Whole-body imaging of the musculoskeletal system : the value of MR imaging In clinical practice various modalities are used for whole-body imaging of the musculoskeletal system , including radiography , bone scintigraphy , computed tomography , magnetic resonance imaging -LRB- MRI -RRB- , and positron emission tomography-computed tomography -LRB- PET-CT -RRB- . Multislice CT is far more sensitive than radiographs in the assessment of trabecular and cortical bone destruction and allows for evaluation of fracture risk . The introduction of combined PET-CT scanners has markedly increased diagnostic accuracy for the detection of skeletal metastases compared with PET alone . The unique soft-tissue contrast of MRI enables for precise assessment of bone marrow infiltration and adjacent soft tissue structures so that alterations within the bone marrow may be detected before osseous destruction becomes apparent in CT or metabolic changes occur on bone scintigraphy or PET scan . Improvements in hard - and software , including parallel image acquisition acceleration , have made high resolution whole-body MRI clinically feasible . Whole-body MRI has successfully been applied for bone marrow screening of metastasis and systemic primary bone malignancies , like multiple myeloma . Furthermore , it has recently been proposed for the assessment of systemic bone diseases predisposing for malignancy -LRB- e.g. , multiple cartilaginous exostoses -RRB- and muscle disease -LRB- e.g. , muscle dystrophy -RRB- . The following article gives an overview on state-of-the-art whole-body imaging of the musculoskeletal system and highlights present and potential future applications , especially in the field of whole-body MRI . Introduction The skeletal system is a frequent target of metastatic spread from various primary tumors like carcinoma of the breast , lung and prostate cancer . Moreover , primary malignancies may also originate from the bone marrow , such as lymphoma and multiple myeloma -LSB- 1 -RSB- . Therefore , it is highly important to accurately assess manifestations of malignant diseases within the bone marrow in order to facilitate adequate therapy and predict prognosis . Only pronounced destruction of bone with loss of bone mineral content exceeding 50 % is readily visible in radiographic examinations -LSB- 2 -RSB- . Computed tomography -LRB- CT -RRB- is definitely more sensitive than radiography and it is the image modality of choice to evaluate the extent of destruction of trabecular and cortical bone and to assess stability and fracture risk . Magnetic resonance imaging -LRB- MRI -RRB- , on the other hand , allows bone marrow components , such as hematopoietic and fat cells , to be visualized . Moreover , tumor infiltration into the spinal canal and paravertebral soft tissues is clearly depicted . Compared with other imaging modalities like radiography , CT or bone scintigraphy , it is the most sensitive technique for the detection of pathologies restricted to the bone marrow , even if trabecular bone is not destroyed -LSB- 3 , 4 -RSB- . It has been reported that up to 40 % of skeletal metastases occur outside the field of view covered by a routine assessment of the axial skeleton , underlining the importance of whole-body bone marrow imaging -LSB- 5 -RSB- . In the past , different requirements for patient positioning and coil set-up complicated the introduction of MRI as a practicable whole-body application . With multi-channel whole-body MRI -LRB- WB-MRI -RRB- scanners , however , head-to-toe assessment of the whole skeletal system has become a realistic option without compromises in image quality compared with dedicated examinations of limited anatomical areas . Beyond the assessment of malignant bone neoplasms , WB-MRI has recently been proposed for the whole-body imaging of systemic muscle disease and may prove useful for an evidence-based screening of patients suffering from diseases that predispose to bone malignancy -LRB- e.g. , multiple cartilaginous exostoses -RRB- . Technical aspects of whole-body MRI Due to its lack of ionizing radiation MRI seems suitable for whole-body imaging , but for a long time its primary application has been the assessment of focal pathologies within particular organs and body parts . The most severe challenges of WB-MRI in the past have been long examination times , mainly caused by time-consuming patient repositioning and changing of the array configuration . Initially , the sequential scanning approach for WB-MRI of the skeletal system consisted of separate scanning steps of T1-weighted and STIR -LRB- short tau inversion recovery -RRB- imaging at five body levels with at least one patient repositioning process using conventional head , neck , body , and spine array coils . For a complete whole-body examination , including dedicated imaging of the spine in sagittal orientation , a total room time of at least 60 min had to be taken in account . Steinborn et al. introduced for the first time this whole-body bone marrow scanning concept for the screening of bone metastases and , despite the considerable complexity of the examination , reported advantages in diagnostic accuracy for MRI compared with conventional WB imaging techniques , like skeletal scintigraphy -LSB- 6 -RSB- . Later , attempts to overcome FOV restrictions and increase patient comfort were based on a rolling platform concept mounted on top of the scanner table , making the patient glide in between a `` coil sandwich '' comprised of the body coil and the integrated spine coil -LRB- AngioSURF ™ / BodySURF ™ ; MR-Innovation , Essen , Germany -RRB- . However , with this approach considerable compromises in spatial resolution , especially in peripheral body regions like the head/neck and lower extremities , had to be tolerated -LSB- 7 -RSB- . With the introduction of multi-channel MR scanners , using a system of multiple phased array coils covering the whole body like a matrix , imaging of the total skeletal system without compromises in spatial resolution became possible . In particular , the combination of free table movement with parallel imaging acquisition techniques -LRB- PAT -RRB- resulted in substantially shorter room time and allowed to integrate otherwise time-consuming , but indispensable sequence types for bone marrow imaging -LRB- e.g. , STIR sequences -RRB- . The proposed imaging protocol for high resolution T1-weighted turbo spin echo -LRB- TSE -RRB- and STIR imaging from head to toe is performed with 1.3 × 1.1-mm and 1.8 × 1.3-mm plane resolution respectively -LRB- 5-mm slices , matrix 384 , PAT 2 -- 3 -RRB- . Additionally , dedicated T1-weighted TSE and STIR imaging of the complete spine is performed -LRB- 1.0 × 1.0-mm plane , 3-mm slices , matrix 384 -RRB- , which results in a total scan time of 43 min . A promising new concept for WB-MRI is the continuously moving table technique with the use of PAT . Recently , a SENSE reconstruction algorithm has been successfully applied on stationary receiver coils with arbitrary coil dimensions for continuously 3D gradient echo imaging of the complete body without significant constraints in image quality -LSB- 8 -RSB- . Zenge et al. have reported promising initial results for 3D whole-body continuous data acquisition using the rolling table concept as a new potential strategy for WB-MRI metastases screening , especially for large field-of-view imaging in short bore systems -LSB- 9 -RSB- . Technical aspects of whole-body CT Multislice CT -LRB- MS-CT -RRB- is frequently used in oncologic imaging , and in the detection of bone destruction CT is far more sensitive than radiography -LSB- 10 -RSB- . Moreover , it is unique in its ability to evaluate the extent of osseous destruction and to assess stability and fracture risk -LSB- 11 -RSB- . Whole-body imaging usually implies CT of the neck , thorax , abdomen/pelvis in axial orientation with multi-planar reconstructions and recalculation of bone window setting . Continuous hardware improvements for CT imaging from single-slice scanners to 64-slice scanners have resulted in larger FOV and faster acquisition times with high resolution . Examination time now is reduced to 1 -- 2 min and improvement in resolution with the resulting formation of isotropic voxels allows high quality multiplanar reconstructions . In particular , the use of ultrathin collimation -LRB- 0,5 mm -RRB- can provide excellent image quality for the neck and peripheral skeleton . Furthermore , with automated tube current dose modulation systems exposure of the patient to ionizing radiation could be reduced by 10 -- 68 % on average , depending on the anatomical region , without substantially sacrificing image quality -LSB- 12 -RSB- . Absolute dose reduction -LRB- described as volume CT dose index -RRB- ranges from 11.97 / 8.18 mGy for a pelvic examination to 23.28 / 7.45 mGy when a combined angular and z-axis modulation system is used . Multislice CT enables bone destruction to be detected as well as osteoblastic and mixed patterns with osteosclerosis and destruction . In cases of diffuse bone marrow infiltration inhomogeneous osteoporosis may be detected . However , as in radiography , this may mimic osteoporosis , unless areas of bony destruction are present . 3D reconstruction algorithms , like VRT -LRB- volume rendering technique -RRB- , can be used to display complex fractures -LRB- e.g. , pathological fracture -RRB- and further increases the reliability to detect occult vertebral fractures compared with plain radiographs . Furthermore , the 3D morphology of vertebral fractures may give indications concerning the nature of the fracture -LRB- e.g. , tumorous vs. osteoporotic fracture -RRB- . Clinical application of whole-body MRI Whole-body MRI is increasingly used in the field of oncologic imaging as an adjunct or alternative to established multi-modality approaches -LRB- e.g. , radiographs , MS-CT , ultrasound , scintigraphy -RRB- for initial tumor staging or screening for tumor recurrence after curative therapy . Promising results have been reported for the detection of distant metastatic disease , especially in tumors that frequently metastasize to the bone , liver , and brain -LRB- Fig. 1 -RRB- -LSB- 13 , 31 -RSB- . Recently , WB-MRI has been proposed as a sensible application for a more integrated assessment of multiple myeloma and systemic muscle diseases -LSB- 16 , 17 , 18 , 19 -RSB- . Fig. 1A 60-year-old patient with a malignant melanoma . a Coronal T1-weighted turbo spin echo -LRB- TSE -RRB- whole-body -LRB- WB -RRB- magnetic resonance imaging -LRB- MRI -RRB- indicates multifocal metastatic disease of the liver -LRB- arrow -RRB- . b Whole-body positron emission tomography-computed tomography -LRB- PET-CT -RRB- shows multiple areas of pathologic -LSB- 18F -RSB- - fluorodeoxyglucose -LRB- FDG -RRB- - uptake in the right atrium -LRB- arrow -RRB- , the liver -LRB- arrowheads -RRB- , and in the right iliac bone -LRB- arrowhead -RRB- . c Contrast-enhanced CT reveals a metastasis within the right atrium . d T1-weighted TSE WB-MRI confirms a hypointense lesion in the right iliac bone indicating bone metastasis . e Axial fat-saturated contrast-enhanced MRI of the pelvis shows another bone metastasis in the right sacral bone -LRB- arrow -RRB- . f , g The corresponding CT images in the bone window setting show extensive osteolysis within the right iliac bone ; however , no morphologic changes are found in the right sacral bone Metastasis Based on morphological criteria in radiography , CT , and MRI , skeletal metastases are classified as osteolytic -LRB- approximately 50 % -RRB- , osteoblastic -LRB- 35 % -RRB- , and mixed type -LRB- 15 % -RRB- . For MRI bone screening , the combination of unenhanced T1-weighted spin echo and turbo-STIR sequences proved to be highly sensitive in discriminating benign from malignant marrow disorders -LSB- 20 -RSB- . On T1-weighted sequences tumor spread is identified by replacement of normal fat containing marrow , resulting in a hypointense signal . Fat-suppressed sequences , such as STIR , depict neoplastic lesions by virtue of the hyperintense signal due to increased content of water within the tumor cells -LRB- Fig. 2 -RRB- . However , osteoblastic metastases may be depicted in STIR sequences with variable signal intensities from hypointense in dense sclerotic lesions to hyperintense when more cellular components are present -LSB- 21 -RSB- . The unique soft-tissue contrast of MRI allows precise assessment of tumor infiltration within the bone marrow and even diffuse infiltration of the bone marrow with neoplastic cells , not associated with focal bone destructions or formation of new bone , is detected -LSB- 22 -RSB- . In some cases additional sequences , such as dynamic studies of signal enhancement after gadolinium injection , may be performed for accurate differentiation from benign bone marrow changes , such as hyperplastic bone marrow formation -LSB- 23 -RSB- . Finally , MRI allows for precise assessment of adjacent paraosseous structures , such as the spinal canal . Whole-body MRI compared with bone scintigraphy In clinical practice multi-modality algorithms are most commonly used when metastatic bone disease is suspected . They include radiography , bone scintigraphy , PET , CT , and MRI . In many institutions 99mTc-phosphonate-based bone scanning is performed as the method of initial bone marrow screening . However , scintigraphy provides only limited spatial resolution and at an early stage of disease lesions may remain invisible in the absence of an osteoblastic response -LSB- 24 -RSB- . Furthermore , misinterpretation of tracer uptake in healing fractures or degenerative disease may lead to false-positive findings . The diagnostic performance of MRI compared with bone scintigraphy for the detection of skeletal metastases has been examined in various studies and higher specificity and sensitivity in the early detection of skeletal metastases have been reported -LSB- 6 , 24 , 25 -RSB- . Steinborn et al. compared combined T1-weighted and STIR WB-MRI with bone scintigraphy using the sequential scanning approach in a lesion-by-lesion analysis -LSB- 6 -RSB- . WB-MRI reliably detected more confirmed skeletal metastases -LRB- 91 % -RRB- than bone scintigraphy -LRB- 85 % -RRB- . Another study group reported higher sensitivity and specificity of WB-MRI -LRB- 92 % / 90 % -RRB- compared with scintigraphy -LRB- 83 % / 80 % -RRB- on a patient-by-patient basis -LSB- 20 -RSB- . Daldrup-Link et al. analyzed both methods for the detection of bone metastases in 39 children and young adults and observed a higher sensitivity of 82 % for WB-MRI compared with 71 % for scintigraphy , with this difference increasing , especially in medium-sized lesions between 1 and 5 cm -LSB- 3 -RSB- . Interestingly , both methods showed differences in performance according to lesion location . Most false-negatives in scintigraphy were found in the spine , while diagnostic problems for WB-MRI occur in the thoracic cage and skull , especially when coronal imaging orientation is used , a problem that is certainly increased by motion artefacts . These problems might be overcome when using fast turbo spin echo sequences for thoracic imaging in combination with axial slice orientation . Whole-body MRI compared with MS-CT Multislice CT is far more sensitive than radiography in the assessment of focal bone destructions . Krahe et al. compared radiography and CT examinations in 112 patients with metastases of the spine -LSB- 10 -RSB- . MS-CT identified 268 involved vertebrae while radiography depicted 88 % of these lesions when the vertebral body was involved and only 66 % when other parts of the vertebrae were affected . Intraspinal and paravertebral tumor extension was correctly assessed by plain radiography in only 23 % and 33 % of cases respectively . Recently , multidetector MS-CT has been proposed for whole-body screening of the skeletal system as an alternative to bone scintigraphy -LSB- 26 -RSB- . Groves et al. investigated 43 patients with suspected bone metastases using bone scintigraphy and 16-detector MS-CT and detected metastatic disease in 14 out of 43 and 13 out of 43 patients respectively , with an agreement of 84 % , suggesting a similar diagnostic performance of both modalities . The authors concluded that in case of suspected skeletal metastasis , scintigraphic studies may not be needed , when an adequate whole-body MS-CT tumor staging with recalculation of bone window setting has been performed . Consecutively , this might shorten diagnostic pathways and save resources . However , it is not yet clear whether MS-CT is equal to MRI for the assessment of bony metastases . First results have demonstrated the superior detection rate of MRI -LRB- Fig. 1 -RRB- -LSB- 27 -RSB- . Whole-body MRI compared with PET-CT In contrast to MRI and MS-CT , positron emission tomography -LRB- PET -RRB- using -LSB- 18F -RSB- - fluorodeoxyglucose -LRB- FDG -RRB- provides functional information by tracing increased FDG uptake directly into the tumor cells . Recent studies indicate that whole-body FDG-PET increases specificity of bone screening compared with bone scintigraphy , although there is conflicting evidence whether there is a significant gain in sensitivity -LSB- 28 -RSB- . Still , FDG is a tracer that is not tumor-specific and may also accumulate in the presence of inflammation and thus lead to false-positive findings . Also , FDG is not suitable for several tumor entities due to poor tracer uptake , e.g. , prostate cancer , myxoid tumors of the gastrointestinal tract , low-grade sarcomas or renal cell carcinomas -LSB- 29 -RSB- . A clear technical disadvantage of PET , similar to scintigraphy , is its poor anatomical resolution , which often makes the exact localization of a lesion difficult . Fused PET-CT scanners combine the functional data of PET with the detailed anatomical information of MS-CT scanners in a single examination and have further improved diagnostic accuracy . Various authors have reported a significant decrease in ambiguous lesions and an improvement in the specificity of PET-CT compared to that of PET alone in the detection of malignant disease -LSB- 14 , 30 -RSB- . Only a few study groups have directly compared the performance of WB-MRI with FDG-PET-CT in the detection of skeletal metastases -LSB- 15 , 31 -RSB- . Antoch et al. analyzed the accuracy of both modalities in 98 patients in terms of TNM-based tumor staging . Both imaging procedures revealed a similar diagnostic sensitivity to the detection of distant metastases -LRB- WB-MRI 93 % , PET-CT 94 % -RRB- . Regarding bone metastases , the sensitivity was significantly higher when using WB-MRI -LRB- 85 % -RRB- instead of PET-CT -LRB- 62 % -RRB- . Our own observations confirm these data . We examined 41 patients with suspected skeletal metastases with both FDG-PET-CT and WB-MRI using a multi-channel scanner with PAT -LSB- 31 -RSB- . In a lesion-by-lesion analysis 102 malignant and 25 benign bone lesions were confirmed by histology or follow-up . WB-MRI showed a significantly higher diagnostic accuracy than PET-CT -LRB- 91 % vs. 78 % , Figs. 1 , 2 -RRB- . In particular , lesions smaller than 5 mm were visualized by WB-MRI with a cut-off size of 2 mm for WB-MRI compared with 5 mm for PET-CT . Lesions less than double the size of the spatial resolution of the PET scanner -LRB- usually 6 mm -RRB- can especially lead to false-negative results . Additionally , 10 bone metastases in distal parts of the body were revealed by WB-MRI due to the larger field of view -LRB- the FOV of a routine PET-CT is restricted to the diagnostic spiral CT , usually ranging from the skull base to the proximal femora -RRB- . However , specificity was higher in PET-CT -LRB- PET-CT 80 % vs. WB-MRI 76 % -RRB- . Here , certainly , the additional metabolic information of PET plays the most important role in reliably discriminating between malignant and benign lesions -LRB- e.g. , atypical haemangioma -RRB- -LSB- 32 -RSB- . Fig. 2A 28-year-old man with non-Hodgkin 's lymphoma . a Coronal whole-body STIR imaging shows suspect areas with hyperintense signal in the right clavicular region and both iliac bones . b Magnification shows a mass extending from the right clavicular fossa and infiltrating the right apical thoracic cage . c The lesion shows a pathological FDG uptake in PET-CT , indicating malignancy . d The T1-weighted sagittal image of the spine shows extensive multifocal lymphoma manifestations . e PET-CT underestimates the degree of tumor involvement by showing tracer uptake only in the thoraco-lumbar region On the other hand , at least in breast cancer , different patterns of FDG uptake have been reported in osteoblastic , osteolytic or mixed lesions , indicating that sclerotic lesions may be less FDG-avid -LSB- 33 -RSB- . The additional morphologic information of PET/CT compared with PET alone is certainly of great value in increasing diagnostic sensitivity . Also , significant improvement in diagnostic accuracy has been reported when 18F-fluoride is used for PET or PET-CT for the assessment of malignant skeletal disease . 18F-fluoride is a tracer that , similar to 99mTC-diphosphonate , specifically adsorbs onto bony surfaces with a predilection for sites of active bone formation -LSB- 30 -RSB- . An important indication in bone imaging is lesion monitoring after chemotherapy or radiation therapy . It has to be taken into account that on MRI necrotic bone metastases may remain virtually unchanged in morphology or signal characteristics , which may make evaluation of therapy response difficult . Compared with viable tumors , the contrast enhancement is frequently less pronounced and slower in tumors that have responded to a particular therapy . Reduction in tumor size may be delayed and is not a sensitive sign in the assessment of response . Tumor metabolism , and consequently FDG uptake , is highly susceptible to chemotherapy . On the CT image , osteolytic metastases often demonstrate typical sclerotic transformation . In this setting , future studies are needed to evaluate the sensitivity of FDG-PET-CT in assessing the response to chemotherapy and whether sensitivity is reduced in the first days after initiation of therapy . After radiation therapy MRI is particularly helpful , because irradiated lesions are easily distinguishable from new lesions because of the high signal of normal bone marrow on T1-weighted SE images , which is due to conversion of hematopoietic into fatty bone marrow . Multiple myeloma Multiple myeloma is a frequent neoplastic disease affecting the bone marrow . It is characterized by expansive growth of malignant plasma cell clones with consecutive destruction of the bony architecture . Predilection sites are the axial skeleton -LRB- spine and pelvis -RRB- , but also the ribs , the shoulder region , skull , and proximal femurs , stressing the need for total body imaging for adequate assessment of the extent of disease . The bone marrow may either be diffusely infiltrated or there may be focal accumulations of atypical plasma cells -LRB- Fig. 3 -RRB- . Fig. 3A 70-year-old man with multiple myeloma . a The radiograph of the pelvis is inconspicuous . b Coronal MS-CT reconstruction of the pelvis in a bone window setting reveals a large area of destruction within the left iliac bone -LRB- arrow -RRB- . c -RRB- STIR-WB-MRI confirms focal tumor manifestation within the iliac bone -LRB- arrow -RRB- and reveals multiple small nodular infiltrations within the sacral bone and pelvis . d MS-CT of the spine shows a compression fracture of Th9 . e , f T1-weighted SE - and STIR imaging of the spine reveals diffuse myeloma infiltration of the spine . g Coronal STIR sequences of the pelvis show additional focal infiltration of the left femoral head missed on radiography and MS-CT In patients with myeloma the basic diagnostic work-up in many institutions includes radiographic examinations of the skull -LRB- two planes -RRB- , the rib cage , the upper arms , the spine -LRB- two planes -RRB- , the pelvis , and the upper legs . This diagnostic approach is still represented in the classic Salmon and Durie staging system of the disease , which includes radiographic , immunohistochemical , and serological factors of the disease , and defines the selection of adequate therapy -LSB- 34 -RSB- . However , diagnostic sensitivity of radiography in the detection of myeloma manifestations is rather low and thus allows diagnosis only at advanced stages of the disease when at least 50 % of the bone mineral content has been lost -LSB- 2 -RSB- . In particular , a diffuse bone marrow infiltration pattern may cause diagnostic problems as it can easily be misdiagnosed as senile osteoporosis . In a study conducted by Baur et al. 55 % of focal and 59 % of diffuse infiltrations were missed by radiography -LSB- 35 -RSB- . With the use of contrast-enhanced sequences and calculation of percentage signal increases the sensitivity of MRI for diffuse myeloma infiltration , especially at earlier stages , can be further increased -LSB- 36 -RSB- . Schreiman et al. examined 32 patients with multiple myeloma using single-row CT and radiography -LSB- 37 -RSB- . Twelve patients showed osseous affections in both modalities . CT , however , usually demonstrated a more extensive involvement and in 6 out of 13 patients only CT detected myeloma involvement despite normal radiographs . Another study group recently proposed FDG-PET-CT as an alternative to radiographic imaging of the whole body -LSB- 38 -RSB- . PET-CT detected more lesions in 16 out of 28 patients -LRB- 57 % -RRB- and 9 of these patients had completely negative radiography . Ghanem et al. compared WB-STIR-MRI using the conventional radiographic skeletal survey in 54 patients with plasma cell neoplasms -LSB- 16 -RSB- . Whole-body MRI correctly revealed bone marrow infiltration in 74 % of patients , while radiography depicted pathological changes in 55 % of patients . Moreover , WB-MRI showed a larger extent of infiltration in 90 % of concordant findings . In two studies , the diagnostic accuracy of MS-CT and MRI was analyzed . Mahnken et al. compared results of four-detector MS-CT and MRI examination of the spine and pelvis in 18 