- Email: [email protected]
Acute light chain tubulopathy in myeloma
300
CORRESPONDENCE
HyperIgG4 disease/IgG4-related sclerosing disease is a clinically distinct condition that can be diagnosed on serology and histology with good treatment outcome. The significance of this condition is further emphasised by the differential diagnoses that vary from tuberculosis to cancer. This diagnosis highlights the association of high concentrations of serum IgG4 plasma cells to entities previously known as idiopathic systemic fibrosis. Our case reiterates mediastinal lymphadenopathy, RPF and chronic sclerosing sialadenitis as clinical manifestations. Jespal Gill* Graeme Taylor* Logan Carpenter* Christopher Lewis{ Weldon Chiu* *Department of Pathology, Labplus, Auckland City Hospital, and {Auckland City Hospital, Auckland, New Zealand Contact Dr J. Gill. E-mail: [email protected]
1. Neild G, Rodriguez-Justo M, Wall C, et al. Hyper-IgG4 disease: report and characterization of a new disease. BMC Med 2006; 4: 23. 2. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: 732–8. 3. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002; 359: 1403–4. 4. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4 – related autoimmune disease. J Gastroenterol 2003; 38: 982–4. 5. Zen Y, Sawazaki A, Miyama S, et al. A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol 2006; 37: 239–43. 6. Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cell in inflammatory pseudotumour (plasma cell granuloma) of the lung. Hum Pathol 2005; 36: 710–7. 7. Kitagawa S, Zen Y, Harada K. Abundant IgG4 positive plasma cell infiltration characterizes chronic sclerosing siladenitis (Kuttner’s tumor). Am J Surg Pathol 2005; 29: 783–91. 8. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholangitis with and without inflammatory pseudotumour and sclerosing pancreatitis-associated sclerosing cholangitis. Do they belong to a spectrum of sclerosing pancreatitis. Am J Surg Pathol 2004; 28: 1193–203. 9. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4 related sclerosing disease. J Gastroenterol 2006; 41: 613–25. 10. Deshpande V, Chiocca S, Finkelberg D, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006; 30: 1537–45. 11. Kamisawa T, Chen PY, Tu Y, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 2006; 12: 6225–8. 12. Noonan C, Pfau J, Larson T, et al. Nested case–control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect 2006; 114: 1243–7.
DOI: 10.1080/00313020902756394
Acute light chain tubulopathy in myeloma Sir, In myeloma patients renal biopsies may show tubular casts with cellular reaction, deposits of amyloid or features of
Pathology (2009), 41(3), April
light chain nephropathy in the form of nodular glomerular lesions similar to the type seen in Type I mesangiocapillary glomerulonephritis or diabetic glomerulosclerosis. The production of excessive amounts of abnormal light chains in myeloma or in other cases of monoclonal gammopathy may lead to acute tubular damage or so called acute light chain tubulopathy. We report a case of myeloma associated acute light chain tubulopathy with dual staining for kappa (k) and lambda (l) light chain deposition forming crystalloid bodies. The patient was a 67-year-old man who presented with symptoms of acute on chronic renal failure. He had a serum creatinine of 250 mmol/L, 9.648 g/L of free kappa light chains, 5.4 mg/L free lambda light chains and urinary paraprotein. Haematological tests showed a negative vasculitic screen and a bone marrow aspirate diagnostic of multiple myeloma. His renal biopsy contained 15 glomeruli, two of which were globally sclerosed, the others were generally of normal appearance. The lining epithelial cells of the proximal tubules were swollen with surface irregularities and disrupted brush borders (Fig. 1). There were occasional protein casts and desquamated epithelial cells and no deposits of amyloid. Immunofluorescence microscopy (IF) was negative for all classes of immunoglobulin, C1q, C3c, k light chains, l light chains and fibrinogen. Immunoperoxidase studies showed positive staining for k and l light chains in the cytoplasm of tubule epithelial cells and desquamated cells in the lumen (Fig. 1). Electron microscopy of proximal tubules showed large numbers of