Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
JCP Online First, published on February 26, 2015 as 10.1136/jclinpath-2014-202847 PostScript
CORRESPONDENCE
ALK positive large B-cell lymphoma with a massive neutrophilic infiltrate: report of a case mimicking epithelioid inflammatory myofibroblastic tumour Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (ALK+LBCL) is a rare, distinct and aggressive entity defined as a neoplasm of ALK-positive monomorphic large immunoblastic-like B cells.1 The tumour cells are considered to be derived from post-germinal centre B cells with plasmablastic differentiation and frequently show a cytoplasmic granular pattern of ALK.1 Nodal (most commonly to be cervical nodes) and extranodal presentation (including bone, head and neck, liver and spleen, gastrointestinal tract) have been reported.2 Here we reported a case of intestinal ALK+LBCL with systemic involvement mimicking the epithelioid variant of inflammatory myofibroblastic tumour (epiIMT).
A 46-year-old woman presented in March 2014 with repeated episodes of melaena for 1 month associated with general weakness, vomiting, body weight loss and pitting oedema of bilateral lower limbs. At the Emergency Department, ileus and anaemia (haemoglobin at 6.4 g/dL) were noted, and chest X-ray revealed a mass in the right lower lobe of lung. CT scans of chest and abdomen showed a 7 cm tumour in the right lower lobe of lung, a 3 cm nodule in the abdominal wall and a 12 cm polypoid tumour in the jejunum with adhesion to sigmoid colon (figure 1). She underwent resection of the tumours in the jejunum and abdominal wall. The upper jejunal tumour was located 40 cm distal to Treitz ligament with adhesion to the sigmoid colon. Grossly, the jejunal tumour was fungating, soft and necrotic, measuring 12 cm in size with ulceration. Five regional lymph nodes were dissected out and one was necrotic. Histological examination of the jejunal tumour revealed a diffuse transmural infiltration by neoplastic cells extending from the ulcerated mucosa to the serosa with extensive tumour necrosis. The tumour cells were admixed with a massive neutrophilic infiltration
(figure 2A). Under high power, the neoplastic cells were large and epithelioid with round and vesicular nuclei and a prominent central nucleolus (figure 2B). Some kidneyshaped or Reed–Sternberg-like giant cells were noted. One of the five regional lymph nodes showed tumour involvement by neoplastic cells. The abdominal wall tumour revealed a similar infiltration by anaplastic cells dissecting between the muscle bundles. Immunohistochemically, the neoplastic cells were diffusely positive for vimentin, IgA (figure 2C), myc (figure 2D) and ALK (a cytoplasmic granular staining pattern; figure 2E). The expression of epithelial membrane antigen (EMA), cytokeratin AE1/ AE3 and CD30 (figure 2F) were all focal. They were negative to most lymphoid markers (CD45, CD3, CD5, CD20, CD79a, PAX5, CD34, CD68, TIA-1) and plasma cell markers (CD138 and MUM-1). A proportion of cells were positive for κ light chain, while λ light chain staining was entirely negative (figure 2G, H), indicating a light chain restriction. In situ hybridisation for Epstein–Barr virus was negative. PCR-based clonality study was performed according to the BIOMED-2 protocols.3 The assay for IGH gene failed, but that for
Figure 1 CT scans of chest and abdomen, showing a 7 cm tumour with central necrosis in the right lower lobe of lung (A), a 3 cm nodule in the abdominal wall (B, arrow) and a 12 cm polypoid tumour in the jejunum with adhesion to sigmoid colon (C and D). J Clin Pathol Month 2015 Vol 0 No 0
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript
Figure 2 Histopathological examination at medium-power, showing diffuse sheets of large tumour cells admixed with numerous neutrophils (A). High-power view reveals large, epithelioid-to-round cells with anaplastic vesicular nuclei and prominent central nucleoli with neutrophils in the background (B). The tumour cells are diffusely positive for IgA (C), myc (D), with a cytoplasmic granular staining of anaplastic lymphoma kinase (ALK) (E), and show focal expression of CD30 (F). A proportion of tumour cells are positive for κ light chain, while λ light chain staining is entirely negative (G and H). IGK gene rearrangement revealed a clonal result (figure 3). Fluorescence in situ hybridisation with break apart probes showed translocation at the ALK locus at 2p23 (figure 4), but not at the BCL2, BCL6 or MYC loci. The final diagnosis was ALK +LBCL. She received one course of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy. 2
Unfortunately, her disease progressed rapidly and she passed away 3 months after diagnosis with respiratory failure. The final pleural effusion cytology before her death also confirmed lymphoma involvement. There was a significant overlap in the clinical presentation, morphology and immunohistochemistry between our case and epiIMT. Similar to our case, most of the epiIMT cases are intra-abdominal,
epithelioid in morphology and, in particular, frequently associated with a prominent neutrophilic infiltrate.4 Furthermore, CD30 and ALK are expressed in the neoplastic cells of epiIMT cases,4 which is also present in our case; in contrast, CD30 is usually negative in ALK+LBCLs.1 2 However, there were some clues in our case leading towards the diagnosis of lymphoma. First, a spindle cell component, even minor, is present in all J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript Figure 3 Clonal IGK gene rearrangement with PCR-based clonality study. Each peak represents clonal rearrangement of Vκ1f/6–Jκ or Vκ7–Jκ (tube A, upper), Vκ3–Kde or intron–Kde (tube B, lower left) and Vκ2f–Kde, Vκ4–Kde or Vκ5–Kde (tube B, lower right).
Correspondence to Dr Chien-Chen Tsai, Department of Anatomical Pathology, Far Eastern Memorial Hospital, No.21, Sec. 2, Nanya S. Rd., Banciao Dist., New Taipei City 220, Taiwan; a0970295250@gmail. com Contributors S-SC, KS, KT and AB: Performed the experiments and analysed the data. S-SC, J-YJ, KT, AB and C-CT: Examined the case and made the final diagnosis. S-YL, S-SC and C-CT: Wrote the manuscript. All authors approved the manuscript. Competing interests None. Ethics approval Research Ethics Review Committee of the Far Eastern Memorial Hospital, Taiwan. Provenance and peer review Not commissioned; internally peer reviewed. To cite Lin S-Y, Chuang S-S, Jhuang J-Y, et al. J Clin Pathol Published Online First: [please include Day Month Year] doi:10.1136/jclinpath-2014-202847
Figure 4 Fluorescent in situ hybridisation (FISH) that reveals anaplastic lymphoma kinase (ALK) translocation at the 2p23 locus using dual colour break apart rearrangement probe.
Received 30 December 2014 Revised 4 February 2015 Accepted 5 February 2015
cases of epiIMT,4 but not in our case. Second, expression of IgA and a hint of light chain restriction in our case pointed to a phenotype of lymphoma rather than sarcoma. Third, desmin and smooth muscle actin (SMA), which are commonly expressed in epiIMT, were both negative in our case.4 Finally, IGK gene rearrangement study confirmed a clonal B-cell proliferation and supported the diagnosis of ALK +LBCL. In recent years, various translocation partners of ALK in ALK+DLBL have been identified, including CLTC–ALK fusion (most common),5 NPM–ALK fusion6 and SQSTM1–ALK fusion,7 while RANBP2–ALK has been reported in both ALK+LBCL and epiIMT.4 8 Identification of the translocation partner in our case might shed light on the pathogenesis and possible relationship of ALK+LBCL and epiIMT, which share several morphological and immunophenotypical features.