patients with stage III multiple myeloma -LSB- 39 -RSB- . A total number of 325 vertebral bodies were evaluated . In MS-CT 231 vertebral bodies were classified as `` affected '' , compared with only 224 vertebral bodies in MRI . These `` false-negative '' findings might have been a consequence of response to previous treatment . However , no information about previous therapy was provided in this study . On the other hand , MRI showed 5 affected vertebrae that were considered normal on MS-CT . The false-negatives on MS-CT might be due to early bone marrow infiltration without signs of osseous destruction . Furthermore , the surprisingly high sensitivity of MS-CT in this study may also be caused by pre-selection of a patient group with advanced disease . In our own study , 30 patients with multiple myeloma were examined with a 1.5-Tesla multi-channel WB-MRI scanner and a 16 - and 64-detector MS-CT scanner -LSB- 17 -RSB- . MRI showed superior diagnostic accuracy to MS-CT . In particular , the diagnostic sensitivity of MS-CT was inferior to that of WB-MRI -LRB- Fig. 3 -RRB- . The high amount of false-negatives on MS-CT may be explained by the fact that early stages of the disease can be visualized on MRI , displaying bone marrow replacement before any destruction of trabecular and cortical bone occurs . False-positive results on MS-CT , on the other hand , may be due to misinterpretation of inhomogeneous osteoporosis as diffuse myeloma infiltration . Baur et al. were able to show that an extended staging system , including MRI of the spine , has a significant influence on the assessment of prognosis . Using the classic staging system of Durie and Salmon without MRI , 25 out of 77 patients would have been understaged , thus underlining the importance of incorporating the MRI bone marrow status into staging and therapy planning of this disease -LSB- 40 -RSB- . Muscle disease Diagnostic imaging of muscle disease -LRB- e.g. , polymyositis or muscle dystrophy -RRB- represents a challenge as it requires high-resolution whole-body coverage of soft tissue structures to adequately assess the pattern , distribution , and extent of the disease . CT , scintigraphy , and ultrasound are not suitable for this purpose as all these modalities lack sufficient soft tissue contrast , spatial resolution or large FOV imaging options . Other diagnostic tests frequently used , like electromyography , are unspecific and muscle biopsies used as the gold standard have been reported to be false-negative in 10 -- 25 % of cases due to sampling errors -LSB- 41 -RSB- . MRI , with its precise delineation of fat , muscle , and bone is an ideal candidate for imaging of systemic muscle disease . Moreover , substantial dose exposure in a predominantly younger patient cohort commonly affected by muscle diseases can be avoided . Previously , MRI has been used for a targeted assessment of muscle disease -LSB- 41 , 42 -RSB- . A combination of T1-weighted SE and T2-weighted pulse sequences with fat saturation , such as STIR , are indispensable for assessing increased fat and water content within the muscle tissue respectively -LRB- Fig. 4 -RRB- . Contrast enhancement with Gadolinium chelates also adds to diagnostic accuracy , especially when combined with fat suppression . Since various muscle groups and body parts may be involved in an unpredictable distribution , coverage of the whole body is important . Fig. 4a Whole-body MRI of a 60-year-old man suffering from severe progressive muscle dystrophy , symmetrically affecting the muscles of the rib cage , abdomen , pelvis , and lower extremities . b WB-STIR shows signs of diffuse reactive edematous processes in the left upper thighs and muscles of the distal lower limbs . c , d T1-weighted imaging displays fatty tissue replacement affecting most of the muscles of the pelvis . Residual adductor muscle tissue is shown with high contrast due to its hypointense signal . e Progressive muscle dystrophy has also occurred in the lower extremities , affecting all compartments O'Connell et al. previously described WB-STIR imaging for the diagnosis of patients suffering from polymyositis -LSB- 18 -RSB- . With the use of parallel imaging techniques WB-STIR imaging can be performed in under 13 min at an inplane resolution of 1.3 × 1.1 mm . With this method , symmetry of muscle involvement and the extent and severity of inflammation can be analyzed , so that an adequate target for biopsy can be identified . During therapy , WB-MRI is particularly helpful in monitoring the disease outcome by visualizing the muscle-to-fat tissue relation or to verify a decrease in inflammation . Also , various drugs , such as steroids , may have side effects that involve the muscles and result in various types of myopathy . Lenk et al. proposed coronal and axial WB-STIR imaging in combination with coronal T1-weighted SE imaging and sagittal T1 - / T2-weighted imaging of the spine , as a sensible protocol for systemic muscle disease , resulting in an approximate total scan time of 45 min -LSB- 19 -RSB- . However , assessment of distal parts of the upper extremity may be limited . This is due to positioning of the arms on the pelvis and thighs . If the muscles of the forearm are in the focus of interest , additional examination with dedicated coil systems may be required . Patients with muscular dystrophy , an X-chromosome recessive disease , suffer from progressive destruction of muscle tissue with subsequent replacement by fatty and fibrous tissue . In addition to the morphological information concerning the distribution and extent of replacement of muscle by fatty tissue as provided by WB-MRI , exact quantification of the muscle-to-fat relation is of substantial diagnostic and prognostic importance . In particular , T1-weighted axial WB-MRI in combination with CAD -LRB- computer aided diagnostics -RRB- applications may be useful for the quantification of total body fat distribution . Interesting results have been reported by Brennan et al. who introduced a fast , automated approach to body fat measurement in healthy individuals as a useful alternative to the body mass index -LSB- 43 -RSB- . Future applications Eustace et al. have proposed WB-MRI for trauma assessment in patients referred for suspected child abuse -LSB- 44 -RSB- . For a rapid assessment of acute trauma , especially when multiple organs are affected , MS-CT provides fast and detailed systemic information on potentially life-threatening organ , vessel or bone injury and is the imaging technique of choice . Recently , an accelerated triage MS-CT protocol has been proposed by Koerner et al. for time-effective handling of mass casualty incidents using MS-CT . For a scenario of 15 multiple trauma patients admitted over a period of 2 h within a mass casualty incident a mean total time in the scanner room of 8.9 min was calculated , including patient preparation and image reconstruction -LSB- 45 -RSB- . Finally , there may be potential for WB-MRI in the secondary screening of congenital skeletal diseases predisposing to malignancies , like multiple cartilaginous exostoses or histiocytosis X -LRB- Fig. 5 -RRB- . However , only case reports have been published on the potential benefits or therapeutic impact in these specific patient groups . Fig. 5A 35-year-old man with multiple cartilaginous exostoses . a , b Whole-body MRI shows typical manifestations in the metaphyseal parts of the long bones of the upper and lower extremities . c Enlargement of the left knee joint shows an exostosis at the medial side of the femur and at the proximal tibia . d Deformation of the radius . e Exostoses and deformation of both femoral necks . In summary , no indications of malignant transformation -LRB- e.g. , widening of the cartilaginous cap -RRB- were found in this patient Conclusion Whole-body imaging is increasingly successfully applied in musculoskeletal imaging , especially in the field of systemic malignant diseases affecting the bone and in diseases predisposing to malignant transformation . Whole-body MRI is able to depict bone marrow pathologies with high resolution and excellent soft tissue contrast by demonstrating signal alterations due to changes in its fat , water , and hematopoietic cell components with high resolution and excellent soft tissue contrast . Together with CT or PET-CT and its valuable additional metabolic information , it has great potential in the more comprehensive , more accurate , and earlier diagnosis of musculoskeletal diseases . Although further evaluation of the true potential of whole-body applications is awaited , they are promising tools aiding the more efficient management of patients suffering from systemic malignant or benign diseases of the soft tissue and bone .