lysosomal inclusions and crystalloids in the cytoplasm of affected cells (Fig. 1). The crystalloids were rhomboid to hexagonal in outline and usually embedded in an amorphous matrix contained in secondary lysosomes. Our case is illustrative or prototypical of acute light chain tubulopathy due to deposition of light chains. The histological changes in renal biopsies in these cases are subtle and may not be appreciated or may be missed, especially when light chain deposits are not detected by routine IF. In our case, neither k nor l light chains were detected by IF and both forms of light chain were demonstrated by immunohistochemistry. Likewise, other reports have pointed out negative immunofluorescence in cases with k light chain crystalline deposits that were 1,2 subsequently detected by immunoelectron microscopy. Others have been able to demonstrate positive immunofluorescence associated with k light chain crystalloids,3 and because of variability in staining with monoclonal antibodies, the use of polyclonal light chain type-specific antibodies for immunofluorescence has been advocated for routine investigation.4 The reason for the discrepancy in the detection of light chain deposits by IF and immnuohistochemistry may be due to a difference in sensitivity of the methods used for detecting antigens. It may be due in part to deposition of the crystalline form of light chain rendering the immunolabelling epitope inaccessible or below the threshold of detection, or the fact that both our immunohistochemistry and immunoelectron microscopy protocols employ antigen retrieval steps whereas the immunofluorescence protocol does not. Regardless of the explanation, the main point to note is that light chain crystalloids may not show up with conventional IF or, if present, this fluorescence should not be interpreted as
CORRESPONDENCE
FIG. 1 Immunohistochemical localisation and electron microscopy of l light chain (LLC) and k light chain (KLC) staining associated with crystalloid bodies in proximal tubular epithelium. (A) Widespread k light chain deposition with most tubules affected (arrows) (anti-k light chain stain). (B) Focal l light chain deposition affecting only occasional cells (arrows) while some tubules (arrowheads) are spared (anti-l light chain stain). (C) Granular light chain crystalloids (arrows) in lysosomes. Inset: k light chain crystalloids from another file case showing alternative needlelike morphology (bar¼5000 nm). (D) Rhomboid and hexagonal light chain crystalloids from the present case (arrow) embedded in pale amorphous lysosomal matrix (arrowhead). Inset: High power view of a light chain crystalloid showing 6 nm periodicity and adjacent spiral shaped structure (arrow) lying internal to the limiting membrane (arrowhead) (bar¼100 nm).
non-specific.2 Transmission electron microscopy can also assist with recognition of finely granular deposits in basement membrane,5 atypical lysosomes6 and intracellular crystalloid inclusions. These structures serve as morphological markers for monoclonal light chain deposition. Excessive or abnormal light chain production in multiple myeloma patients is a common manifestation. The association of myeloma nephropathy with crystalloid formation and its association with secondary Fanconi’s syndrome is not discussed here. There is also ample knowledge of the pathological renal changes in myeloma nephropathy. Myeloma cast nephropathy causes acute renal failure by obstructing distal tubules with dense protein casts containing light chains and sometimes amyloid.7 Amyloid may form as a result of chemical and structural alteration of
301
light chains, which may be k or l. In some myeloma patients light chains are deposited in glomeruli and tubular basement membranes and can be seen as electron dense granular deposits. In other myeloma patients the renal lesions are in the form of amyloid deposits in glomeruli, tubules and blood vessels and, in more advanced stages, other renal structures. In our patient there were no glomerular lesions by conventional light or electron microscopy, the lesions being predominantly proximal tubular. The light chains were taken up by the tubule epithelium and incorporated into the endolysosomal system where presumably conversion to the crystalloid