J Clin Pathol 2015;0:1–4. doi:10.1136/jclinpath-2014-202847
J Clin Pathol Month 2015 Vol 0 No 0
In brief, we reported an unusual case of CD30-expressing ALK+LBCL accompanied by a prominent neutrophilic infiltrate but devoid of plasma cell differentiation, making the distinction from epiIMT challenging. A correct diagnosis was reached through detailed morphological examination, immunohistochemical and molecular studies. Shih-Yao Lin,1 Shih-Sung Chuang,2 Jie-Yang Jhuang,1 Kana Sakamoto,3 Kengo Takeuchi,3 Armita Bahrami,4 Chien-Chen Tsai1
REFERENCES 1
2
3
1
Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City, Taiwan Department of Pathology and Taipei Medical University, Chi-Mei Medical Centre, Tainan, Taiwan 3 Pathology Project for Molecular Targets of the Cancer Institute/Division of Pathology of the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 4 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 2
4
Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissue. 4th edn. Lyon: IARC Press, 2008:254–5. Beltran B, Castillo J, Salas R, et al. ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. J Hematol Oncol 2009;2:11. van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98–3936. Leukemia 2003;17:2257–317. Mariño-Enríquez A, Wang WL, Roy A, et al. Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol 2011;35:135–44.
3
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript 5
6
4
Gascoyne RD, Lamant L, Martin-Subero JI, et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 2003;102:2568–73. Onciu M, Behm FG, Downing JR, et al. ALK-positive plasmablastic B-cell lymphoma with expression of the
7
NPM-ALK fusion transcript: report of 2 cases. Blood 2003;102:2642–4. Takeuchi K, Soda M, Togashi Y, et al. Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma. Haematologica 2011;96:464–7.
8
Lee SE, Kang SY, Takeuchi K, et al. Identification of RANBP2–ALK fusion in ALK positive diffuse large B-cell lymphoma. Hematol Oncol 2014;32:221–4.
J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
ALK positive large B-cell lymphoma with a massive neutrophilic infiltrate: report of a case mimicking epithelioid inflammatory myofibroblastic tumour Shih-Yao Lin, Shih-Sung Chuang, Jie-Yang Jhuang, Kana Sakamoto, Kengo Takeuchi, Armita Bahrami and Chien-Chen Tsai J Clin Pathol published online February 26, 2015
Updated information and services can be found at: http://jcp.bmj.com/content/early/2015/02/26/jclinpath-2014-202847
These include:
References Email alerting service
This article cites 7 articles, 3 of which you can access for free at: http://jcp.bmj.com/content/early/2015/02/26/jclinpath-2014-202847 #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/
JCP Online First, published on February 26, 2015 as 10.1136/jclinpath-2014-202847 PostScript
CORRESPONDENCE
ALK positive large B-cell lymphoma with a massive neutrophilic infiltrate: report of a case mimicking epithelioid inflammatory myofibroblastic tumour Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (ALK+LBCL) is a rare, distinct and aggressive entity defined as a neoplasm of ALK-positive monomorphic large immunoblastic-like B cells.1 The tumour cells are considered to be derived from post-germinal centre B cells with plasmablastic differentiation and frequently show a cytoplasmic granular pattern of ALK.1 Nodal (most commonly to be cervical nodes) and extranodal presentation (including bone, head and neck, liver and spleen, gastrointestinal tract) have been reported.2 Here we reported a case of intestinal ALK+LBCL with systemic involvement mimicking the epithelioid variant of inflammatory myofibroblastic tumour (epiIMT).
A 46-year-old woman presented in March 2014 with repeated episodes of melaena for 1 month associated with general weakness, vomiting, body weight loss and pitting oedema of bilateral lower limbs. At the Emergency Department, ileus and anaemia (haemoglobin at 6.4 g/dL) were noted, and chest X-ray revealed a mass in the right lower lobe of lung. CT scans of chest and abdomen showed a 7 cm tumour in the right lower lobe of lung, a 3 cm nodule in the abdominal wall and a 12 cm polypoid tumour in the jejunum with adhesion to sigmoid colon (figure 1). She underwent resection of the tumours in the jejunum and abdominal wall. The upper jejunal tumour was located 40 cm distal to Treitz ligament with adhesion to the sigmoid colon. Grossly, the jejunal tumour was fungating, soft and necrotic, measuring 12 cm in size with ulceration. Five regional lymph nodes were dissected out and one was necrotic. Histological examination of the jejunal tumour revealed a diffuse transmural infiltration by neoplastic cells extending from the ulcerated mucosa to the serosa with extensive tumour necrosis. The tumour cells were admixed with a massive neutrophilic infiltration
(figure 2A). Under high power, the neoplastic cells were large and epithelioid with round and vesicular nuclei and a prominent central nucleolus (figure 2B). Some kidneyshaped or Reed–Sternberg-like giant cells were noted. One of the five regional lymph nodes showed tumour involvement by neoplastic cells. The abdominal wall tumour revealed a similar infiltration by anaplastic cells dissecting between the muscle bundles. Immunohistochemically, the neoplastic cells were diffusely positive for vimentin, IgA (figure 2C), myc (figure 2D) and ALK (a cytoplasmic granular staining pattern; figure 2E). The expression of epithelial membrane antigen (EMA), cytokeratin AE1/ AE3 and CD30 (figure 2F) were all focal. They were negative to most lymphoid markers (CD45, CD3, CD5, CD20, CD79a, PAX5, CD34, CD68, TIA-1) and plasma cell markers (CD138 and MUM-1). A proportion of cells were positive for κ light chain, while λ light chain staining was entirely negative (figure 2G, H), indicating a light chain restriction. In situ hybridisation for Epstein–Barr virus was negative. PCR-based clonality study was performed according to the BIOMED-2 protocols.3 The assay for IGH gene failed, but that for
Figure 1 CT scans of chest and abdomen, showing a 7 cm tumour with central necrosis in the right lower lobe of lung (A), a 3 cm nodule in the abdominal wall (B, arrow) and a 12 cm polypoid tumour in the jejunum with adhesion to sigmoid colon (C and D). J Clin Pathol Month 2015 Vol 0 No 0
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript
Figure 2 Histopathological examination at medium-power, showing diffuse sheets of large tumour cells admixed with numerous neutrophils (A). High-power view reveals large, epithelioid-to-round cells with anaplastic vesicular nuclei and prominent central nucleoli with neutrophils in the background (B). The tumour cells are diffusely positive for IgA (C), myc (D), with a cytoplasmic granular staining of anaplastic lymphoma kinase (ALK) (E), and show focal expression of CD30 (F). A proportion of tumour cells are positive for κ light chain, while λ light chain staining is entirely negative (G and H). IGK gene rearrangement revealed a clonal result (figure 3). Fluorescence in situ hybridisation with break apart probes showed translocation at the ALK locus at 2p23 (figure 4), but not at the BCL2, BCL6 or MYC loci. The final diagnosis was ALK +LBCL. She received one course of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy. 2
Unfortunately, her disease progressed rapidly and she passed away 3 months after diagnosis with respiratory failure. The final pleural effusion cytology before her death also confirmed lymphoma involvement. There was a significant overlap in the clinical presentation, morphology and immunohistochemistry between our case and epiIMT. Similar to our case, most of the epiIMT cases are intra-abdominal,
epithelioid in morphology and, in particular, frequently associated with a prominent neutrophilic infiltrate.4 Furthermore, CD30 and ALK are expressed in the neoplastic cells of epiIMT cases,4 which is also present in our case; in contrast, CD30 is usually negative in ALK+LBCLs.1 2 However, there were some clues in our case leading towards the diagnosis of lymphoma. First, a spindle cell component, even minor, is present in all J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript Figure 3 Clonal IGK gene rearrangement with PCR-based clonality study. Each peak represents clonal rearrangement of Vκ1f/6–Jκ or Vκ7–Jκ (tube A, upper), Vκ3–Kde or intron–Kde (tube B, lower left) and Vκ2f–Kde, Vκ4–Kde or Vκ5–Kde (tube B, lower right).
Correspondence to Dr Chien-Chen Tsai, Department of Anatomical Pathology, Far Eastern Memorial Hospital, No.21, Sec. 2, Nanya S. Rd., Banciao Dist., New Taipei City 220, Taiwan; a0970295250@gmail. com Contributors S-SC, KS, KT and AB: Performed the experiments and analysed the data. S-SC, J-YJ, KT, AB and C-CT: Examined the case and made the final diagnosis. S-YL, S-SC and C-CT: Wrote the manuscript. All authors approved the manuscript. Competing interests None. Ethics approval Research Ethics Review Committee of the Far Eastern Memorial Hospital, Taiwan. Provenance and peer review Not commissioned; internally peer reviewed. To cite Lin S-Y, Chuang S-S, Jhuang J-Y, et al. J Clin Pathol Published Online First: [please include Day Month Year] doi:10.1136/jclinpath-2014-202847
Figure 4 Fluorescent in situ hybridisation (FISH) that reveals anaplastic lymphoma kinase (ALK) translocation at the 2p23 locus using dual colour break apart rearrangement probe.
Received 30 December 2014 Revised 4 February 2015 Accepted 5 February 2015
cases of epiIMT,4 but not in our case. Second, expression of IgA and a hint of light chain restriction in our case pointed to a phenotype of lymphoma rather than sarcoma. Third, desmin and smooth muscle actin (SMA), which are commonly expressed in epiIMT, were both negative in our case.4 Finally, IGK gene rearrangement study confirmed a clonal B-cell proliferation and supported the diagnosis of ALK +LBCL. In recent years, various translocation partners of ALK in ALK+DLBL have been identified, including CLTC–ALK fusion (most common),5 NPM–ALK fusion6 and SQSTM1–ALK fusion,7 while RANBP2–ALK has been reported in both ALK+LBCL and epiIMT.4 8 Identification of the translocation partner in our case might shed light on the pathogenesis and possible relationship of ALK+LBCL and epiIMT, which share several morphological and immunophenotypical features.
J Clin Pathol 2015;0:1–4. doi:10.1136/jclinpath-2014-202847
J Clin Pathol Month 2015 Vol 0 No 0
In brief, we reported an unusual case of CD30-expressing ALK+LBCL accompanied by a prominent neutrophilic infiltrate but devoid of plasma cell differentiation, making the distinction from epiIMT challenging. A correct diagnosis was reached through detailed morphological examination, immunohistochemical and molecular studies. Shih-Yao Lin,1 Shih-Sung Chuang,2 Jie-Yang Jhuang,1 Kana Sakamoto,3 Kengo Takeuchi,3 Armita Bahrami,4 Chien-Chen Tsai1
REFERENCES 1
2
3
1
Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City, Taiwan Department of Pathology and Taipei Medical University, Chi-Mei Medical Centre, Tainan, Taiwan 3 Pathology Project for Molecular Targets of the Cancer Institute/Division of Pathology of the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 4 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA 2
4
Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissue. 4th edn. Lyon: IARC Press, 2008:254–5. Beltran B, Castillo J, Salas R, et al. ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. J Hematol Oncol 2009;2:11. van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98–3936. Leukemia 2003;17:2257–317. Mariño-Enríquez A, Wang WL, Roy A, et al. Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol 2011;35:135–44.
3
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
PostScript 5
6
4
Gascoyne RD, Lamant L, Martin-Subero JI, et al. ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 2003;102:2568–73. Onciu M, Behm FG, Downing JR, et al. ALK-positive plasmablastic B-cell lymphoma with expression of the
7
NPM-ALK fusion transcript: report of 2 cases. Blood 2003;102:2642–4. Takeuchi K, Soda M, Togashi Y, et al. Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma. Haematologica 2011;96:464–7.
8
Lee SE, Kang SY, Takeuchi K, et al. Identification of RANBP2–ALK fusion in ALK positive diffuse large B-cell lymphoma. Hematol Oncol 2014;32:221–4.
J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on April 26, 2015 - Published by group.bmj.com
ALK positive large B-cell lymphoma with a massive neutrophilic infiltrate: report of a case mimicking epithelioid inflammatory myofibroblastic tumour Shih-Yao Lin, Shih-Sung Chuang, Jie-Yang Jhuang, Kana Sakamoto, Kengo Takeuchi, Armita Bahrami and Chien-Chen Tsai J Clin Pathol published online February 26, 2015
Updated information and services can be found at: http://jcp.bmj.com/content/early/2015/02/26/jclinpath-2014-202847
These include:
References Email alerting service
This article cites 7 articles, 3 of which you can access for free at: http://jcp.bmj.com/content/early/2015/02/26/jclinpath-2014-202847 #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/