O B O O B O O O O O O B O O O O O O O O O B O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Frequency

and

diagnostic

patterns

of

lymphomas

in

liver

biopsies

with

respect

to

the

WHO

classification

The

recent

World

Health

Organization

-LRB-

WHO

-RRB-

classification

of

hematopoietic

and

lymphoid

tissue

tumors

represents

the

first

worldwide

consensus

classification

of

these

malignancies

However

the

applicability

of

this

classification

to

a

representative

number

of

hepatic

lymphomas

in

liver

biopsy

specimens

has

not

yet

been

investigated

The

frequency

and

infiltration

pattern

of

a

series

of

liver

biopsies

with

lymphoma

manifestations

was

analyzed

with

the

aid

of

immunohistochemical

and

molecular

pathological

analyses

Diffuse

large

B-cell

lymphoma

-LRB-

DLBCL

-RRB-

was

by

far

the

most

frequent

entity

comprising

of

the

cases

analyzed

Using

a

previously

published

immunohistochemical

algorithm

of

DLBCL

were

assigned

to

a

germinal

center

B-cell-like

-LRB-

GCB

-RRB-

and

to

a

non-GCB

group

Most

B-cell

lymphoma

entities

involving

the

liver

revealed

a

characteristic

infiltration

pattern

Diagnostically

challenging

entities

were

T-cell-rich

B-cell

lymphomas

anaplastic

large

cell

lymphomas

and

peripheral

T-cell

lymphomas

which

frequently

required

additional

molecular

clonality

assessment

Overall

the

percentage

of

T-cell

lymphomas

in

the

liver

-LRB-

-RRB-

was

higher

as

compared

to

other

extranodal

sites

except

for

the

skin

and

the

small

intestine

This

study

provides

relevant

data

on

the

distribution

of

hepatic

lymphomas

and

demonstrates

the

applicability

of

the

WHO

classification

proposing

a

diagnostic

algorithm

for

liver

biopsies

Introduction

The

liver

is

most

commonly

involved

in

non-Hodgkin

lymphomas

-LRB-

NHL

-RRB-

next

to

lymph

nodes

spleen

and

bone

marrow

In

the

vast

majority

of

cases

hepatic

involvement

reflects

secondary

dissemination

in

advanced

disease

-LSB-

-RSB-

rather

than

a

primary

site

according

to

the

definition

of

Caccamo

and

coworkers

-LSB-

-RSB-

Histopathological

analysis

of

liver

biopsy

may

be

required

in

patients

with

an

established

diagnosis

of

malignant

lymphoma

to

differentiate

lymphoma

manifestation

from

other

causes

of

hepatic

dysfunction

or

to

clarify

elevated

transaminases

such

as

toxic

damage

because

of

chemotherapy

or

other

medications

On

the

other

hand

a

biopsy

may

reveal

a

previously

unknown

lymphoma

during

the

exploration

of

a

solid

hepatic

mass

or

after

measuring

elevated

liver

enzyme

serology

-LSB-

-RSB-

Occasionally

a

malignant

lymphoma

can

be

detectable

in

the

setting

of

other

liver

diseases

such

as

chronic

hepatitis

B

-LSB-

-RSB-

chronic

hepatitis

C

-LSB-

-RSB-

or

primary

biliary

cirrhosis

-LRB-

PBC

-RRB-

-LSB-

-RSB-

The

goals

of

the

present

study

were

to

test

the

feasibility

of

lymphoma

subtyping

according

to

the

World

Health

Organisation

-LRB-

WHO

-RRB-

classification

of

tumors

of

hematopoietic

and

lymphoid

tissues

-LSB-

-RSB-

in

liver

biopsy

specimens

and

to

describe

the

frequencies

by

which

the

different

entities

occur

For

this

purpose

a

series

of

liver

biopsies

with

a

diagnosis

of

malignant

lymphoma

were

analyzed

retrospectively

with

a

specific

focus

on

the

histopathology

especially

infiltration

patterns

which

may

ultimately

allow

the

use

of

diagnostic

algorithms

for

subtyping

of

lymphomas

in

liver

biopsies

This

is

an

important

addition

in

relation

to

previous

studies

which

have

mainly

described

the

frequency

of

liver

involvement

in

autopsy

material

of

patients

with

leukemia

or

lymphoma

-LSB-

-RSB-

differentiating

only

between

low-grade

and

high-grade

NHL

-LSB-

-RSB-

or

having

performed

a

categorization

according

to

the

outdated

Kiel

classification

-LSB-

-RSB-

Overall

this

study

represents

the

largest

series

on

hepatic

lymphomas

to

date

and

due

to

its

restriction

to

bioptic

material

reflects

the

primary

diagnostic

situation

Materials

and

methods

All

cases

of

hepatic

lymphoma

involvement

diagnosed

by

liver

biopsy

during

the

years

were

retrieved

from

the

archives

of

the

Institute

of

Pathology

Campus

Benjamin

Franklin

Charité-University

Medicine

Berlin

and

the

Institute

of

Pathology

University

of

Cologne

Germany

The

series

comprised

a

total

of

cases

with

cases

from

Berlin

and

cases

from

Cologne

All

cases

were

reevaluated

and

reclassified

independently

by

three

pathologists

-LRB-

C.L.

T.L.

H.S.

-RRB-

according

to

the

WHO

classification

-LSB-

-RSB-

For

cases

in

which

the

diagnosis

was

not

unanimous

a

final

consensus

diagnosis

was

reached

after

further

immunophenotyping

molecular

analyses

and

final

consultation

In

six

cases

initially

considered

suspicious

for

lymphoma

a

final

diagnosis

of

lymphoma

was

made

after

reevaluation

and

additional

analyses

Nine

liver

biopsies

with

insufficient

material

for

additional

immunohistochemical

or

molecular

analyses

were

excluded

beforehand

as

well

as

five

cases

where

T-cell

receptor

-LRB-

TCR

-RRB-

polymerase

chain

reaction

-LRB-

PCR

-RRB-

had

revealed

a

polyclonal

or

oligoclonal

rearrangement

pattern

without

a

reproducible

dominant

PCR

product

Overall

-LRB-

-RRB-

cases

were

reclassified

including

eight

low-grade

-LSB-

B-CLL

follicular

lymphomas

-LRB-

FL

-RRB-

marginal

zone

lymphoma

-LRB-

MZL

-RRB-

-RSB-

and

high-grade

-LSB-

DLBCL

Burkitt

lymphoma

-LRB-

BL

-RRB-

-RSB-

B-cell

NHL

that

were

assigned

to

a

specific

WHO

lymphoma

category

as

well

as

four

cases

with

a

change

in

the

final

diagnosis

-LSB-

BL

classical

Hodgkin

lymphoma

-LRB-

cHL

-RRB-

T-cell-rich

B-cell

lymphoma

-LRB-

TCRBCL

-RRB-

lymphoplasmacytic

lymphoma

-LRB-

LPL

-RRB-

to

DLBCL

anaplastic

large

cell

lymphoma

-LRB-

ALCL

-RRB-

peripheral

T-cell

lymphoma

-LRB-

pTCL

-RRB-

and

B-CLL

respectively

-RSB-

The

analyses

of

the

infiltration

pattern

were

based

on

the

assessment

of

the

hepatic

architecture

Three

main

patterns

were

distinguished

Infiltrates

for

which

an

exclusive

or

predominant

association

to

portal

tracts

was

evident

were

recorded

as

portal

infiltrates

The

second

pattern

consisted

of

lymphoma

infiltrates

which

showed

a

coherent

growth

pattern

thus

predominantly

resulting

in

the

replacement

of

the

acinar

structures

These

infiltrates

were

designated

as

a

nodular

growth

pattern

Finally

infiltrates

that

showed

prominent

intrasinusoidal

dispersion

of

the

lymphoma

cells

were

recorded

as

a

sinusoidal

growth

pattern

Additionally

the

density

of

the

infiltrate

was

semiquantitatively

assessed

The

presence

of

scattered

neoplastic

cells

in

a

background

rich

in

reactive

bystander

cells

-LRB-

e.g.

