Critical Role of PET-Scan in Unravelling the Dual PathologyReview of Literature and a Case Presentation
Islam MS*Department of Hematology, Consultant Hematologist, Guy’s Hospital and Queen Elizabeth Hospital, Stadium Road, London, UK
Volume 2 Issue 3- 2019
Received Date: 30 Nov 2019
Accepted Date: 16 Dec 2019
Published Date: 24 Dec 2019
2. Keywords: Myeloma; Lymphoma; DLBCL; PET/CT scan; Biopsy
3. Introduction
1. Abstract
Simultaneous presentation of two lymphatic haematological malignancies is extremely rare. Adequate and optimal diagnostic steps including various imaging techniques and histopathological biopsies are required unpin the exact diagnoses to be able to deliver the best management strategies. Positron Emission Tomography/Computerised Tomography scan (PET/CT) can be used to determine the sites of disease with the highest Standardized Uptake Value (SUV) and hence, the preferred site of biopsy.
The simultaneous occurrence of two lymphatic malignancies in one patient is extremely rare with an incidence rate of 1.4–6.5 cases/1,000,000 individuals [8]. Co-existence of MM and other lymphoid malignancies like Chronic Lymphocytic Leukemia (CLL) [9], MM and Hodgkin’s Disease (HD) [10], MM and Lympho Plasmacytic Lymphoma (LPL) [11] has been reported. However, there are less than 5 reported cases in PubMed of simultaneous presentation of DLBCL and MM [12].
Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL), comprising about 24% of new cases of NHL [1, 2]. DLBCL is an aggressive NHL which usually present with rapidly enlarging lymph nodes. Positron Emission Tomography/Computerised Tomography scan (PET/ CT) can be used to determine the sites of disease with the highest Standardized Uptake Value (SUV) and hence, the preferred site of biopsy.
Multiple Myeloma (MM), a plasma cell neoplasm involving clonal proliferation of terminally differentiated plasma cells and MM is the second most common hematologic cancer [3]. Unlike other metastatic bone malignancies, multiple myeloma related osteolyticbone lesions exhibit no new bone formation [4]. Myeloma
relatedbone disease is one of the main causes of morbidity and this can be detected on skeletal radiographs, low-dose Whole Body Computed Tomography (WB-CT), Magnetic Resonance Imaging (MRI) or PET/CT [5,6]. About 1% to 2% of MM patients presents with Extrame Dullary Disease (EMD) and an accurate differentiation of this finding from nodal lymphoma is very crucial as treatments are very different for these two haematological cancers [7].
Positron Emission Tomography (PET) scan is a functional imaging developed in the late 1950s. Radio-labelled glucose analogue Fluorine-18 Fluorodeoxy-Glucose (F-18 FDG) is the most frequently used PET tracer and it allows visualization of the cellular uptake of glucose, which is often up regulated in malignant neoplasms. FDG-PET has replaced Gallium-67 scintigraphy, which was previously used to assess the extent and viability of lymphoma [13, 14]. A major advantage of FDG-PET is the ability to quantify the level of FDG uptake from PET images and resulting in a Standardized Uptake Value (SUV). The combined PET and CT isan important evolution of imaging technique and the CT component of PET/CT provides anatomical information and PET component provides tissue metabolic activity. Combined PET/CT results in a reduced incidence of false-positive and false-negative PET findings.
4. Case Presentation
70 years old gentleman referred to hematology department with four months history of lethargy. He was initially referred to the gastroenterologist for investigations for his weight loss but he has no clear bowel symptoms and any change of his bowel habits. A colonoscopy and upper gastrointestinal endoscopy did not show any significant pathological findings to cause the patient’s symptoms. As part of his investigation, he had a CT scan that showed mediastinal lymphadenopathy as well as bone lesions at thoracic ten vertebra level (T10). There were borderline enlarged left supraclavicular nodes, with some para-vertebral tissue around T10 and the bone lesions. Previous blood test showed an increase of serum kappa light chains to 2148 mg/L, serum lambda light chains were 11mg/L and the kappa lambda ratio was elevated to 189. Serum protein electrophoresis did not show any para protein. Subsequently, he had a Magnetic Resonance Imaging (MRI) of the whole spine which showed multiple marrow deposits through out the spine, with a compression fracture of the T10 vertebra body, with no signs of cord compression. Patient had a biopsy of the T10 para spinal mass, which was compatible with a diagnosis of plasma cell neoplasm (Table 1 and Figure 1). He also had a bone marrow biopsy findings are summarised in (Table 1). He subsequently had a PET (Positron Emission Tomography) /CT scan finding are illustrated in (Table 2).
This case was discussed multi-disciplinary haematological malignancy meeting and the plan was to treat the patient with VTD regimen for myeloma as he renal function was deteriorating. However, as PET/CT showed discrepancies in FDG uptake in myelomatous bone lesion and in inguinal lymph node, a core biopsy of that lymph gland was taken which confirmed a diagnosis of DLBCL (Table 3 and Figure 2).
A PET/CT scans showed innumerable lucencies throughout the imaged skeleton with mild FDG uptake, comparable with adjacent marrow uptake. There was slightly high FDG uptake (SUVmax 4.3), above background marrow uptake, associated with the moderate to severe pathological collapse of the T10 vertebral body. There were also enlarged left inguinal lymph nodes of (39 x 28) mm diameter which showed much higher FDG uptake of SUVmax 12.4.