form takes place. This process appears to be detrimental to the cells’ on-going viability with cell fallout and desquamation into the lumen commonly associated with affected tubules. The pathogenesis of this degeneration is still not fully understood. One possible explanation, albeit simplistic, is that the amount of light chains filtered into the tubules far exceeds the catabolic capacity of the epithelium. The accumulation of large amounts of light chains is thought to overload the lysosomal system6 and lead to cytoplasmic and membrane disruption. Alternatively, light chains may be directly toxic to tubular epithelium. Light chains obtained from myeloma patients at clinically relevant concentrations may act as potent inhibitors of both glucose and phosphate uptake, directly affecting transport at the cell plasma membrane,8 and may induce cytoskeletal injury and DNA damage consistent with apoptosis followed by secondary necrosis.9 Dual staining for k and l light chains is rare and light chain deposition disease of the kidney is held to be monotypic. Certainly in this case k light chains were the predominant free light chain in the serum; however, free l light chain was also detected in the serum at a much lower level. We speculate that the dual staining may have resulted from excess loading of the endolysosomal system with k light chain M-protein and that this in turn may have led to a secondary restriction of l light chains. We feel alternative explanations are less likely, such as plural light chains derived from a single plasma cell10 or dual surface light chain expression as has been described in a case of B-cell lymphoma.11 The case reported here also illustrates some aspects of the intracellular processing pathway for light chains in proximal tubules. Electron microscopy of k light chain crystalloids generally shows elongated single membranebound bodies containing little or no other lysosomal material.3 The crystalloids in our case, on the other hand, were mainly rhomboidal structures embedded in a pale amorphous matrix typical of secondary lysosomes or residual bodies. Occasional crystalloids displayed a spiral shaped structure at their margin (Fig. 1). The formation of secondary lysosomal and residual material suggests that this crystalloid material may be a persistent cargo that is poorly susceptible to cellular lysosomal breakdown. The spiral shaped structure observed at the periphery of some light chain crystalloids to our knowledge has not been previously described. Its presence in endosomes and absence in lysosomes requires further investigation. The deposition and conversion of light chains to intracytoplasmic crystalloid structures or lysosomal inclusions in proximal tubules is complex and the exact mechanism of this transformation is still not clearly
302
CORRESPONDENCE
understood. The crystalloids, whether experimentally induced or occurring in myeloma patients, may take many morphological forms. Alternatively, l light chains in some cases may deposit as extracellular AL-amyloid.4 Such selective involvement of extracellular or intracellular sites appears to be related to the physicochemical characteristics of light chains5,7 with conformational differences in deposits related to the tertiary structure of constituent proteins forming the basic subunits.12 Small variations in the amino acid sequence of light chain fragments are considered responsible for modifying the severity of disease.13 Our case has demonstrated that in myeloma patients acute renal tubular damage may be the lesions seen in renal biopsy rather than nodular glomerulopathy, with or without amyloid deposits or cast nephropathy. Conventional immunofluoresence microscopy may not reveal light chain deposits and therefore may lead to misdiagnosis. In such cases it is recommended that immunohistochemistry and electron microscopy be performed. Jim L. C. Yong Murray C. Killingsworth Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool, NSW, Australia. Contact Professor Jim Yong. E-mail: [email protected]
1. Carstens PH, Woo D. Crystalline glomerular inclusions in multiple myeloma. Am J Kidney Dis 1989; 14: 56–60. 2. Herrera GA, Sanders PW, Vishnu Reddy B, et al. Ultrastructural immunolabelling: a unique diagnostic tool in monoclonal light chainrelated renal diseases. Ultrastruct Pathol 1994; 18: 401–16. 3. Cai G, Sidhu GS, Wieczorek R, et al. Plasma cell dyscrasia with kappa light-chain crystals in proximal tubular cells: A histological, immunofluorescent, and ultrastructural study. Ultrastruct Pathol 2006; 30: 315–9. 4. Sanders PW, Herrera GA, Kirk KA, et al. Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991; 64: 527–37. 5. Bradley JR, Thira S, Evans DB. Light chains and the kidney. J Clin Pathol 1987; 40: 53–60. 6. Sanders PW, Herrera GA, Lott RL, et al. Morphologic alterations of the proximal tubules in light chain-related renal disease. Kidney Int 1988; 33: 881–9. 7. Santostefano M, Zanchelli F, Zaccaria A, et al. The ultrastructural basis of renal pathology in monoclonal gammopathies. J Nephrol 2005; 18: 659–75. 8. Batuman V, Guan S, O’Donovan R, et al. Effect of myeloma light chains on phosphate and glucose transport in renal proximal tubule cells. Renal Physiol 1994; 17: 294–300. 9. Pote A, Zwizinski C, Simon EE, et al. Cytotoxicity of myeloma light chains in cultured human kidney proximal tubule cells. Am J Kidney Dis 2000; 36: 735–44. 10. Saito N, Konishi K, Ohta S, et al. Plural light chains in a single plasma cell of a monoclonal gammopathy undetermined significance case: An ultrastructural study. Hum Cell 2007; 20: 10–4. 11. Fujiwara T, Ishizawa K, Kohata K, et al. Aggressive B-cell lymphoma with dual surface immunoglobulin light-chain expression. Intern Med 2007; 46: 1458–61. 12. Schormann N, Murrell JR, Liepnieks JJ, et al. Tertiary structure of an amyloid immunoglobulin light chain protein: A proposed model for amyloid fibril formation. Proc Natl Acad Sci 1995; 92: 9490–4. 13. Decourt C, Bridoux F, Touchard G, et al. A monoclonal Vkl light chain responsible for incomplete proximal tubulopathy. Am J Kidney Dis 2003; 41: 497–504.
DOI: 10.1080/00313020902756352
Pathology (2009), 41(3), April
Presacral extramedullary haematopoiesis Sir, Extramedullary haematopoiesis (EMH) is a compensatory phenomenon in diseases in which erythrocyte production is diminished or destruction is accelerated. It typically involves the liver, spleen and lymph nodes.1 Presacral EMH is very uncommon. In this paper, the authors report a new case of presacral EMH confirmed by fine-needle aspiration cytology and tissue biopsy. A 53-year-old male patient with a medical history significant for thalassaemia intermedia presented with complaints of dysuria and pelvic pain radiating to the left leg for 8 months. On admission, the patient was pale and mildly jaundiced. Physical examination revealed a palpable, firm and tender pelvic mass. On digital examination of the rectum, it was felt to impinge over the posterior rectal wall. A complete blood count revealed a haemoglobin level of 8.7 g/dL, a haematocrit of 24.7% and a mean corpuscular volume of 63.7 fL. Computed tomography (CT) scan revealed a heterogeneous soft tissue density mass, anterior to the sacrum, with smooth lobulated margins, extending from L5 to S2 and measuring 87 6 85 mm. This mass displaced the rectum anteriorly and to the right (Fig. 1). It showed a high-signal intensity on T1 and T2 weighted images. CT-guided core biopsy and fine needle aspiration of the mass were performed. Cytology of the aspirated fluid from the presacral mass showed haematopoietic elements comprising neutrophils, eosinophils, immature red blood cells and megakaryocytes suggestive of extramedullary haematopoietic focus (Fig. 2A). Histopathological examination of the biopsy specimen showed normal haematopoietic tissue with normal maturation of all three cell lineages consisting of granulopoiesis, erythropoiesis and occasional megakaryocytes (Fig. 2B). The final pathological diagnosis was extramedullary haematopoiesis. A specific treatment based on blood transfusion and hydroxyurea was first proposed. During the 2 month follow-up period, pain relief was obtained, but the tumour did not decrease in size. At present, the patient is still on follow-up in the haematology department.
FIG. 1 CT scan of the pelvis demonstrates a heterogeneous soft tissue density mass closely adherent to the sacrum, with smooth lobulated margins and focal low density due to fatty infiltration. Note needle biopsy on the left.
CORRESPONDENCE
HyperIgG4 disease/IgG4-related sclerosing disease is a clinically distinct condition that can be diagnosed on serology and histology with good treatment outcome. The significance of this condition is further emphasised by the differential diagnoses that vary from tuberculosis to cancer. This diagnosis highlights the association of high concentrations of serum IgG4 plasma cells to entities previously known as idiopathic systemic fibrosis. Our case reiterates mediastinal lymphadenopathy, RPF and chronic sclerosing sialadenitis as clinical manifestations. Jespal Gill* Graeme Taylor* Logan Carpenter* Christopher Lewis{ Weldon Chiu* *Department of Pathology, Labplus, Auckland City Hospital, and {Auckland City Hospital, Auckland, New Zealand Contact Dr J. Gill. E-mail: [email protected]
1. Neild G, Rodriguez-Justo M, Wall C, et al. Hyper-IgG4 disease: report and characterization of a new disease. BMC Med 2006; 4: 23. 2. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: 732–8. 3. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 2002; 359: 1403–4. 4. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4 – related autoimmune disease. J Gastroenterol 2003; 38: 982–4. 5. Zen Y, Sawazaki A, Miyama S, et al. A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol 2006; 37: 239–43. 6. Zen Y, Kitagawa S, Minato H, et al. IgG4-positive plasma cell in inflammatory pseudotumour (plasma cell granuloma) of the lung. Hum Pathol 2005; 36: 710–7. 7. Kitagawa S, Zen Y, Harada K. Abundant IgG4 positive plasma cell infiltration characterizes chronic sclerosing siladenitis (Kuttner’s tumor). Am J Surg Pathol 2005; 29: 783–91. 8. Zen Y, Harada K, Sasaki M, et al. IgG4-related sclerosing cholangitis with and without inflammatory pseudotumour and sclerosing pancreatitis-associated sclerosing cholangitis. Do they belong to a spectrum of sclerosing pancreatitis. Am J Surg Pathol 2004; 28: 1193–203. 9. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4 related sclerosing disease. J Gastroenterol 2006; 41: 613–25. 10. Deshpande V, Chiocca S, Finkelberg D, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006; 30: 1537–45. 11. Kamisawa T, Chen PY, Tu Y, et al. Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 2006; 12: 6225–8. 12. Noonan C, Pfau J, Larson T, et al. Nested case–control study of autoimmune disease in an asbestos-exposed population. Environ Health Perspect 2006; 114: 1243–7.
DOI: 10.1080/00313020902756394
Acute light chain tubulopathy in myeloma Sir, In myeloma patients renal biopsies may show tubular casts with cellular reaction, deposits of amyloid or features of
Pathology (2009), 41(3), April
light chain nephropathy in the form of nodular glomerular lesions similar to the type seen in Type I mesangiocapillary glomerulonephritis or diabetic glomerulosclerosis. The production of excessive amounts of abnormal light chains in myeloma or in other cases of monoclonal gammopathy may lead to acute tubular damage or so called acute light chain tubulopathy. We report a case of myeloma associated acute light chain tubulopathy with dual staining for kappa (k) and lambda (l) light chain deposition forming crystalloid bodies. The patient was a 67-year-old man who presented with symptoms of acute on chronic renal failure. He had a serum creatinine of 250 mmol/L, 9.648 g/L of free kappa light chains, 5.4 mg/L free lambda light chains and urinary paraprotein. Haematological tests showed a negative vasculitic screen and a bone marrow aspirate diagnostic of multiple myeloma. His renal biopsy contained 15 glomeruli, two of which were globally sclerosed, the others were generally of normal appearance. The lining epithelial cells of the proximal tubules were swollen with surface irregularities and disrupted brush borders (Fig. 1). There were occasional protein casts and desquamated epithelial cells and no deposits of amyloid. Immunofluorescence microscopy (IF) was negative for all classes of immunoglobulin, C1q, C3c, k light chains, l light chains and fibrinogen. Immunoperoxidase studies showed positive staining for k and l light chains in the cytoplasm of tubule epithelial cells and desquamated cells in the lumen (Fig. 1). Electron microscopy of proximal tubules showed large numbers of lysosomal inclusions