nonneoplastic

T-cells

and/or

macrophages

in

T-cell

rich

B-cell

lymphoma

-RRB-

was

defined

as

a

loose

infiltration

pattern

whereas

the

appearance

of

coherently

appearing

neoplastic

B

or

T-cells

was

referred

to

as

a

dense

infiltrate

According

to

clinical

information

available

in

-LRB-

-RRB-

of

the

cases

the

diagnosis

of

a

lymphoma

had

been

previously

established

from

extrahepatic

biopsies

or

peripheral

blood

indicating

secondary

involvement

of

the

liver

In

four

of

these

cases

with

known

low-grade

lymphoma

-LRB-

B-CLL

FL

-RRB-

liver

biopsy

revealed

transformation

to

a

high-grade

lymphoma

-LRB-

DLBCL

-RRB-

In

the

remaining

cases

the

biopsy

obtained

from

the

liver

represented

the

site

of

primary

diagnosis

In

-LRB-

-RRB-

patients

additional

biopsies

from

extrahepatic

sites

were

available

-LRB-

bone

marrow

biopsies

lymph

node

biopsies

and

three

spleen

biopsies

-RRB-

Furthermore

in

a

few

cases

clinical

data

regarding

a

potential

predisposing

condition

for

a

primary

hepatic

lymphoma

was

available

chronic

hepatitis

C

was

reported

in

four

patients

-LRB-

DLBCL

B-CLL

-RRB-

HIV

infection

was

present

in

three

patients

-LRB-

DLBCL

BL

-RRB-

and

one

marginal

zone

lymphoma

occurred

in

a

patient

after

liver

transplantation

The

frequency

of

the

various

lymphoma

entities

diagnosed

in

liver

biopsy

specimen

was

compared

to

their

frequency

and

distribution

in

other

extranodal

sites

-LRB-

cases

from

the

Consultation

and

Reference

Center

for

Lymph

Node

Pathology

and

Hematopathology

Berlin

-RRB-

Immunohistochemistry

For

immunostaining

μm

thick

sections

were

cut

deparaffinized

and

subjected

to

heat-induced

epitope

retrieval

before

incubation

with

antibodies

For

this

purpose

sections

were

immersed

either

in

sodium

citrate

buffer

at

pH

or

alternatively

in

ethylenediamintetraacetic

acid

-LRB-

EDTA

-RRB-

at

pH

and

heated

in

a

high-pressure

cooker

After

cooking

the

slides

were

rinsed

in

running

water

washed

with

Tris-buffered

saline

pH

and

incubated

with

the

respective

primary

antibodies

All

primary

antibodies

employed

are

listed

in

Table

With

the

exception

of

immunoglobulin

detection

in

which

the

streptavidin

biotin

peroxidase

method

was

applied

-LSB-

-RSB-

labeling

was

carried

out

using

the

alkaline

phosphatase/anti-alkaline

phosphatase

complex

method

-LSB-

-RSB-

Alkaline

phosphatase

was

developed

using

Fast

Red

as

the

chromogen

whereas

peroxidase

was

visualized

with

diaminobenzidine

chromogen

as

the

substrate

Table

used

in

this

studyAntibodyCloneAntigen

chainRabbit

chainRabbit

chainRabbit

chainRabbit

provided

by

Prof.

B.

Falini

Perugia

Molecular

pathology

analyses

Additional

molecular

pathology

analyses

were

selectively

performed

for

those

cases

in

which

immunoprofiling

alone

was

not

sufficient

to

establish

a

definite

diagnosis

of

a

malignant

lymphoma

For

this

purpose

DNA

was

extracted

after

dewaxing

paraffin

sections

with

QIAEX

-LRB-

Qiagen

Hilden

Germany

-RRB-

according

to

the

manufacturer

's

recommendations

TCR-gamma

rearrangements

were

analyzed

using

four

different

primer

combinations

-LRB-

Set

A

and

Set

B

-RRB-

The

primer

combinations

und

suitable

to

amplify

the

most

frequent

TCR-gamma

rearrangements

were

used

in

a

two-step

seminested

PCR

The

primer

sets

A

and

B

able

to

detect

all

possible

TCR-gamma

rearrangements

were

performed

as

single

round

PCRs

The

detailed

cycling

conditions

-LRB-

rounds

of

amplification

for

set

A

and

set

B

two-time

cycles

for

primer

combinations

and

-RRB-

for

all

PCRs

have

been

described

in

detail

elsewhere

-LSB-

-RSB-

Amplification

of

rearranged

IgH

genes

was

independently

performed

at

least

twice

per

case

employing

three

different

framework

primer

sets

-LRB-

and

-RRB-

separately

in

conjunction

with

a

JH

primer

-LRB-

-RRB-

PCR

conditions

consisted

of

cycles

of

denaturation

-LRB-

°C

s

-RRB-

primer

annealing

-LRB-

°C

s

-RRB-

and

elongation

-LRB-

°C

s

-RRB-

and

the

reaction

mixture

contained

mM

mM

deoxyribonucleotide

triphosphates

-LRB-

dNTPs

-RRB-

pmol

VH

primers

pmol

primer

and

U

of

AmpliTaq

Gold

polymerase

-LRB-

Applied

Biosystems

Weiterstadt

Germany

-RRB-

Results

Characteristics

of

hepatic

lymphomas

Almost

-LRB-

-RRB-

of

the

hepatic

lymphomas

belonged

to

the

group

of

NHL

whereas

only

of

the

cases

were

cHL

Regarding

NHL

-LRB-

-RRB-

were

of

B-cell

and

-LRB-

-RRB-

of

T-cell

origin

Overall

diffuse

large

B-cell

lymphoma

-LRB-

DLBCL

-RRB-

was

the

most

common

type

-LSB-

-LRB-

-RRB-

of

all

B-NHL

analyzed

-RSB-

with

TCRBCL

a

morphologic

variant

of

DLBCL

comprising

-LRB-

-RRB-

of

all

DLBCL

According

to

the

algorithm

of

Hans

et

al.

-LSB-

-RSB-

a

predominance

of

DLBCL

of

non-GCB

-LRB-

germinal

center

B-cell-like

-RRB-

type

-LRB-

-RRB-

compared

to

the

DLBCL

of

GCB

type

-LRB-

-RRB-

was

found

-LRB-

Fig.

d

f

-RRB-

Only

out

of

cases

-LRB-

-RRB-

corresponded

to

the

group

of

DLBCL

-LRB-

Fig.

-RRB-

Fig.

pattern

DLBCL

of

GCB

group

positive

for

-LRB-

a

-RRB-

and

-LRB-

b

-RRB-

and

negative

for

-LRB-

few

scattered

plasma

cells

serve

as

positive

intrinsic

control

c

-RRB-

positive

DLBCL

of

ABC

type

negative

for

-LRB-

positive

bile

canaliculi

serve

as

intrinsic

control

d

-RRB-

positive

for

-LRB-

e

-RRB-

and

-LRB-

f

-RRB-

TCRBCL

with

less

than

large

positive

neoplastic

B-cells

-LRB-

g

-RRB-

associated

with

numerous

positive

T-cells

-LRB-

h

-RRB-

and

positive

histiocytes

-LRB-

i

-RRB-

In

all

lymphoma

subtypes

men

were

affected

more

often

except

for

FL

which

occurred

with

equal

frequencies

in

both

sexes

The

male

predominance

was

most

striking

in

lymphomas

of

T-cell

origin

in

which

ALCL

and

hepatosplenic

T-cell

lymphoma

-LRB-

HSTCL

-RRB-

were

encountered

exclusively

in

men

Additional

molecular

analyses

were

essential

to

confirm

the

suspected

diagnosis

of

a

lymphoma

in

out

of

T-cell

lymphomas

-LRB-

-RRB-

and

out

of

-LRB-

-RRB-

B-NHLs

-LRB-

Fig.

-RRB-

Fig.

fragment

analyses

-LRB-

GeneScan

-RRB-

of

the

amplificates

after

TCR-gamma

PCR

-LRB-

primer

combination

-RRB-

Fluorescence-labelled

PCR

products

-LRB-

blue

lines

-RRB-

were

separated

on

capillary

electrophoresis

system

-LRB-

Applied

Biosystems

Model

-RRB-

in

parallel

to

a

size

standard

-LRB-

red

line

-RRB-

The

dominant

PCR

product

-LRB-

arrow

-RRB-

indicating

the

presence

of

a

clonal

T-cell

population

was

reproducibly

detectable

in

addition

to

a

moderate

oligo

polyclonal

T-cell

background

The

relative

frequencies

of

the

lymphoma

subtypes

the

available

patient

data

and

the

infiltration

patterns

are

summarized

in

Table

Table

age

distribution

and

pattern

of

infiltration

in

the

different

lymphoma

entities

presenting

in

the

liver

-LRB-

Berlin/Cologne

-RRB-

BerlinCologneBerlin

Cologne

n

-LRB-

-RRB-

Age

-LRB-

range

-RRB-

Age

-LRB-

mean

-RRB-

Male/femalePatternDensity

of

infiltrateSinusoidalPortalNodularDenseLooseDiffuse

large

B-cell

lymphoma

-LRB-

DLBCL

-RRB-

-LRB-

-RRB-

rich

B-cell

lymphoma

-LRB-

TCRBCL

-RRB-

-LRB-

-RRB-

chronic

lymphocytic

leukemia

-LRB-

B-CLL

-RRB-

-LRB-

-RRB-

Hodgkin

lymphoma

-LRB-

cHL

-RRB-

-LRB-

-RRB-

lymphoma

-LRB-

FL

-RRB-

-LRB-

-RRB-

zone

lymphoma

-LRB-

MZL

-RRB-

-LRB-

-RRB-

Plasmacytoma

-LRB-

PL

-RRB-

-LRB-

-RRB-

lymphoma

-LRB-

BL

-RRB-

-LRB-

-RRB-

cell

lymphoma

-LRB-

MCL

-RRB-

-LRB-

-RRB-

leukaemia

-LRB-

B-ALL

-RRB-

-LRB-

-RRB-

cell

leukaemia

-LRB-

HCL

-RRB-

T-cell

lymphoma

unspecified

-LRB-

pTCL

-RRB-

-LRB-

-RRB-

large

cell

lymphoma

-LRB-

ALCL

-RRB-

-LRB-

-RRB-

T-cell

lymphoma

-LRB-

HSTCL

-RRB-

-LRB-

-RRB-

centroblastic

-LRB-

n

-RRB-

immunoblastic

-LRB-

n

-RRB-

and

anaplastic

variant

-LRB-

n

-RRB-

bIncluding

one

anaplastic

large

cell

lymphoma

kinase

-LRB-

ALK

-RRB-

protein

positive

case

Infiltration

patterns

of

the

various

lymphoma

types

Most

of

the

cases

showed

the

predominance

of

a

certain

growth

pattern

although

some

cases

exhibited

more

than

one

growth

pattern

Almost

all

DLBCL

and

BL

showed

a

nodular

infiltration

pattern

-LRB-

-RRB-

composed

of

a

dense

infiltrate

-LRB-

Table

-RRB-

except

for

the

TCRBCL

variant

which

was

located

predominantly

within

the

portal

tracts

-LRB-

-RRB-

and

exhibited

the

characteristic

scattered

infiltrate

of

fewer

than

large

neoplastic

B-cells

admixed

with

many

reactive

T-cells

and

histiocytes

-LRB-

Fig.

i

-RRB-

Lymphomas

showing

a

dense

portal

infiltration

pattern

were

chronic

lymphocytic

leukemia/small

lymphocytic

lymphoma

-LRB-

Fig.

c

-RRB-

FL

-LRB-

Fig.

f

-RRB-

MZL

-LRB-

Fig.

i

-RRB-

and

mantle

cell

lymphoma

-LRB-

-RRB-

In

contrast

in

precursor

B

lymphoblastic

leukemia/lymphoblastic

lymphoma

-LRB-

B-ALL/B-LBL

Fig.

c

-RRB-

HSTCL

-LRB-

Fig.

f

-RRB-

leukemic

plasmacytoma

-LRB-

Fig.

i

-RRB-

and

hairy

cell

leukemia

a

sinusoidal

infiltration

pattern

was

observed

in

the

majority

of

cases

The

cHL

displayed

a

predominantly

portal

infiltration

pattern

-LRB-

Fig.

c

-RRB-

Peripheral

T-cell

lymphoma

and

ALCL

showed

a

spectrum

of

portal

sinusoidal

nodular

or

mixed

patterns

with

a

varying

density

of

infiltration

and

thus

did

not

allow

for

pattern-based

selection

of

additional

analyses

-LRB-

Fig.

f

-RRB-

The

infiltration

patterns

differential

diagnoses

and

discriminative

immunohistochemical

markers

are

summarized

in

Table

Table

pattern

differential

diagnosis

and

characteristic

immunohistochemical

markersFig

pattern

chronic

lymphocytic

leukemia

-LRB-

B-CLL

-RRB-

with

a

predominantly

portal

infiltrate

of

small

lymphocytes

-LRB-

a

-RRB-

with

expression

of

-LRB-

b

-RRB-

and

-LRB-

c

-RRB-

FL

-LRB-

d

-RRB-

with

expression

of

-LRB-

e

-RRB-

and

-LRB-

f

-RRB-

Marginal

zone

B-cell

lymphoma

with

portal

involvement

-LRB-

g

-RRB-

expression

of

memory

B-cell

marker

-LRB-

h

-RRB-

and

a

lymphoepithelial

lesion

of

a

positive

bile

duct

-LRB-

i

-RRB-

Fig.

pattern

precursor

B

lymphoblastic

lymphoma

-LRB-

B-LBL

-RRB-

with

a

sinusoidal

infiltrate

of

small

blasts

-LRB-

a

-RRB-

with

cytoplasmic

expression

of

-LRB-

b

-RRB-

and

nuclear

expression

of

terminal

deoxynucleotidyl

transferase

-LRB-

TdT

c

-RRB-

HSTCL

with

a

sinusoidal

infiltrate

of

monotonous

neoplastic

cells

-LRB-

d

-RRB-

with

expression

of

-LRB-

e

-RRB-

and

the

cytotoxic

granule

associated

protein

-LRB-

f

-RRB-

Peripheral

blood

involvement

-LRB-

plasma

cell

leukemia

-RRB-

in

a

plasmacytoma

with

a

sinusoidal

infiltrate

of

plasma

cells

-LRB-

g

-RRB-

with

expression

of

-LRB-

h

-RRB-

and

IgG

-LRB-

i

-RRB-

Fig.

Hodgkin

lymphoma

vs.

anaplastic

large

cell

lymphoma

cHL

with

portal

infiltrates

of

Hodgkin

and

Reed-Sternberg

HRS

cells

-LRB-

arrows

-RRB-

in

a

background

rich

in

eosinophils

-LRB-

a

-RRB-

The

HRS

cells

strongly

express

-LRB-

b

-RRB-

and

the

EBV

encoded

latent

membrane

protein

-LRB-

-RRB-

-LRB-

c

-RRB-

Anaplastic

large

cell

lymphoma

-LRB-

ALCL

-RRB-

with

portal

infiltrates

of

pleomorphic

large

cells

resembling

HRS

cells

-LRB-

arrows

-RRB-

-LRB-

d

-RRB-

and

strong

positivity

for

-LRB-

e

-RRB-

and

the

cytotoxic

molecule

perforin

-LRB-

f

-RRB-

Comparison

of

hepatic

lymphomas

with

other

extranodal

lymphomas

The

percentage

of

T-cell

lymphomas

was

considerably

higher

in

the

liver

-LRB-

-RRB-

when

compared

to

other

extranodal

sites

-LRB-

-RRB-

except

for

the

skin

-LRB-

mainly

mycosis

fungoides/Sézary

syndrome

-RRB-

and

small

intestine

-LRB-

mainly

enteropathy-type

T-cell

lymphomas

-RRB-

The

high

proportion

of

DLBCL

in

lymphomas

of

the

liver

-LRB-

-RRB-

was

only

surpassed

by

the

small

intestine

-LRB-

-RRB-

the

brain

-LRB-

-RRB-

and

the

testis

-LRB-

-RRB-

Of

note

TCRBCL

was

extremely

rare

in

other

extranodal

sites

-LRB-

-RRB-

with

only

a

few

cases

occurring

in

the

bone

marrow

and

spleen

Interestingly

one

case

fulfilled

the

criteria

of

TCRBCL

in

the

liver

and

an

additional

lymph

node

biopsy

showed

the

picture

of

a

typical

DLBCL

whereas

in

another

case

both

liver

and

spleen

biopsy

showed

the

characteristic

features

of

TCRBCL

The

frequencies

of

other

extranodal

lymphomas

compared

to

hepatic

lymphomas

are

summarized

in

Table

Table

of

extranodal

lymphoma

at

different

sites

-LRB-

Berlin

-RRB-

Brain

-LRB-

n

-RRB-

Testis

-LRB-

n

-RRB-

Lung

-LRB-

n

-RRB-

Bone

marrow

-LRB-

n

-RRB-

Stomach

-LRB-

n

-RRB-

Small

intestine

-LRB-

n

-RRB-

Large

intestine

-LRB-

n

-RRB-

Spleen

-LRB-

n

-RRB-

Skin

-LRB-

n

-RRB-

Liver

-LRB-

n

-RRB-

HCL

total

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

T-ALL

ALCL

TCL

HSTCL

T-NHL

total

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Including

nine

cases

of

splenic

marginal

zone

lymphoma

-LRB-

SMZL

-RRB-

Discussion

To

the

best

of

our

knowledge

this

study

represents

the

largest

series

focusing

on

the

histopathology

of

hepatic

lymphoma

involvement

and

the

first

application

of

the

WHO

classification

of

tumors

of

hematopoietic

and

lymphoid

tissues

for

this

purpose

-LSB-

-RSB-

Our

data

demonstrate

the

feasibility

of

in

vivo

lymphoma

subtyping

in

liver

biopsy

with

the

aid

of

infiltration

pattern

analysis

the

selection

of

differentiating

immunophenotypic

markers

and

additional

molecular

methods

Many

B-cell-derived

lymphomas

involving

the

liver

revealed

a

characteristic

infiltration

pattern

which

facilitated

the

use

of

a

restricted

panel

of

immunohistochemical

markers

to

reach

a

final

diagnosis

This

approach

is

critical

in

those

liver

biopsies

in

which

a

lymphoma

diagnosis

has

previously

not

been

established

as

accurate

subtyping

of

lymphomas

is

fundamental

for

the

initiation

of

adequate

treatment

Diffuse

large

B-cell

lymphomas

-LRB-

DLBCL

-RRB-

accounted

for

of

all

B-NHL

cases

DLBCL

was

recently

subdivided

into

different

prognostic

groups

designated

GCB

activated

B-cell-like

-LRB-

ABC

or

non-GCB

-RRB-

and

Type

according

to

their

gene

expression

profiles

-LSB-

-RSB-

The

GCB

group

is

described

to

have

a

better

survival

than

the

ABC

group

and

the

heterogeneous

Type

group

Hans

et

al.

-LSB-

-RSB-

have

proposed

a

simple

immunohistochemical

algorithm

to

assign

cases

to

a

GCB

and

a

non-GCB

group

In

the

present

study

the

frequency

of

either

group

in

liver

biopsies

with

DLBCL

was

investigated

excluding

the

T-cell/histiocyte

rich

variant

-LRB-

n

-RRB-

DLBCL

of

non-GCB

type

-LRB-

-RRB-

were

more

frequent

in

the

liver

than

the

GCB

type

-LRB-

-RRB-

whereas

these

two

groups

are

described

in

other

sites

at

about

equal

frequency

-LSB-

-RSB-

As

liver

involvement

with

malignant

lymphomas

occurs

secondary

in

advanced

disease

-LSB-

-RSB-

this

observation

may

reflect

the

biological

behavior

of

ABC-group

DLBCLs

through

the

selection

of

more

aggressive

cases

by

liver

biopsy

Approximately

of

the

de

novo

DLBCL

express

-LSB-

-RSB-

and

may

have

a

poor

outcome

-LSB-

-RSB-

They

tend

to

be

associated

with

extranodal

sites

especially

bone

marrow

and

spleen

-LSB-

-RSB-

In

the

present

series

of

hepatic

lymphoma

involvement

the

number

of

positive

DLBCL

-LRB-

or

-RRB-

was

not

increased

The

TCRBCL

a

variant

of

DLBCL

in

which

the

majority

of

cells

are

nonneoplastic

T-cells

and

histiocytes

are

often

misdiagnosed

as

a

reactive

inflammatory

condition

or

as

a

T-cell

lymphoma

infiltration

of

the

liver

-LSB-

-RSB-

TCRBCL

is

relatively

rare

in

lymph

node

biopsies

-LSB-

-LRB-

-RRB-

or

of

the

DLBCL

in

the

Berlin

Reference

Centre

for

Lymph

Node

Pathology

from

-RSB-

However

in

the

present

study

-LRB-

-RRB-

of

the

DLBCL

in

the

liver

were

found

to

fulfill

the

WHO

criteria

for

TCRBCL

thus

confirming

previous

data

from

Dargent

and

coworkers

in

their

series

of

liver

specimens

-LSB-

-RSB-

Additionally

one

case

with

TCRBCL

characteristics

in

the

liver

showed

the

typical

morphology

of

a

conventional

DLBCL

in

an

additional

lymph

node

biopsy

This

finding

indicates

that

the

composition

of

the

reactive

coinfiltrate

may

be

influenced

by

the

tissue-specific

microenvironment

Therefore

the

specific

environment

of

a

certain

organ

may

influence

the

intensity

of

the

T-cell

response

and

subsequently

explain

the

higher

frequency

of

the

TCRBCL

variant

of

DLBLC

presenting

in

the

liver

-LSB-

-RSB-

Limitations

were

encountered

in

the

grading

of

follicular

lymphoma

and

the

subtyping

of

the

cHL

which

is

generally

not

possible

with

sufficient

certainty

in

needle

biopsies

In

contrast

to

B-cell

lymphomas

T-cell

lymphomas

infiltrating

the

liver

generally

lack

a

typical

infiltration

pattern

making

their

diagnosis

more

challenging

In

particular

ALCL

may

mimic

cHL

due

to

the

possible

resemblance

of

Hodgkin

and

Reed-Sternberg

cells

and

expression

of

Thus

additional

markers

against

pan-T

and

pan-B

cell

antigens

-LRB-

including

-RRB-

cytotoxic

molecules

e.g.

granzyme

B

and

perforin

-RRB-

are

required

when

confronted

with

this

differential

diagnosis

-LRB-

Fig.

-RRB-

Similarly

the

distinction

between

a

T-cell

lymphoma

and

a

drug-induced

or

viral

hepatitis

-LRB-

e.g.

due

to

Epstein-Barr

virus

-RRB-

can

be

very

difficult

in

biopsies

containing

an

increased

number

of

sinusoidal

T-cells

Therefore

additional

clonality

analyses

by

TCR

or

IgH

PCR

were

necessary

in

out

of

-LRB-

-RRB-

T-cell

lymphomas

compared

to

only

out

of

-LRB-

-RRB-

B-cell

lymphomas

to

establish

a

diagnosis

The

reason

for

the

relatively

high

frequency

of

liver

involvement

by

T-cell

lymphomas

is

not

known

As

T-cells

play

an

important

role

in

the

regulation

of

the

hepatic

immune

responses

especially

in

chronic

viral

and

autoimmune

hepatitis

-LSB-

-RSB-

it

is

tempting

to

speculate

whether

this

may

influence

the

relatively

high

incidence

of

T-cell

lymphomas

in

the

liver

compared

to

other

extranodal

sites

In

the

present

study

of

the

-LRB-

-RRB-

cases

were

found

to

represent

lymphomas

derived

from

T-cells

whereas

lymphomas

of

the

testis

brain

lung

and

stomach

were

B-cell

lymphomas

in

nearly

all

instances

-LRB-

Table

-RRB-

In

summary

the

present

study

demonstrates

the

feasibility

of

subtyping

lymphoma

infiltrates

in

liver

biopsies

according

to

the

WHO

classification

The

large

number

of

cases

provides

reliable

information

regarding

the

relative

frequencies

of

the

different

lymphoma

entities

encountered

in

the

liver

and

demonstrates

the

usefulness

of

infiltration

pattern

analysis

for

diagnostic

purposes

O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O B O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O

lymphoma
liver
differential diagnosis
immunohistochemistry
pcr