A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene

L.A. Muscarella, G. Rossi, D. Trombetta, A. La Torre, L. Candia, Maria Cecilia Mengoli, A. Sparaneo, V.M. Fazio, P. Graziano

Research output: Contribution to journalArticle

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Abstract

Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. © 2017, Spandidos Publications. All rights reserved.
Original languageEnglish
Pages (from-to)593-598
Number of pages6
JournalOncology Letters
Volume13
Issue number2
DOIs
Publication statusPublished - 2017

Fingerprint

Hypopharynx
Gene Fusion
Neoplasms
Neck
Head
anaplastic lymphoma kinase
MAP4
Fluorescence In Situ Hybridization
Publications
Genes

Keywords

  • Anaplastic lymphoma kinase
  • Echinoderm microtubule associated protein like 4
  • Fusion variants
  • Inflammatory myofibroblastic tumor
  • Molecular markers

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A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene. / Muscarella, L.A.; Rossi, G.; Trombetta, D.; La Torre, A.; Candia, L.; Mengoli, Maria Cecilia; Sparaneo, A.; Fazio, V.M.; Graziano, P.

In: Oncology Letters, Vol. 13, No. 2, 2017, p. 593-598.

Research output: Contribution to journalArticle

@article{3034781b07b7403c86ccf5748ad688c3,
title = "A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene",
abstract = "Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50{\%} of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20{\%} of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. {\circledC} 2017, Spandidos Publications. All rights reserved.",
keywords = "Anaplastic lymphoma kinase, Echinoderm microtubule associated protein like 4, Fusion variants, Inflammatory myofibroblastic tumor, Molecular markers",
author = "L.A. Muscarella and G. Rossi and D. Trombetta and {La Torre}, A. and L. Candia and Mengoli, {Maria Cecilia} and A. Sparaneo and V.M. Fazio and P. Graziano",
note = "Export Date: 22 March 2017 Correspondence Address: Muscarella, L.A.; Laboratory of Oncology, Scientific Institute for Research and Healthcare, Casa Sollievo della Sofferenza, Viale Padre Pio, Italy; email: l.muscarella@operapadrepio.it References: Surabhi, V.R., Chua, S., Patel, R.P., Takahashi, N., Lalwani, N., Prasad, S.R., Inflammatory myofibroblastic tumors: Current update (2016) Radiol Clin North Am, 54, pp. 553-563; Griffin, C.A., Hawkins, A.L., Dvorak, C., Henkle, C., Ellingham, T., Perlman, E.J., Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors (1999) Cancer Res, 59, pp. 2776-2780; Lawrence, B., Perez-Atayde, A., Hibbard, M.K., Rubin, B.P., Dal Cin, P., Pinkus, J.L., Pinkus, G.S., Fletcher, J.A., TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors (2000) Am J Pathol, 157, pp. 377-384; Coffin, C.M., Patel, A., Perkins, S., Elenitoba-Johnson, K.S., Perlman, E., Griffin, C.A., ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor (2001) Mod Pathol, 14, pp. 569-576; Antonescu, C.R., Suurmeijer, A.J., Zhang, L., Sung, Y.S., Jungbluth, A.A., Travis, W.D., Al-Ahmadie, H., Alaggio, R., Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 fusions and rare novel RET rearrangement (2015) Am J Surg Pathol, 39, pp. 957-967; Butrynski, J.E., D'adamo, D.R., Hornick, J.L., Dal Cin, P., Antonescu, C.R., Jhanwar, S.C., Ladanyi, M., Ramaiya, N., Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor (2010) N Engl J Med, 363, pp. 1727-1733; Mano, H., ALKoma: A cancer subtype with a shared target (2012) Cancer Discov, 2, pp. 495-502; Sanders, H., Li, H., Bruey, J.M., Scheerle, J.A., Meloni-Ehrig, A.M., Kelly, J.C., Novick, C., Albitar, M., Exon scanning by reverse transcriptase polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer (2011) Cancer Genet, 204, pp. 45-52; Fletcher, C., Bridge, J.A., Hogendoorn, P.C., (2013) WHO Classification of Tumours of Soft Tissue and Bone, , IARC, Lyon; Graefe, H., Stellmacher, F., Sotlar, K., Wollenberg, B., Gehrking, E., Inflammatory pseudotumor of the hypopharynx: Clinical diagnosis, immunohistochemical findings and treatment of this rare disease (2008) Vivo, 22, pp. 817-820; Nakayama, K., Inoue, Y., Aiba, T., Kono, K., Wakasa, K., Yamada, R., Unusual CT and MR findings of inflammatory pseudotumor in the parapharyngeal space: Case report (2001) AJNR am J Neuroradiol, 22, pp. 1394-1397; Lovly, C.M., Gupta, A., Lipson, D., Otto, G., Brennan, T., Chung, C.T., Borinstein, S.C., Coffin, C.M., Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions (2014) Cancer Discov, 4, pp. 889-895; Cook, J.R., Dehner, L.P., Collins, M.H., Ma, Z., Morris, S.W., Coffin, C.M., Hill, D.A., Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: A comparative immunohistochemical study (2001) Am J Surg Pathol, 25, pp. 1364-1371; Ni, C., Xu, Y.Y., Zhou, S.H., Wang, S.Q., Differential diagnosis of inflammatory myofibroblastic tumour and low-grade myofibroblastic sarcoma: Two case reports with a literature review (2011) J Intern Med Res, 39, pp. 311-320; Soda, M., Choi, Y.L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Hatanaka, H., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer (2007) Nature, 448, pp. 561-566; Bridge, J.A., Kanamori, M., Ma, Z., Pickering, D., Hill, D.A., Lydiatt, W., Lui, M.Y., Morris, S.W., Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor (2001) Am J Pathol, 159, pp. 411-415; Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Marynen, P., Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor (2002) Genes Chromosomes Cancer, 34, pp. 354-362; Ma, Z., Hill, D.A., Collins, M.H., Morris, S.W., Sumegi, J., Zhou, M., Zuppan, C., Bridge, J.A., Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor (2003) Genes Chromosomes Cancer, 37, pp. 98-1053; Debiec-Rychter, M., Marynen, P., Hagemeijer, A., Pauwels, P., ALK-ATIC fusion in urinary bladder inflammatory myofibroblastic tumor (2003) Genes Chromosomes Cancer, 38, pp. 187-190; Panagopoulos, I., Nilsson, T., Domanski, H.A., Isaksson, M., Lindblom, P., Mertens, F., Mandahl, N., Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor (2006) Int J Cancer, 118, pp. 1161-1181; Takeuchi, K., Soda, M., Togashi, Y., Sugawara, E., Hatano, S., Asaka, R., Okumura, S., Ishikawa, Y., Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: Reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification (2011) Clin Cancer Res, 17, pp. 3341-3381; Wang, X., Krishnan, C., Nguyen, E.P., Meyer, K.J., Oliveira, J.L., Yang, P., Yi, E.S., Oliveira, A.M., Fusion of dynactin 1 to anaplastic lymphoma kinase in inflammatory myofibroblastic tumor (2012) Hum Pathol, 43, pp. 2047-2052; Mari{\~n}o-Enr{\'i}quez, A., Wang, W.L., Roy, A., Lopez-Terrada, D., Lazar, A.J., Fletcher, C.D., Coffin, C.M., Hornick, J.L., Inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK (2011) Am J Surg Pathol, 35, pp. 135-144",
year = "2017",
doi = "10.3892/ol.2016.5504",
language = "English",
volume = "13",
pages = "593--598",
journal = "Oncology Letters",
issn = "1792-1074",
publisher = "Spandidos Publications",
number = "2",

