Jpn J Clin Oncol 2014;44(9)868 – 871 doi:10.1093/jjco/hyu069 Advance Access Publication 15 July 2014
Case Reports
A Case Report of Epithelioid Inflammatory Myofibroblastic Sarcoma with RANBP2-ALK Fusion Gene Treated with the ALK Inhibitor, Crizotinib Shiro Kimbara1, Koji Takeda1, Hiroko Fukushima2, Toru Inoue3, Hideaki Okada1, Yumi Shibata1, Utae Katsushima1, Asuka Tsuya1, Shinya Tokunaga1, Haruko Daga1, Takahiro Okuno2 and Takeshi Inoue2 1
Department of Clinical Oncology, Osaka City General Hospital, Osaka, 2Department of Pathology, Osaka City General Hospital, Osaka and 3Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan
Received December 28, 2013; accepted April 29, 2014
Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor. Key words: epithelioid inflammatory myofibroblastic sarcoma – RANBP2-ALK – crizotinib
INTRODUCTION Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of intermediate biological potential. About 50% of cases of IMT harbor a variant anaplastic lymphoma kinase (ALK) gene or overexpress ALK protein (1, 2). Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a variant of IMT that can be distinguished from conventional IMT via study of its morphologic, immunohistochemical and genetic features (3, 4). Epithelioid morphology and a nuclear membrane or perinuclear pattern of immunostaining for ALK and RANBP2-ALK fusion are key findings of EIMS. EIMS carries poor prognosis and is associated with rapid development of local recurrence (3). Surgical resection has been the mainstay of treatment for IMT, and steroids, radiotherapy and
chemotherapy have limited success in unresectable cases (5). Recent studies suggest that the ALK inhibitor, crizotinib, is a promising treatment for ALK-positive IMT (6).
CASE In November 2012, a 22-year-old man with a history of pure germinoma in the pineal region that was treated with chemoradiotherapy at 20 years of age, presented with fever, fatigue and abdominal pain in the right lower quadrant. Physical examination showed localized abdominal tenderness without rebound tenderness. Laboratory studies showed elevated serum C-reactive protein (4.73 mg/dl, normal range ,0.30 mg/dl) and serum creatinine (1.13 mg/dl, normal range
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
*For reprints and all correspondence: Shiro Kimbara, 2-13-22 Miyakojima-hondori, Miyakojima-ku, Osaka 531-0021, Japan. E-mail: [email protected]
Jpn J Clin Oncol 2014;44(9)
2014, 10 months after initiation of crizotinib, disease control is still achieved (Fig. 2D), and the patient resumes a daily life without tumor burden.
DISCUSSION IMT is a rare mesenchymal neoplasm that occurs in children and adolescents. Its clinical course is relatively indolent, but it is sometimes associated with poor prognosis. In general, pathologic features, such as tumor size, mitotic activity and the presence of necrosis or nuclear atypia, do not seem to influence clinical outcome. On the other hand, a positive finding for ALK is associated with a high risk of local recurrence (7). The relationship between IMT and ALK was first described by Griffin et al. in 1999 (8). Cook et al. examined 73 cases of IMTs and detected ALK protein in 44 (60%) cases. There were several ALK fusion partner genes: TPM3/4, CLTC and RANBP2. Interestingly, ALK immunostaining patterns seemed to be determined by fusion partners. There were three ALK staining patterns: smooth cytoplasmic staining, granular cytoplasmic staining and distinctive nuclear membrane staining, and these patterns were associated with TPM3/4-ALK, CLTC-ALK and RANBP2-ALK, respectively (1). IMT with RANBP2-ALK arises commonly in intraabdominal. Although no consistent correlation between ALK partners and prognosis, RANBP2-ALK fusion may be associated with poor prognosis (3, 4, 9), as illustrated in the present case. RANBP2-ALK fusion may also predict the clinical course as well as the efficacy of the ALK inhibitor. Butrynski et al. described two IMT patients, one with RANBP2-ALK and another without ALK rearrangement, who were treated with crizotinib. The patient with RANBP-ALK, whose tumor was resistant to doxorubicin, ifosfamide and imatinib, achieved a durable response to crizotinib. On the other hand, ALK-negative patients did not respond, although both of these patients had an epithelioid tumor (6). Since Morris et al. first described NPM-ALK fusion in 1994, extensive studies had revealed that various tumors have genetic changes in ALK. For example, anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), renal