Sudden appearance and spontaneous regression of diffuse large B cell lymphoma in a man with a broken arm

Abstract

An elderly, demented man with stable κ bi-clonal gammopathy of unknown significance suffered a severe displaced right humeral fracture in a fall. One week later a rapidly enlarging head, neck and axillary adenopathy first appeared, including a 2 cm tonsillar node that partially obstructed the oropharynx. A left cervical node biopsy demonstrated diffuse large B cell lymphoma with CD20+, bcl-2+, κ+, CD3–, Epstein–Barr virus negative malignant cells. During the next month lymphadenopathy regressed more than 90% in the absence of treatment with chemotherapeutic agents, radiation or glucocorticoids. Following 2 months of clinical improvement, he died of pneumonia 95 days after the injury. An autopsy demonstrated residual right hilar and mediastinal malignant lymphadenopathy. These unusual events may be related to immunosuppressive and other systemic effects of acute injury on tumour behaviour.

BACKGROUND

Spontaneous remissions rarely occur in diffuse large B cell lymphoma (DLBCL), which is an aggressive lymphoproliferative malignancy.^1–10 In the few reported cases “spontaneous” refers to a remission in the absence of treatment, although the clinical contexts of such remissions are rarely mentioned.^7,8 Factors promoting rapid growth or regression of DLBCL are poorly understood. Significant injury has never been temporally associated with the sudden appearance or regression of DLBCL as described here.

CASE PRESENTATION

An elderly, demented man with severe osteoporosis suffered a displaced fracture of the right proximal humerus as the result of a fall. He was fitted with a stabilising cast and transferred to a nursing home. No lymphadenopathy was observed during the admission examination 6 days following the injury. During the following 6 days a visibly enlarging mass developed in the left anterior neck and dysphagia became prominent. At 13 days post-injury, clusters of firm, non-tender 0.5–1.5 cm nodes appeared in the left anterior and posterior cervical chains as did bilateral axillary adenopathy and a 2.0 cm mass of the left tonsil that partially obstructed the posterior pharynx (fig 1). Right cervical and supraclavicular adenopathy developed the following week. A left neck mass biopsy on day 22 showed obliteration of normal nodal architecture by a diffuse infiltrate of atypical, large immunoreactive B cells (CD20+, bcl-2+, CD3–, κ+), and background T cells (CD3 +) (fig 2). Flow cytometry of biopsy material quantified T cells (CD3+) at 77.9% and B cells (CD19+) at 14.4% with a B cell κ-λ light chain ratio of 4.7. Malignant cells were negative for Epstein–Barr virus RNA by in situ hybridisation.¹¹

Figure 1.

Computerised tomographic image showing mass of the left tonsil (arrow).

Figure 2.

The large atypical lymphoid cells have round or indented nuclei and prominent nucleoli (arrowhead). The small lymphocytes (long arrow) are admixed with the large cells. One endothelial cell (short arrow) is shown for comparison of nuclear size ×400.

The patient had a stable bi-clonal IgA κ, IgM κ gammopathy of unknown significance discovered 3 years earlier when a bone marrow biopsy identified scattered plasmacytoid cells of less than 10%. Serum IgA, 485 mg/dl, IgM 1376 mg/dl and urinary free κ light chain remained stable subsequently. Serial examinations showed no lymphadenopathy or splenomegaly.

OUTCOME AND FOLLOW-UP

The patient was transferred to a hospice unit on day 29 where he received no chemotherapeutic agents, radiation or glucocorticoids. During the next 4 weeks, neck and axillary adenopathy regressed more than 90% and the tonsillar mass completely disappeared. He became more interactive and began feeding himself until a week before death when he stopped eating and became increasingly somnolent. He died of pneumonia 95 days after the injury.

The post-mortem examination demonstrated malignant enlargement of mediastinal and right hilar lymph nodes. Microscopic features of these nodes and of bone marrow were identical to the original findings.

DISCUSSION

The few reports that address spontaneous remissions of aggressive lymphoma and leukaemia rarely note the clinical circumstances in which tumour presentations or regressions occurred. Regressions are reported days to months after biopsy, withdrawal of immunosuppressant agents, febrile illness and bacterial infection.^1–8,12,13 Several malignancy types, including lymphoma, may develop at the site of recent trauma.^14–17 We are not aware of any reports that describe the presentation or remission of lymphoma following trauma at a distant anatomic site. The mechanisms driving lymphoma behaviour in this case remain speculative but raise the possibility that the fracture and tumour behaviour are related.

Significant injury induces humoral and cellular immunosuppression, the release of proinflammatory cytokines and a variety of neuroendocrine responses collectively known as the systemic injury response. Various observations suggest a link between this systemic response to injury and tumour growth.^18–21 Surgical trauma suppresses humoral and cellular immunity in proportion to injury severity with more severe injury associated with more robust growth of several malignant cell lines.^18,19 This injury effect is amplified in immunotolerant athymic nude mice where growth of B cell lymphoma and other malignant cell lines implanted in one flank is enhanced up to threefold by skin incision and abrasion in the opposite flank.²⁰ In humans the contribution of immune function to lymphoma behaviour is suggested by the identification of endogenous anti-idiotypic antibodies to malignant B cell antigens that inhibit cell growth, an effect that is enhanced by passive or active immunisation.²² T cells found in DLBCL nodes, as occurred in our patient implicate cellular immunity as a modulator of tumour growth. The specific type of T cell response is likely relevant as a predominance of activated polyclonal CD4+ T cells predicts a better prognosis.^23,24 Lymphoma regression following withdrawal of immunosuppressive agents is compatible with these observations.^7,8 Moreover, malignant B cells that retain normal signalling mechanisms may proliferate in the manner of normal B cells when exposed to high circulating levels of interleukin-6 induced by significant trauma.^25–30 These data suggest a potential connection between the acute fracture and abrupt lymphoma growth mediated by immunosuppression and proinflammatory cytokine release that reversed during fracture healing.

The patient’s κ bi-clonal gammopathy may reflect a pre-malignant phase of an illness that progressed to a κ-positive DLBCL. Less than 0.2% of all patients with monoclonal gammopathy of unknown significance develop DLBCL. This association is the first to our knowledge with a bi-clonal gammopathy.^31,32

We are not aware of any other reports that describe aggressive proliferation of DLBCL days after significant trauma followed by spontaneous regression. Further studies of this heterogeneous malignancy may determine whether this observed temporal link between trauma and tumour behaviour represents more than happenstance.

LEARNING POINTS

• Sudden appearance and spontaneous regression of DLBCL is rare.

• Neither growth nor regression of DLBCL has been associated with trauma as described for the first time in this report.

• Systemic effects of injury, including transient immunosuppression and release of pro-inflammatory cytokines, may modulate growth and regression of DLBCL.

• This patient is the first reported with κ DLBCL preceded by a stable bi-clonal κ gammopathy of unknown significance.