Furthermore, there was no difference in 2-year progression-free survival between BMB-positive patients and those with negative BMB but multifocal skeletal lesions, suggesting the prognostic value of the finding was similar regardless of the means of determination. Pooled analysis of studies addressing this question suggests that 1% of patients with negative PET-CT have positive BMB and would be missed by omission of the procedure.[1,3,8-14] Although rare, such a finding has high clinical impact-particularly if treatment algorithms for limited-stage disease incorporate radiotherapy; in patients with a high International Prognostic Score, which is directly impacted by bone marrow status; or in patients who receive escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) rather than ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

In DLBCL, a recent study from the United Kingdom found the sensitivity of PET-CT (94%) was greater than that of BMB (40%) for detecting marrow involvement; however, the clinical significance of this finding is called into question by the lack of impact on patient outcomes of bone marrow involvement detected by PET (but not biopsy), compared with marrow involvement documented by histology, which predicted for an inferior outcome.[4] It is worth remembering that marrow involvement (equating to stage IV) thus potentially increases the score on the International Prognostic Index, which was generated in an era when BMB was standard. Furthermore, BMB can detect discordant marrow involvement in low-grade lymphoma. It appears that these patients have a greater tendency toward indolent relapse,[15,16] and one study has suggested benefit from up-front transplantation in such patients.[17] Such a management strategy is dependent upon thorough staging, including BMB. Finally, marrow involvement was identified as an independent risk factor for central nervous system involvement in older series[18,19]; however, more recent studies in patients treated with rituximab-containing chemotherapy regimens suggest that this may no longer be true.[20,21] Nonetheless, it appears to be too early to dispense with BMB in the management of DLBCL.

In mantle cell lymphoma (MCL), nearly all patients are shown to have marrow or gastrointestinal infiltration if sufficiently sensitive techniques are used.[22,23] Therefore, outside of a clinical trial, if all patients are treated as being at an advanced stage, BMB may be omitted without consequence. However, the European MCL Network has demonstrated that bone-marrow molecular remission is an independent predictor of superior clinical outcome[24]; post-induction minimal residual disease status has been incorporated into future trial protocols as a risk stratification criterion for maintenance/consolidation (M. Dreyling, personal communication).

Finally, in the case of indolent lymphomas such as follicular lymphoma, BMB remains a mandatory component of staging, as (1) marrow involvement is a specific component of the FLIPI-2,[25] and (2) limited-stage disease is treated with radiotherapy, while advanced-stage disease is observed or treated with systemic therapy.

Thus, although the prospect is tempting, we do not believe there are sufficient grounds at this time to abandon BMB in patients with lymphoma. BMB still provides robust prognostic information, and in the majority of patients it remains an indispensable staging tool. Many of the published series of PET assessment of bone marrow status are from academic tertiary referral centers with high scan volumes and considerable reporting expertise; the generalizability of their findings remains uncertain. Nevertheless, such sensitive imaging modalities are likely to replace BMB in selected scenarios, such as HL, once clear and reproducible internationally accepted criteria for positivity are established and validated in community practice settings.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol. 2012;30:4508-14.

2. Hamilton R, Andrews I, McKay P, Leach M. Loss of utility of bone marrow biopsy as a staging evaluation for Hodgkin lymphoma in the positron emission tomography-computed tomography era: a West of Scotland study. Leuk Lymphoma. 2013 Aug 5. [Epub ahead of print]

3. Richardson SE, Sudak J, Warbey V, et al. Routine bone marrow biopsy is not necessary in the staging of patients with classical Hodgkin lymphoma in the 18F-fluoro-2-deoxyglucose positron emission tomography era. Leuk Lymphoma. 2012;53:381-5.

4. Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122:61-7.

5. Bain BJ. Bone marrow biopsy morbidity and mortality. Br J Haematol. 2003;121:949-51.

6. Hjortholm N, Jaddini E, Halaburda K, Snarski E. Strategies of pain reduction during the bone marrow biopsy. Ann Hematol. 2013;92:145-9.

7. Campbell JK, Matthews JP, Seymour JF, et al. Optimum trephine length in the assessment of bone marrow involvement in patients with diffuse large cell lymphoma. Ann Oncol. 2003;14:273-6.

8. Elstrom R, Guan L, Baker G, et al. Utility of FDG-PET scanning in lymphoma by WHO classification. Blood. 2003;101:3875-6.

9. Jerusalem G, Beguin Y, Fassotte MF, et al. Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin’s disease. Haematologica. 2001;86:266-73.

10. Muzahir S, Mian M, Munir I, et al. Clinical utility of 18F FDG-PET/CT in the detection of bone marrow disease in Hodgkin’s lymphoma. Br J Radiol. 2012;85:e490-6.

11. Naumann R, Beuthien-Baumann B, Reiss A, et al. Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin’s lymphoma. Br J Cancer. 2004;90:620-5.

12. Pelosi E, Penna D, Douroukas A, et al. Bone marrow disease detection with FDG-PET/CT and bone marrow biopsy during the staging of malignant lymphoma: results from a large multicentre study. Q J Nucl Med Mol Imaging. 2011;55:469-75.

13. Purz S, Mauz-Korholz C, Korholz D, et al. [18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol. 2011;29:3523-8.

14. Rigacci L, Vitolo U, Nassi L, et al. Positron emission tomography in the staging of patients with Hodgkin’s lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi. Ann Hematol. 2007;86:897-903.

15. Campbell J, Seymour JF, Matthews J, et al. The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement. Eur J Haematol. 2006;76:473-80.

16. Sehn LH, Scott DW, Chhanabhai M, et al. Impact of concordant and discordant bone marrow involvement on outcome in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2011;29:1452-7.

17. Ghesquieres H, Berger F, Felman P, et al. Clinicopathologic characteristics and outcome of diffuse large B-cell lymphomas presenting with an associated low-grade component at diagnosis. J Clin Oncol. 2006;24:5234-41.

18. Bos GM, van Putten WL, van der Holt B, et al. For which patients with aggressive non-Hodgkin’s lymphoma is prophylaxis for central nervous system disease mandatory? Dutch HOVON Group. Ann Oncol. 1998;9:191-4.

19. Tomita N, Kodama F, Kanamori H, et al. Prophylactic intrathecal methotrexate and hydrocortisone reduces central nervous system recurrence and improves survival in aggressive non-Hodgkin lymphoma. Cancer. 2002;95:576-80.

20. Kumar A, Vanderplas A, LaCasce AS, et al. Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database. Cancer. 2012;118:2944-51.

21. Schmitz N, Zeynalova S, Nickelsen M, et al. A new prognostic model to assess the risk of CNS disease in patients with aggressive B-cell lymphoma. Hematol Oncol. 2013;31:96-150.

22. Böttcher S, Ritgen M, Buske S, et al. Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations. Haematologica. 2008;93:551-59.

23. Romaguera JE, Medeiros LJ, Hagemeister FB, et al. Frequency of gastrointestinal involvement and its clinical significance in mantle cell lymphoma. Cancer. 2003;97:586-91.

24. Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010;115:3215-23.

25. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555-62.