The tumour cells express CD20, CD79a, BCL-6 (weak), CD10, MUM1, BCL-2, IgM and kappa but are negative for CD3, CD5, CD23, CD117, EMA, CD30 and EBER. The MIB-1 labelling index averages 90%. The tumour cells are negative for CD138.FISH: No evidence of high risk cytogenetic abnormalities. Cyclin D1 is negative, MYC not re-arranged.
Trephine:Interstitial infiltrate of kappa light chain restricted neoplastic plasma cell (30-40% disease bulk). Neoplastic cells expessed-IRF4/ MUM1, CD20, CD79a, Cyclin D1, CD117 and EMA. Negative for heavy chain expression and Negative for amyloid.
Cytogenetic:By interphase FISH analysis on bone marrow aspirate sample showed-presence of IGH-CCND1[t(11;14)] and additional copy of ATM(11q22.3).
T10 mass: Biopsy showed infiltration of cells withplasmacytic differentiation and the cells are CD138 positive. MNF116 immunostaining is negative for cytokeratin.Further immunostaining shows most cells are positive for MUM1, cyclin D1, CD117 and EMA along with kappa restriction. There is no convincing positivity with IgG, IgA or IgM. There is extensive deposition of amorphous eosinophilic material, both within and outside vessel walls, almost certainly representing amyloid deposition. Congo Red staining confirmed that.
Conclusion: Plasma cell neoplasm and amyloid deposition.
Patient was subsequently started treatment with a combination ofrituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) plusbortezomiband is he is currently responding very well to treatment with interim PET/CT showed completed resolution of inguinal lymph nodesand improvement in myeloma markers-latestserum Kappa Light Chains 47.94 mg/L, Serum Lambda Light Chains 7.30 mg/L and Kappa Lambda Ratio 6.57, and resolution of T10 vertebra mass. This patient is now undergoing assessment for an Autologous Stem Cell Transplant (ASCT).
5. Discussion
MM is well recognised to be associated with an increased risk of secondary malignancies [15, 16]. However coexistence of DLBCL and MM very rare, and the pathogenesis of this dual diagnosis of DLBCL with MM are not yet well understood. The two malignancies may have been different manifestations of a unique clonal disorder and it has been suggested that NHL clone continues to mature and may eventually rise to MM [17]. A retrospective study showed 6 out of 4165 patients with B-NHL developed MM and only 1 out of 804 MM patients developed B-NHL [18]. Although it has been postulated a common clonal cell of origin
for the coexisting malignancies but studiesusing immunoglobulin light and heavy chain isotype analysis or genotypic studies have demonstrated disparate clonal evolutions in concomitant malignancies. The separate clonal origins indicate DLBCL and MM evolve independently and not from transformation of a B-cell clone [19].
Myeloma Working Group (IMWG) criteria for the diagnosis of MM highlighted the importance of new imaging techniques for the management of MM in order to early detection of bone disease as a symptomatic MM criterion requiring treatment even when asymptomatic [27]. Studies conducted over recent years have shown better performance using low-dose whole-body CT and MRI scans than standard skeletal radiographs [28, 29]. However PET/CT scan may be better imaging technique as it can simultaneously show the functionality of neoplastic cells as well as show their anatomical position.
A more recent study suggests that PET/CT scan is a reliable imaging for initial staging, therapeutic monitoring and relapse workup in MM, especially because of its prognostic potential [30]. PET/CT scan is very useful in evaluating metabolic activity in malignant tumor. For MM staging PET-FDG allows whole-body exploration and has 90% sensitivity for the detection of medullary disease and 70-100% specificity [31-33]. PET scans are shown to have prognostic importance in myeloma patients as the presence of at least 3 Focal Lesions (FL) and EMD predicted inferior Overall Survival (OS) as well as Progression Free Survival (PFS) [34, 35].
The PET scan identifies the location of lymphoma uptake and distinguishes it from physiologic uptake or other causes of increased FDG uptake i.e. infection, inflammation or any second malignancy as in our case according to distribution and characteristics of FDG uptake. PET/CT appears to be very sensitive and highly specific for detecting NHL in nodal and extra-nodal siteshowever, the reliability of detection lymphoma in bone marrow involvement is no consistent [36-39].
Until the early 2000s, lymphoma staging was based mainly on CT scan as the main imaging modality along with results from clinical examination and bone marrow biopsy [20]. Since then studies have shown that combined FDG-PET/CT is superior to FDGPET or contrast-enhanced CT as separate imaging procedures in the staging of lymphoma [21-26]. The 2014 International
However, PET scan findings are usually different between MM and high grade lymphoma as the latter group shows more intense FDG uptake than neoplastic cell of MM [40-45]. Moreover, MM does not usually present with lymphadenopathy. Our patient had lymphadenopathy as well as there was a differential FDG uptake between para-spinal mass and the groin lymph nodes which prompted further investigation in our patient. In this case, the patient was found to have a second malignancy in the form of DLBCL which is potentially curable versus myeloma which at present time is an incurable malignancy. Therapeutic decision making was complicated by the fact that for these two different malignancies patients usually receive very different treatment regimens. However, our patient was treated with a regimen based on the ReMODL-B trial with excellent response for both MM and
NHL [46].
6. Conclusion
PET/CT is an invaluable diagnostic tool that should be integrated in evaluating lymphoid malignancies, during initial diagnosis and as subsequent response assessment. The specific mechanisms underlying the simultaneous presentation of two B-cell malignancies have yet to be established. Hence, there are no consistent treatment guidelines. Due to the lack of specific guidelines management of such should be based on available evidence and the doctor’s experience, the characteristics of the patient’s illness and the performance status.
7. Acknowledgement:
Talhah S Bin-Islam for helping with the typing and editing the manuscript.
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