and crystalloids in the cytoplasm of affected cells (Fig. 1). The crystalloids were rhomboid to hexagonal in outline and usually embedded in an amorphous matrix contained in secondary lysosomes. Our case is illustrative or prototypical of acute light chain tubulopathy due to deposition of light chains. The histological changes in renal biopsies in these cases are subtle and may not be appreciated or may be missed, especially when light chain deposits are not detected by routine IF. In our case, neither k nor l light chains were detected by IF and both forms of light chain were demonstrated by immunohistochemistry. Likewise, other reports have pointed out negative immunofluorescence in cases with k light chain crystalline deposits that were 1,2 subsequently detected by immunoelectron microscopy. Others have been able to demonstrate positive immunofluorescence associated with k light chain crystalloids,3 and because of variability in staining with monoclonal antibodies, the use of polyclonal light chain type-specific antibodies for immunofluorescence has been advocated for routine investigation.4 The reason for the discrepancy in the detection of light chain deposits by IF and immnuohistochemistry may be due to a difference in sensitivity of the methods used for detecting antigens. It may be due in part to deposition of the crystalline form of light chain rendering the immunolabelling epitope inaccessible or below the threshold of detection, or the fact that both our immunohistochemistry and immunoelectron microscopy protocols employ antigen retrieval steps whereas the immunofluorescence protocol does not. Regardless of the explanation, the main point to note is that light chain crystalloids may not show up with conventional IF or, if present, this fluorescence should not be interpreted as
CORRESPONDENCE
FIG. 1 Immunohistochemical localisation and electron microscopy of l light chain (LLC) and k light chain (KLC) staining associated with crystalloid bodies in proximal tubular epithelium. (A) Widespread k light chain deposition with most tubules affected (arrows) (anti-k light chain stain). (B) Focal l light chain deposition affecting only occasional cells (arrows) while some tubules (arrowheads) are spared (anti-l light chain stain). (C) Granular light chain crystalloids (arrows) in lysosomes. Inset: k light chain crystalloids from another file case showing alternative needlelike morphology (bar¼5000 nm). (D) Rhomboid and hexagonal light chain crystalloids from the present case (arrow) embedded in pale amorphous lysosomal matrix (arrowhead). Inset: High power view of a light chain crystalloid showing 6 nm periodicity and adjacent spiral shaped structure (arrow) lying internal to the limiting membrane (arrowhead) (bar¼100 nm).
non-specific.2 Transmission electron microscopy can also assist with recognition of finely granular deposits in basement membrane,5 atypical lysosomes6 and intracellular crystalloid inclusions. These structures serve as morphological markers for monoclonal light chain deposition. Excessive or abnormal light chain production in multiple myeloma patients is a common manifestation. The association of myeloma nephropathy with crystalloid formation and its association with secondary Fanconi’s syndrome is not discussed here. There is also ample knowledge of the pathological renal changes in myeloma nephropathy. Myeloma cast nephropathy causes acute renal failure by obstructing distal tubules with dense protein casts containing light chains and sometimes amyloid.7 Amyloid may form as a result of chemical and structural alteration of
301
light chains, which may be k or l. In some myeloma patients light chains are deposited in glomeruli and tubular basement membranes and can be seen as electron dense granular deposits. In other myeloma patients the renal lesions are in the form of amyloid deposits in glomeruli, tubules and blood vessels and, in more advanced stages, other renal structures. In our patient there were no glomerular lesions by conventional light or electron microscopy, the lesions being predominantly proximal tubular. The light chains were taken up by the tubule epithelium and incorporated into the endolysosomal system where presumably conversion to the crystalloid form takes place. This process appears to be detrimental to the cells’ on-going viability with cell fallout and desquamation into the lumen commonly associated with affected tubules. The pathogenesis of this degeneration is still not fully understood. One possible explanation, albeit simplistic, is that the amount of light chains filtered into the tubules far exceeds the catabolic capacity of the epithelium. The accumulation of large amounts of light chains is thought to overload the lysosomal system6 and lead to cytoplasmic and membrane disruption. Alternatively, light chains may be directly toxic to tubular epithelium. Light chains obtained from myeloma patients at clinically relevant concentrations may act as potent inhibitors of both glucose and phosphate uptake, directly affecting transport at the cell plasma membrane,8 and may induce cytoskeletal injury and DNA damage consistent with apoptosis followed by secondary necrosis.9 Dual staining for k and l light chains is rare and light chain deposition disease of the kidney is held to be monotypic. Certainly in this case k light chains were the predominant free light chain in the serum; however, free l light chain was also detected in the serum at a much lower level. We speculate that the dual staining may have resulted from excess loading of the endolysosomal system with k light chain M-protein and that this in turn may have led to a secondary restriction of l light chains. We feel alternative explanations are less likely, such as plural light chains derived from a single plasma cell10 or dual surface light chain expression as has been described in a case of B-cell lymphoma.11 The case reported here also illustrates some aspects of the intracellular processing pathway for light chains in proximal tubules. Electron microscopy of k light chain crystalloids generally shows elongated single membranebound bodies containing little or no other lysosomal material.3 The crystalloids in our case, on the other hand, were mainly rhomboidal structures embedded in a pale amorphous matrix typical of secondary lysosomes or residual bodies. Occasional crystalloids displayed a spiral shaped structure at their margin (Fig. 1). The formation of secondary lysosomal and residual material suggests that this crystalloid material may be a persistent cargo that is poorly susceptible to cellular lysosomal breakdown. The spiral shaped structure observed at the periphery of some light chain crystalloids to our knowledge has not been previously described. Its presence in endosomes and absence in lysosomes requires further investigation. The deposition and conversion of light chains to intracytoplasmic crystalloid structures or lysosomal inclusions in proximal tubules is complex and the exact mechanism of this transformation is still not clearly
302
CORRESPONDENCE
understood. The crystalloids, whether experimentally induced or occurring in myeloma patients, may take many morphological forms. Alternatively, l light chains in some cases may deposit as extracellular AL-amyloid.4 Such selective involvement of extracellular or intracellular sites appears to be related to the physicochemical characteristics of light chains5,7 with conformational differences in deposits related to the tertiary structure of constituent proteins forming the basic subunits.12 Small variations in the amino acid sequence of light chain fragments are considered responsible for modifying the severity of disease.13 Our case has demonstrated that in myeloma patients acute renal tubular damage may be the lesions seen in renal biopsy rather than nodular glomerulopathy, with or without amyloid deposits or cast nephropathy. Conventional immunofluoresence microscopy may not reveal light chain deposits and therefore may lead to misdiagnosis. In such cases it is recommended that immunohistochemistry and electron microscopy be performed. Jim L. C. Yong Murray C. Killingsworth Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool, NSW, Australia. Contact Professor Jim Yong. E-mail: [email protected]