medullary carcinoma and IMT have ALK fusion, neuroblastomas and anaplastic thyroid cancers have ALK mutations, and rhabdomyosarcoma has ALK amplification. However, whether ALK inhibitors have efficacy in all these tumors is not clear, because it is not clear whether these abnormal ALK are essential growth drivers in clinical cases (rather than just in cancer cell lines). Mano (10) discovered EML4-ALK fusion, and suggested that a significant response to targeted drug therapy was an indicator that the corresponding target was an essential growth driver. It was proposed that these tumors be collectively referred to as ‘ALKoma’, in which ALK genetic changes play essential roles in carcinogenesis. Several lines of evidence support this notion. For example, the striking efficacy of crizotinib in NSCLC with EML4-ALK fusion (11) indicates that EML4-ALK fusion is an essential growth driver. Recently, a Phase 1 consortium study revealed that crizotinib
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
0.36 – 1.06 mg/dl). All other blood counts and biochemical examination were within normal limits. Contrast-enhanced computed tomography (CT) revealed unevenly enhanced tumor in the pelvis, invading the distal ileum. There was slight accumulation ascites but no distant metastases. The lesion was suspected to be a submucosal tumor, such as gastrointestinal stromal tumor. Six days later, excision of distal ileum and appendix was performed. Intraoperative finding revealed peritoneal dissemination. The excised tumor was 55 60 mm. On microscopic examination, diffuse growth of predominant well-circumscribed polygonal tumor cells, with distinct nucleoli and eosinophilic cytoplasm was found (Fig. 1A). A minor spindle cell component was present. Various nuclear atypia and mitotic figures also were found. A mesenteric tumor infiltrated the adjacent small bowel wall. Background revealed infiltrating inflammatory cells (mainly neutrophils) along with necrosis. In immunohistochemical study, tumor cells were positive for desmin and smooth muscle actin and were negative for c-kit, myogenin, CD34 and S-100. Of note, tumor cells were positive for ALK immunostaining on the nuclear membrane (Fig. 1B). This ALK immunostaining pattern was characteristic of EIMS (3). As expected, reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed a RANBP2-ALK rearrangement (Fig. 1C). Therefore, this tumor was diagnosed as EIMS with RANBPALK fusion. The first surgery did not result in resolution of abdominal pain, and the patient subsequently experienced recurrent fever. In February 2013, a contrast-enhanced CT revealed two enhancing tumors in the pelvis that were supposed to arise from the peritoneal dissemination. In May 2013, a second tumor excision procedure was performed. Intraoperative examination revealed that each of the masses involved the distal ileum and sigmoid colon. Therefore, excision of the ileum together with the sigmoid colon was conducted. Follow-up CT at 1 month after the second surgery, revealed multiple masses in the pelvis. The patient required opioid therapy for pain control. The patient received doxorubicin at a dose of 70 mg/m2 from May 2013 as palliative chemotherapy. CT imaging performed after one cycle of therapy showed further growth of the metastatic and peritoneal lesions (Fig. 2A). In June 2013, treatment with crizotinib was started at a dose of 250 mg twice daily with the agreement of the patient. Surprisingly, he experienced marked relief in his severe pain over a 1-week period. He experienced fatigue, nausea, dizziness, overlapping shadows, ear ringing, dysgeusia and itching, all of which were not serious. At 3 weeks after starting crizotinib, Grade 3 elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed. Therapy was withheld for 1 week, resulting in resolution of hepatotoxicity. Therapy was resumed, and follow-up CT performed 1 month after starting crizotinib, showed obvious tumor shrinkage (Fig. 2B). Although delay and dose modification to 200 mg twice daily were needed due to hepatotoxicity, toxicities of crizotinib were tolerable. Crizotinib for 2 months achieved further response (Fig. 2C). In March
869
870
EIMS with RANBP2-ALK treated with crizotinib
Figure 2. Despite two surgical excision procedures and conventional chemotherapy with doxorubicin, recurrence rapidly occurred and progressed (A). Crizotinib for 1 month induced a good response (B), and for 2 months induced further tumor shrinkage (C). Crizotinib was keeping a disease control for 10 months (D).
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
Figure 1. Polygonal tumor cells are scattered against an inflammatory background. Tumor cells have distinct nucleoli and eosinophilic cytoplasm (hematoxylin and eosin stain) (A, B). Immunohistochemical stain for anaplastic lymphoma kinase (ALK) shows distinctive nuclear membrane staining pattern (C). Reverse transcriptase-polymerase chain reaction (RT-PCR) with RANBP2 and ALK primers resulted in 194, 171 and 139 bp band in tumor tissue. The primers used in RT-PCR were RANBP2-2644/F and ALK-4191/R, RANBP2-2644/F and ALK-4169/R and RANBP2-2669/F and ALK4162/R, respectively (D). Direct sequence revealed ALK in exon 20 translocation with RANBP2 in exon 18 (E).
Jpn J Clin Oncol 2014;44(9)
Acknowledgements We are grateful to Yoshinao Oda, MD, PhD, Hidetaka Yamamoto, MD, PhD and Kenichi Kohashi, MD, PhD, Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University for their important contributions to the pathological diagnosis.
Conflict of interest statement None declared.
References 1. Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364–71. 2. Coffin CM, Patel A, Perkins S, et al. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001;14:569– 76. 3. Marino-Enriquez 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. 4. Chen ST, Lee JC. An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features. Hum Pathol 2008;39:1854– 8. 5. Tothova Z, Wagner AJ. Anaplastic lymphoma kinase-directed therapy in inflammatory myofibroblastic tumors. Curr Opin Oncol 2012;24:409–13. 6. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727–33. 7. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 2007;31:509–20. 8. Griffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999;59:2776– 80. 9. Li J, Yin WH, Takeuchi K, et al. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review. Diagn Pathol 2013;8:147. 10. Mano H. ALKoma: a cancer subtype with a shared target. Cancer Discov 2012;2:495 –502. 11. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011 –9. 12. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013;14:472–80. 13. Gainor JF, Shaw AT. Emerging Paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013;31:3987 –96. 14. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70:10038–43. 15. Chen Z, Akbay E, Mikse O, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2014;20:1204– 11. 16. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1 – 2 study. Lancet Oncol 2013;14:590– 8.
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
had activity in pediatric patients with ALCL harboring NPM-ALK fusion (12), which suggests that NPM-ALK fusion is another promising target of ALK inhibitors. Finally, there have been two published cases of patients with IMT and RANBP-ALK fusion who experienced good response to crizotinib, suggesting that this fusion is an important component/ target in the carcinogenesis of this disease. Although crizotinib has a dramatic efficacy in ALKtranslocated cancers, acquired resistance seems to be unavoidable. In NSCLC, ALK-positive patients develop disease progression after receiving crizotinib for 8 – 10 months (13). Sasaki et al (14) reported IMT with RANBP2-ALK translocation acquired resistance to crizotinib. They revealed RANBP2ALK F1174L associated with acquired resistance. This secondary mutation causes an increase in ALK phosphorylation, cell growth and downstream signaling. The F1174L is also found in crizotinib resistant NSCLC model (15). Recently, several studies report second-generation ALK inhibitor and HSP90 inhibitor are effective to tumors with acquired resistant to crizotinib in preclinical models and Phase I – II study (14 – 16). In the future, these novel agents may be promising treatments to overcome acquired resistance to crizotinib in EIMS. In conclusion, the ALK inhibitor, crizotinib, should be utilized in the management of patients with EIMS with RANBP2-ALK fusion, and RANBP-ALK fusion likely plays the role of essential growth driver in this disease. Further investigations to overcome acquired resistance to crizotinib are needed in ALKoma.
871
Case Reports
A Case Report of Epithelioid Inflammatory Myofibroblastic Sarcoma with RANBP2-ALK Fusion Gene Treated with the ALK Inhibitor, Crizotinib Shiro Kimbara1, Koji Takeda1, Hiroko Fukushima2, Toru Inoue3, Hideaki Okada1, Yumi Shibata1, Utae Katsushima1, Asuka Tsuya1, Shinya Tokunaga1, Haruko Daga1, Takahiro Okuno2 and Takeshi Inoue2 1
Department of Clinical Oncology, Osaka City General Hospital, Osaka, 2Department of Pathology, Osaka City General Hospital, Osaka and 3Department of Gastroenterological Surgery, Osaka City General Hospital, Osaka, Japan
Received December 28, 2013; accepted April 29, 2014
Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor. Key words: epithelioid inflammatory myofibroblastic sarcoma – RANBP2-ALK – crizotinib
INTRODUCTION Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of intermediate biological potential. About 50% of cases of IMT harbor a variant anaplastic lymphoma kinase (ALK) gene or overexpress ALK protein (1, 2). Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a variant of IMT that can be distinguished from conventional IMT via study of its morphologic, immunohistochemical and genetic features (3, 4). Epithelioid morphology and a nuclear membrane or perinuclear pattern of immunostaining for ALK and RANBP2-ALK fusion are key findings of EIMS. EIMS carries poor prognosis and is associated with rapid development of local recurrence (3). Surgical resection has been the mainstay of treatment for IMT, and steroids, radiotherapy and
chemotherapy have limited success in unresectable cases (5). Recent studies suggest that the ALK inhibitor, crizotinib, is a promising treatment for ALK-positive IMT (6).
CASE In November 2012, a 22-year-old man with a history of pure germinoma in the pineal region that was treated with chemoradiotherapy at 20 years of age, presented with fever, fatigue and abdominal pain in the right lower quadrant. Physical examination showed localized abdominal tenderness without rebound tenderness. Laboratory studies showed elevated serum C-reactive protein (4.73 mg/dl, normal range ,0.30 mg/dl) and serum creatinine (1.13 mg/dl, normal range
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
*For reprints and all correspondence: Shiro Kimbara, 2-13-22 Miyakojima-hondori, Miyakojima-ku, Osaka 531-0021, Japan. E-mail: [email protected]
Jpn J Clin Oncol 2014;44(9)
2014, 10 months after initiation of crizotinib, disease control is still achieved (Fig. 2D), and the patient resumes a daily life without tumor burden.
DISCUSSION IMT is a rare mesenchymal neoplasm that occurs in children and adolescents. Its clinical course is relatively indolent, but it is sometimes associated with poor prognosis. In general, pathologic features, such as tumor size, mitotic activity and the presence of necrosis or nuclear atypia, do not seem to influence clinical outcome. On the other hand, a positive finding for ALK is associated with a high risk of local recurrence (7). The relationship between IMT and ALK was first described by Griffin et al. in 1999 (8). Cook et al. examined 73 cases of IMTs and detected ALK protein in 44 (60%) cases. There were several ALK fusion partner genes: TPM3/4, CLTC and RANBP2. Interestingly, ALK immunostaining patterns seemed to be determined by fusion partners. There were three ALK staining patterns: smooth cytoplasmic staining, granular cytoplasmic staining and distinctive nuclear membrane staining, and these patterns were associated with TPM3/4-ALK, CLTC-ALK and RANBP2-ALK, respectively (1). IMT with RANBP2-ALK arises commonly in intraabdominal. Although no consistent correlation between ALK partners and prognosis, RANBP2-ALK fusion may be associated with poor prognosis (3, 4, 9), as illustrated in the present case. RANBP2-ALK fusion may also predict the clinical course as well as the efficacy of the ALK inhibitor. Butrynski et al. described two IMT patients, one with RANBP2-ALK and another without ALK rearrangement, who were treated with crizotinib. The patient with RANBP-ALK, whose tumor was resistant to doxorubicin, ifosfamide and imatinib, achieved a durable response to crizotinib. On the other hand, ALK-negative patients did not respond, although both of these patients had an epithelioid tumor (6). Since Morris et al. first described NPM-ALK fusion in 1994, extensive studies had revealed that various tumors have genetic changes in ALK. For example, anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), renal medullary carcinoma and IMT have ALK fusion, neuroblastomas and anaplastic thyroid cancers have ALK mutations, and rhabdomyosarcoma has ALK amplification. However, whether ALK inhibitors have efficacy in all these tumors is not clear, because it is not clear whether these abnormal ALK are essential growth drivers in clinical cases (rather than just in cancer cell lines). Mano (10) discovered EML4-ALK fusion, and suggested that a significant response to targeted drug therapy was an indicator that the corresponding target was an essential growth driver. It was proposed that these tumors be collectively referred to as ‘ALKoma’, in which ALK genetic changes play essential roles in carcinogenesis. Several lines of evidence support this notion. For example, the striking efficacy of crizotinib in NSCLC with EML4-ALK fusion (11) indicates that EML4-ALK fusion is an essential growth driver. Recently, a Phase 1 consortium study revealed that crizotinib
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
0.36 – 1.06 mg/dl). All other blood counts and biochemical examination were within normal limits. Contrast-enhanced computed tomography (CT) revealed unevenly enhanced tumor in the pelvis, invading the distal ileum. There was slight accumulation ascites but no distant metastases. The lesion was suspected to be a submucosal tumor, such as gastrointestinal stromal tumor. Six days later, excision of distal ileum and appendix was performed. Intraoperative finding revealed peritoneal dissemination. The excised tumor was 55 60 mm. On microscopic examination, diffuse growth of predominant well-circumscribed polygonal tumor cells, with distinct nucleoli and eosinophilic cytoplasm was found (Fig. 1A). A minor spindle cell component was present. Various nuclear atypia and mitotic figures also were found. A mesenteric tumor infiltrated the adjacent small bowel wall. Background revealed infiltrating inflammatory cells (mainly neutrophils) along with necrosis. In immunohistochemical study, tumor cells were positive for desmin and smooth muscle actin and were negative for c-kit, myogenin, CD34 and S-100. Of note, tumor cells were positive for ALK immunostaining on the nuclear membrane (Fig. 1B). This ALK immunostaining pattern was characteristic of EIMS (3). As expected, reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed a RANBP2-ALK rearrangement (Fig. 1C). Therefore, this tumor was diagnosed as EIMS with RANBPALK fusion. The first surgery did not result in resolution of abdominal pain, and the patient subsequently experienced recurrent fever. In February 2013, a contrast-enhanced CT revealed two enhancing tumors in the pelvis that were supposed to arise from the peritoneal dissemination. In May 2013, a second tumor excision procedure was performed. Intraoperative examination revealed that each of the masses involved the distal ileum and sigmoid colon. Therefore, excision of the ileum together with the sigmoid colon was conducted. Follow-up CT at 1 month after the second surgery, revealed multiple masses in the pelvis. The patient required opioid therapy for pain control. The patient received doxorubicin at a dose of 70 mg/m2 from May 2013 as palliative chemotherapy. CT imaging performed after one cycle of therapy showed further growth of the metastatic and peritoneal lesions (Fig. 2A). In June 2013, treatment with crizotinib was started at a dose of 250 mg twice daily with the agreement of the patient. Surprisingly, he experienced marked relief in his severe pain over a 1-week period. He experienced fatigue, nausea, dizziness, overlapping shadows, ear ringing, dysgeusia and itching, all of which were not serious. At 3 weeks after starting crizotinib, Grade 3 elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed. Therapy was withheld for 1 week, resulting in resolution of hepatotoxicity. Therapy was resumed, and follow-up CT performed 1 month after starting crizotinib, showed obvious tumor shrinkage (Fig. 2B). Although delay and dose modification to 200 mg twice daily were needed due to hepatotoxicity, toxicities of crizotinib were tolerable. Crizotinib for 2 months achieved further response (Fig. 2C). In March
869
870
EIMS with RANBP2-ALK treated with crizotinib
Figure 2. Despite two surgical excision procedures and conventional chemotherapy with doxorubicin, recurrence rapidly occurred and progressed (A). Crizotinib for 1 month induced a good response (B), and for 2 months induced further tumor shrinkage (C). Crizotinib was keeping a disease control for 10 months (D).
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
Figure 1. Polygonal tumor cells are scattered against an inflammatory background. Tumor cells have distinct nucleoli and eosinophilic cytoplasm (hematoxylin and eosin stain) (A, B). Immunohistochemical stain for anaplastic lymphoma kinase (ALK) shows distinctive nuclear membrane staining pattern (C). Reverse transcriptase-polymerase chain reaction (RT-PCR) with RANBP2 and ALK primers resulted in 194, 171 and 139 bp band in tumor tissue. The primers used in RT-PCR were RANBP2-2644/F and ALK-4191/R, RANBP2-2644/F and ALK-4169/R and RANBP2-2669/F and ALK4162/R, respectively (D). Direct sequence revealed ALK in exon 20 translocation with RANBP2 in exon 18 (E).
Jpn J Clin Oncol 2014;44(9)
Acknowledgements We are grateful to Yoshinao Oda, MD, PhD, Hidetaka Yamamoto, MD, PhD and Kenichi Kohashi, MD, PhD, Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University for their important contributions to the pathological diagnosis.
Conflict of interest statement None declared.
References 1. Cook JR, Dehner LP, Collins MH, et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol 2001;25:1364–71. 2. Coffin CM, Patel A, Perkins S, et al. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 2001;14:569– 76. 3. Marino-Enriquez 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. 4. Chen ST, Lee JC. An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features. Hum Pathol 2008;39:1854– 8. 5. Tothova Z, Wagner AJ. Anaplastic lymphoma kinase-directed therapy in inflammatory myofibroblastic tumors. Curr Opin Oncol 2012;24:409–13. 6. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727–33. 7. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 2007;31:509–20. 8. Griffin CA, Hawkins AL, Dvorak C, et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999;59:2776– 80. 9. Li J, Yin WH, Takeuchi K, et al. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review. Diagn Pathol 2013;8:147. 10. Mano H. ALKoma: a cancer subtype with a shared target. Cancer Discov 2012;2:495 –502. 11. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011 –9. 12. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013;14:472–80. 13. Gainor JF, Shaw AT. Emerging Paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013;31:3987 –96. 14. Sasaki T, Okuda K, Zheng W, et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70:10038–43. 15. Chen Z, Akbay E, Mikse O, et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 2014;20:1204– 11. 16. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1 – 2 study. Lancet Oncol 2013;14:590– 8.
Downloaded from http://jjco.oxfordjournals.org/ by guest on March 8, 2015
had activity in pediatric patients with ALCL harboring NPM-ALK fusion (12), which suggests that NPM-ALK fusion is another promising target of ALK inhibitors. Finally, there have been two published cases of patients with IMT and RANBP-ALK fusion who experienced good response to crizotinib, suggesting that this fusion is an important component/ target in the carcinogenesis of this disease. Although crizotinib has a dramatic efficacy in ALKtranslocated cancers, acquired resistance seems to be unavoidable. In NSCLC, ALK-positive patients develop disease progression after receiving crizotinib for 8 – 10 months (13). Sasaki et al (14) reported IMT with RANBP2-ALK translocation acquired resistance to crizotinib. They revealed RANBP2ALK F1174L associated with acquired resistance. This secondary mutation causes an increase in ALK phosphorylation, cell growth and downstream signaling. The F1174L is also found in crizotinib resistant NSCLC model (15). Recently, several studies report second-generation ALK inhibitor and HSP90 inhibitor are effective to tumors with acquired resistant to crizotinib in preclinical models and Phase I – II study (14 – 16). In the future, these novel agents may be promising treatments to overcome acquired resistance to crizotinib in EIMS. In conclusion, the ALK inhibitor, crizotinib, should be utilized in the management of patients with EIMS with RANBP2-ALK fusion, and RANBP-ALK fusion likely plays the role of essential growth driver in this disease. Further investigations to overcome acquired resistance to crizotinib are needed in ALKoma.
871