}

TY - JOUR

T1 - A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene

AU - Muscarella, L.A.

AU - Rossi, G.

AU - Trombetta, D.

AU - La Torre, A.

AU - Candia, L.

AU - Mengoli, Maria Cecilia

AU - Sparaneo, A.

AU - Fazio, V.M.

AU - Graziano, P.

N1 - Export Date: 22 March 2017 Correspondence Address: Muscarella, L.A.; Laboratory of Oncology, Scientific Institute for Research and Healthcare, Casa Sollievo della Sofferenza, Viale Padre Pio, Italy; email: l.muscarella@operapadrepio.it References: Surabhi, V.R., Chua, S., Patel, R.P., Takahashi, N., Lalwani, N., Prasad, S.R., Inflammatory myofibroblastic tumors: Current update (2016) Radiol Clin North Am, 54, pp. 553-563; Griffin, C.A., Hawkins, A.L., Dvorak, C., Henkle, C., Ellingham, T., Perlman, E.J., Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors (1999) Cancer Res, 59, pp. 2776-2780; Lawrence, B., Perez-Atayde, A., Hibbard, M.K., Rubin, B.P., Dal Cin, P., Pinkus, J.L., Pinkus, G.S., Fletcher, J.A., TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors (2000) Am J Pathol, 157, pp. 377-384; Coffin, C.M., Patel, A., Perkins, S., Elenitoba-Johnson, K.S., Perlman, E., Griffin, C.A., ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor (2001) Mod Pathol, 14, pp. 569-576; Antonescu, C.R., Suurmeijer, A.J., Zhang, L., Sung, Y.S., Jungbluth, A.A., Travis, W.D., Al-Ahmadie, H., Alaggio, R., Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 fusions and rare novel RET rearrangement (2015) Am J Surg Pathol, 39, pp. 957-967; Butrynski, J.E., D'adamo, D.R., Hornick, J.L., Dal Cin, P., Antonescu, C.R., Jhanwar, S.C., Ladanyi, M., Ramaiya, N., Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor (2010) N Engl J Med, 363, pp. 1727-1733; Mano, H., ALKoma: A cancer subtype with a shared target (2012) Cancer Discov, 2, pp. 495-502; Sanders, H., Li, H., