Downloaded from http://jcp.bmj.com/ on November 12, 2014 - Published by group.bmj.com
PostScript William Patrick Tormey1,2 1
Department of Chemical Pathology, Beaumont Hospital, Dublin, Ireland 2 Department of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Correspondence to Professor William Patrick Tormey, Department of Chemical Pathology, Beaumont Hospital, Beaumont Road, Dublin D9, Ireland; [email protected] Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. To cite Tormey WP. J Clin Pathol 2014;67:546–547. Received 11 July 2013 Revised 7 August 2013 Accepted 19 August 2013 Published Online First 23 September 2013
▸ http://dx.doi.org/10.1136/jclinpath-2013-202103 J Clin Pathol 2014;67:546–547. doi:10.1136/jclinpath-2013-201859
REFERENCES 1 2 3
4 5
6
Crook MA. Chemical pathology: what has changed? J Clin Pathol 2000;53:1–6. Crook M. Chemical pathology and Krapp’s last tape. J Clin Pathol 2006;58:788. http://www.medicalcouncil.ie/Information-for-Doctors/ Professional-Competence/Professional-CompetenceGuidelines.pdf (accessed 27 Jun 2013). http://www.gmc-uk.org/CPD_guidance_June_12.pdf_ 48970799.pdf (accessed 27 Jun 2013). Academy of Medical Royal Colleges. The ten principles for college/faculty CPD schemes. London: Academy of Medical Royal Colleges, 2007. Lishman S, Croal B. Joint Meeting of the RCPath and the Faculty of Pathology of the RCPI. Bull R Coll Pathol 2013;162:97–8.
Auer rod-like inclusions in plasma cells in multiple myeloma A female patient presented with bone pain. Bone scan demonstrated a focal lesion in the left iliac crest, which was confirmed subsequently as a lytic lesion on CT scanning. Core biopsy showed plasmacytoid cells that were strongly positive for CD138 with extensive strong κ light chain immunostaining. Haemoglobin was 124 g/L, white cell count 5.4×109/L, neutrophils 3.0×109/L, platelets 300×109/L and erythrocyte sedimentation rate 7 mm/h. Serum creatinine was 90 μmol/L; adjusted serum calcium was 2.50 mmol/L with normal serum phosphate and bicarbonate levels and anion gap. Serum protein electrophoresis demonstrated monoclonal IgG κ of 4 g/L and free κ light chain of 5 g/L. Urinary Bence–Jones protein measured 2.45 g/L comprising free κ light chains. Serum free κ light chains were J Clin Pathol June 2014 Vol 67 No 6
Figure 1 Bone marrow aspirate, ×1000 (May–Grünwald–Giemsa stain). >4275.0 mg/L (3.3–19.4) and λ light chains 9.4 mg/L (5.7–26.3) with β2-microglobulin 5.4 mg/L (0.80–3.00). Skeletal survey demonstrated multiple lucencies in both femora, humeri, ribs, thoracic spine, calvarium and left iliac bone. Six years previously, she had been noted to have monoclonal IgG κ measuring 2–3 g/L. Four years ago, the paraprotein remained unchanged at 2–3 g/L with no Bence–Jones proteinuria. A diagnosis of multiple myeloma, having evolved from a monoclonal gammopathy of uncertain significance, was now made. Of note was that bone marrow aspirate from the right superior iliac spine at the time of myeloma diagnosis showed a third of cells being plasma cells, many of which had rod-shaped cytoplasmic inclusions resembling Auer rods on May–Grünwald– Giemsa (MGG) staining (figure 1). A smaller proportion of these inclusions were thinner and more slender in appearance (figure 2). Repeat bone marrow biopsy later showed persistence of these morphological findings. On karyotyping, of 21 cells, only three had normal female metaphase spreads. All other cells were hypodiploid containing between 41 and 46 chromosomes with apparent monosomies of X, 13, 14 and 15, an isodicentric chromosome 1 resulting in three copies of 1q, an abnormality of 2p, an unbalanced 1;14 translocation, trisomy 7 and addition of marker
Figure 2 Bone marrow aspirate, ×1000 (May–Grünwald–Giemsa stain).
chromosomes. Three cells also contained abnormalities of 7p, 6p and 18p. Hütter et al, in a review in 2009 of all reported cases,1 found fewer than 30 since the first description of Auer rod-like cytoplasmic inclusions in plasma cells by Steinmann in 1940. Following that review, a further handful of cases have been described.2–8 Pooling together the cases reviewed by Hütter et al and all reports since then up to and including our case, it appears that almost all displayed κ light chain restriction (24 of 25 cases, 96%); only one case of λ light chain restriction has been described.4 In terms of frequency of the involved immunoglobulin class, one-half of cases were associated with an IgG monoclonal paraprotein (14 of 28 cases, 50%), followed by eight cases (28%) with isolated serum-free light chains or Bence–Jones proteinuria without the involvement of intact immunoglobulins, four of IgA (14%) and one case each of an IgM and combined IgG-IgM paraproteinaemia. The nature of these cytoplasmic inclusions has, to date, not been properly elucidated. Unlike Auer rods in myeloid cells, they are negative for myeloperoxidase. They are not deposits of immunoglobulin or immunoglobulin light chains but stain positively for α-naphthyl acetate esterase (sensitive to sodium fluoride treatment) and β-glucuronidase, suggestive of a lysosomal origin.1 9 An association with Fanconi syndrome has been described in some cases.1 The specific variant structure of the κ light chain, particularly that of the variable domain loops, can cause proximal renal tubular injury by virtue of its resistance to cathepsin B digestion. This results in the formation of crystals in the proximal renal tubular cells and Fanconi syndrome.10 Our patient with no documented hypophosphataemia or acidosis (normal serum bicarbonate and anion gap) did not have features of this syndrome. Due to its rarity, it remains unknown whether this morphological finding confers any prognostic implication for patients with plasma cell dyscrasias. Additionally, there is no known cytogenetic association as most reports have not provided results of karyotyping. In one report, however, a complex hyperdiploid clone comprising multiple numerical and structural abnormalities was described.4 This is in contrast to our case where hypodiploid abnormalities were present. Another report found monosomy 13 in a case.6 Only with the description of more cases in the future may we then be able to draw some conclusions in this regard. 547
Downloaded from http://jcp.bmj.com/ on November 12, 2014 - Published by group.bmj.com
PostScript Wai Khoon Ho, Daniela Zantomio Department of Haematology, Austin Health, Heidelberg, Victoria, Australia Correspondence to Dr Wai Khoon Ho, Department of Haematology, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; [email protected] Contributors Both authors contributed equally to the reporting of the work and drafting of the manuscript. Both authors are also responsible for the content of the article, and act as guarantors of the paper.
To cite Ho WK, Zantomio D. J Clin Pathol 2014;67:547–548. Received 17 January 2014 Accepted 18 February 2014 Published Online First 13 March 2014
6
J Clin Pathol 2014;67:547–548. doi:10.1136/jclinpath-2014-202195
7
REFERENCES
8
1
Competing interests None. Ethics approval
2
Provenance and peer review Not commissioned; externally peer reviewed.
3
4
548
5
Hütter G, Nowak D, Blau IW, et al. Auer rod-like intracytoplasmic inclusions in multiple myeloma. A case report and review of the literature. Int J Lab Hematol 2009;31:236–40. Ali N, Moiz B. Azurophilic inclusions in plasma cells. Singapore Med J 2009;50:e114–15. Frotscher B, Salignac S, Lecompte T. Multiple myeloma with unusual inclusions. Br J Haematol 2009;144:1. Kulbacki EL, Wang E. IgG-λ plasma cell myeloma with cytoplasmic azurophilic inclusion bodies. Am J Hematol 2010;85:516–17.
9
10
Parmentier S, Radke J. Pseudo-Auer rods in a patient with newly diagnosed IgG myeloma. Blood 2012;119:650. Noujaim JC, D’Angelo G. Auer rod-like inclusions in kappa light chain myeloma. Blood 2013;122: 2932. Abdulsalam AH, Bain BJ. Auer-rod like inclusions in multiple myeloma. Am J Hematol Published Online First: 17 Dec 2013. Oh SH, Park CJ. Auer rod-like crystal inclusions in plasma cells of multiple myeloma. Korean J Hematol 2010;45:222. V M, Meenu Bal M, Varma N, et al. Auer rod-like inclusions in immunoglobulin A multiple myeloma. Arch Pathol Lab Med 2005;129:706–7. Déret S, Denoroy L, Lamarine M, et al. Kappa light chain-associated Fanconi’s syndrome: Molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals. Protein Eng 1999;12:363–9.