1. Carstens PH, Woo D. Crystalline glomerular inclusions in multiple myeloma. Am J Kidney Dis 1989; 14: 56–60. 2. Herrera GA, Sanders PW, Vishnu Reddy B, et al. Ultrastructural immunolabelling: a unique diagnostic tool in monoclonal light chainrelated renal diseases. Ultrastruct Pathol 1994; 18: 401–16. 3. Cai G, Sidhu GS, Wieczorek R, et al. Plasma cell dyscrasia with kappa light-chain crystals in proximal tubular cells: A histological, immunofluorescent, and ultrastructural study. Ultrastruct Pathol 2006; 30: 315–9. 4. Sanders PW, Herrera GA, Kirk KA, et al. Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991; 64: 527–37. 5. Bradley JR, Thira S, Evans DB. Light chains and the kidney. J Clin Pathol 1987; 40: 53–60. 6. Sanders PW, Herrera GA, Lott RL, et al. Morphologic alterations of the proximal tubules in light chain-related renal disease. Kidney Int 1988; 33: 881–9. 7. Santostefano M, Zanchelli F, Zaccaria A, et al. The ultrastructural basis of renal pathology in monoclonal gammopathies. J Nephrol 2005; 18: 659–75. 8. Batuman V, Guan S, O’Donovan R, et al. Effect of myeloma light chains on phosphate and glucose transport in renal proximal tubule cells. Renal Physiol 1994; 17: 294–300. 9. Pote A, Zwizinski C, Simon EE, et al. Cytotoxicity of myeloma light chains in cultured human kidney proximal tubule cells. Am J Kidney Dis 2000; 36: 735–44. 10. Saito N, Konishi K, Ohta S, et al. Plural light chains in a single plasma cell of a monoclonal gammopathy undetermined significance case: An ultrastructural study. Hum Cell 2007; 20: 10–4. 11. Fujiwara T, Ishizawa K, Kohata K, et al. Aggressive B-cell lymphoma with dual surface immunoglobulin light-chain expression. Intern Med 2007; 46: 1458–61. 12. Schormann N, Murrell JR, Liepnieks JJ, et al. Tertiary structure of an amyloid immunoglobulin light chain protein: A proposed model for amyloid fibril formation. Proc Natl Acad Sci 1995; 92: 9490–4. 13. Decourt C, Bridoux F, Touchard G, et al. A monoclonal Vkl light chain responsible for incomplete proximal tubulopathy. Am J Kidney Dis 2003; 41: 497–504.
DOI: 10.1080/00313020902756352
Pathology (2009), 41(3), April
Presacral extramedullary haematopoiesis Sir, Extramedullary haematopoiesis (EMH) is a compensatory phenomenon in diseases in which erythrocyte production is diminished or destruction is accelerated. It typically involves the liver, spleen and lymph nodes.1 Presacral EMH is very uncommon. In this paper, the authors report a new case of presacral EMH confirmed by fine-needle aspiration cytology and tissue biopsy. A 53-year-old male patient with a medical history significant for thalassaemia intermedia presented with complaints of dysuria and pelvic pain radiating to the left leg for 8 months. On admission, the patient was pale and mildly jaundiced. Physical examination revealed a palpable, firm and tender pelvic mass. On digital examination of the rectum, it was felt to impinge over the posterior rectal wall. A complete blood count revealed a haemoglobin level of 8.7 g/dL, a haematocrit of 24.7% and a mean corpuscular volume of 63.7 fL. Computed tomography (CT) scan revealed a heterogeneous soft tissue density mass, anterior to the sacrum, with smooth lobulated margins, extending from L5 to S2 and measuring 87 6 85 mm. This mass displaced the rectum anteriorly and to the right (Fig. 1). It showed a high-signal intensity on T1 and T2 weighted images. CT-guided core biopsy and fine needle aspiration of the mass were performed. Cytology of the aspirated fluid from the presacral mass showed haematopoietic elements comprising neutrophils, eosinophils, immature red blood cells and megakaryocytes suggestive of extramedullary haematopoietic focus (Fig. 2A). Histopathological examination of the biopsy specimen showed normal haematopoietic tissue with normal maturation of all three cell lineages consisting of granulopoiesis, erythropoiesis and occasional megakaryocytes (Fig. 2B). The final pathological diagnosis was extramedullary haematopoiesis. A specific treatment based on blood transfusion and hydroxyurea was first proposed. During the 2 month follow-up period, pain relief was obtained, but the tumour did not decrease in size. At present, the patient is still on follow-up in the haematology department.
FIG. 1 CT scan of the pelvis demonstrates a heterogeneous soft tissue density mass closely adherent to the sacrum, with smooth lobulated margins and focal low density due to fatty infiltration. Note needle biopsy on the left.