J Clin Pathol June 2014 Vol 67 No 6
Downloaded from http://jcp.bmj.com/ on November 12, 2014 - Published by group.bmj.com
Auer rod-like inclusions in plasma cells in multiple myeloma Wai Khoon Ho and Daniela Zantomio J Clin Pathol 2014 67: 547-548 originally published online March 13, 2014
doi: 10.1136/jclinpath-2014-202195 Updated information and services can be found at: http://jcp.bmj.com/content/67/6/547
These include:
References Email alerting service
This article cites 9 articles, 3 of which you can access for free at: http://jcp.bmj.com/content/67/6/547#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
PostScript William Patrick Tormey1,2 1
Department of Chemical Pathology, Beaumont Hospital, Dublin, Ireland 2 Department of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Correspondence to Professor William Patrick Tormey, Department of Chemical Pathology, Beaumont Hospital, Beaumont Road, Dublin D9, Ireland; [email protected] Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. To cite Tormey WP. J Clin Pathol 2014;67:546–547. Received 11 July 2013 Revised 7 August 2013 Accepted 19 August 2013 Published Online First 23 September 2013
▸ http://dx.doi.org/10.1136/jclinpath-2013-202103 J Clin Pathol 2014;67:546–547. doi:10.1136/jclinpath-2013-201859
REFERENCES 1 2 3
4 5
6
Crook MA. Chemical pathology: what has changed? J Clin Pathol 2000;53:1–6. Crook M. Chemical pathology and Krapp’s last tape. J Clin Pathol 2006;58:788. http://www.medicalcouncil.ie/Information-for-Doctors/ Professional-Competence/Professional-CompetenceGuidelines.pdf (accessed 27 Jun 2013). http://www.gmc-uk.org/CPD_guidance_June_12.pdf_ 48970799.pdf (accessed 27 Jun 2013). Academy of Medical Royal Colleges. The ten principles for college/faculty CPD schemes. London: Academy of Medical Royal Colleges, 2007. Lishman S, Croal B. Joint Meeting of the RCPath and the Faculty of Pathology of the RCPI. Bull R Coll Pathol 2013;162:97–8.
Auer rod-like inclusions in plasma cells in multiple myeloma A female patient presented with bone pain. Bone scan demonstrated a focal lesion in the left iliac crest, which was confirmed subsequently as a lytic lesion on CT scanning. Core biopsy showed plasmacytoid cells that were strongly positive for CD138 with extensive strong κ light chain immunostaining. Haemoglobin was 124 g/L, white cell count 5.4×109/L, neutrophils 3.0×109/L, platelets 300×109/L and erythrocyte sedimentation rate 7 mm/h. Serum creatinine was 90 μmol/L; adjusted serum calcium was 2.50 mmol/L with normal serum phosphate and bicarbonate levels and anion gap. Serum protein electrophoresis demonstrated monoclonal IgG κ of 4 g/L and free κ light chain of 5 g/L. Urinary Bence–Jones protein measured 2.45 g/L comprising free κ light chains. Serum free κ light chains were J Clin Pathol June 2014 Vol 67 No 6
Figure 1 Bone marrow aspirate, ×1000 (May–Grünwald–Giemsa stain). >4275.0 mg/L (3.3–19.4) and λ light chains 9.4 mg/L (5.7–26.3) with β2-microglobulin 5.4 mg/L (0.80–3.00). Skeletal survey demonstrated multiple lucencies in both femora, humeri, ribs, thoracic spine, calvarium and left iliac bone. Six years previously, she had been noted to have monoclonal IgG κ measuring 2–3 g/L. Four years ago, the paraprotein remained unchanged at 2–3 g/L with no Bence–Jones proteinuria. A diagnosis of multiple myeloma, having evolved from a monoclonal gammopathy of uncertain significance, was now made. Of note was that bone marrow aspirate from the right superior iliac spine at the time of myeloma diagnosis showed a third of cells being plasma cells, many of which had rod-shaped cytoplasmic inclusions resembling Auer rods on May–Grünwald– Giemsa (MGG) staining (figure 1). A smaller proportion of these inclusions were thinner and more slender in appearance (figure 2). Repeat bone marrow biopsy later showed persistence of these morphological findings. On karyotyping, of 21 cells, only three had normal female metaphase spreads. All other cells were hypodiploid containing between 41 and 46 chromosomes with apparent monosomies of X, 13, 14 and 15, an isodicentric chromosome 1 resulting in three copies of 1q, an abnormality of 2p, an unbalanced 1;14 translocation, trisomy 7 and addition of marker
Figure 2 Bone marrow aspirate, ×1000 (May–Grünwald–Giemsa stain).
chromosomes. Three cells also contained abnormalities of 7p, 6p and 18p. Hütter et al, in a review in 2009 of all reported cases,1 found fewer than 30 since the first description of Auer rod-like cytoplasmic inclusions in plasma cells by Steinmann in 1940. Following that review, a further handful of cases have been described.2–8 Pooling together the cases reviewed by Hütter et al and all reports since then up to and including our case, it appears that almost all displayed κ light chain restriction (24 of 25 cases, 96%); only one case of λ light chain restriction has been described.4 In terms of frequency of the involved immunoglobulin class, one-half of cases were associated with an IgG monoclonal paraprotein (14 of 28 cases, 50%), followed by eight cases (28%) with isolated serum-free light chains or Bence–Jones proteinuria without the involvement of intact immunoglobulins, four of IgA (14%) and one case each of an IgM and combined IgG-IgM paraproteinaemia. The nature of these cytoplasmic inclusions has, to date, not been properly elucidated. Unlike Auer rods in myeloid cells, they are negative for myeloperoxidase. They are not deposits of immunoglobulin or immunoglobulin light chains but stain positively for α-naphthyl acetate esterase (sensitive to sodium fluoride treatment) and β-glucuronidase, suggestive of a lysosomal origin.1 9 An association with Fanconi syndrome has been described in some cases.1 The specific variant structure of the κ light chain, particularly that of the variable domain loops, can cause proximal renal tubular injury by virtue of its resistance to cathepsin B digestion. This results in the formation of crystals in the proximal renal tubular cells and Fanconi syndrome.10 Our patient with no documented hypophosphataemia or acidosis (normal serum bicarbonate and anion gap) did not have features of this syndrome. Due to its rarity, it remains unknown whether this morphological finding confers any prognostic implication for patients with plasma cell dyscrasias. Additionally, there is no known cytogenetic association as most reports have not provided results of karyotyping. In one report, however, a complex hyperdiploid clone comprising multiple numerical and structural abnormalities was described.4 This is in contrast to our case where hypodiploid abnormalities were present. Another report found monosomy 13 in a case.6 Only with the description of more cases in the future may we then be able to draw some conclusions in this regard. 547
Downloaded from http://jcp.bmj.com/ on November 12, 2014 - Published by group.bmj.com
PostScript Wai Khoon Ho, Daniela Zantomio Department of Haematology, Austin Health, Heidelberg, Victoria, Australia Correspondence to Dr Wai Khoon Ho, Department of Haematology, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; [email protected] Contributors Both authors contributed equally to the reporting of the work and drafting of the manuscript. Both authors are also responsible for the content of the article, and act as guarantors of the paper.
To cite Ho WK, Zantomio D. J Clin Pathol 2014;67:547–548. Received 17 January 2014 Accepted 18 February 2014 Published Online First 13 March 2014
6
J Clin Pathol 2014;67:547–548. doi:10.1136/jclinpath-2014-202195
7
REFERENCES
8
1
Competing interests None. Ethics approval
2
Provenance and peer review Not commissioned; externally peer reviewed.
3
4
548
5
Hütter G, Nowak D, Blau IW, et al. Auer rod-like intracytoplasmic inclusions in multiple myeloma. A case report and review of the literature. Int J Lab Hematol 2009;31:236–40. Ali N, Moiz B. Azurophilic inclusions in plasma cells. Singapore Med J 2009;50:e114–15. Frotscher B, Salignac S, Lecompte T. Multiple myeloma with unusual inclusions. Br J Haematol 2009;144:1. Kulbacki EL, Wang E. IgG-λ plasma cell myeloma with cytoplasmic azurophilic inclusion bodies. Am J Hematol 2010;85:516–17.
9
10
Parmentier S, Radke J. Pseudo-Auer rods in a patient with newly diagnosed IgG myeloma. Blood 2012;119:650. Noujaim JC, D’Angelo G. Auer rod-like inclusions in kappa light chain myeloma. Blood 2013;122: 2932. Abdulsalam AH, Bain BJ. Auer-rod like inclusions in multiple myeloma. Am J Hematol Published Online First: 17 Dec 2013. Oh SH, Park CJ. Auer rod-like crystal inclusions in plasma cells of multiple myeloma. Korean J Hematol 2010;45:222. V M, Meenu Bal M, Varma N, et al. Auer rod-like inclusions in immunoglobulin A multiple myeloma. Arch Pathol Lab Med 2005;129:706–7. Déret S, Denoroy L, Lamarine M, et al. Kappa light chain-associated Fanconi’s syndrome: Molecular analysis of monoclonal immunoglobulin light chains from patients with and without intracellular crystals. Protein Eng 1999;12:363–9.
J Clin Pathol June 2014 Vol 67 No 6
Downloaded from http://jcp.bmj.com/ on November 12, 2014 - Published by group.bmj.com
Auer rod-like inclusions in plasma cells in multiple myeloma Wai Khoon Ho and Daniela Zantomio J Clin Pathol 2014 67: 547-548 originally published online March 13, 2014
doi: 10.1136/jclinpath-2014-202195 Updated information and services can be found at: http://jcp.bmj.com/content/67/6/547
These include:
References Email alerting service
This article cites 9 articles, 3 of which you can access for free at: http://jcp.bmj.com/content/67/6/547#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
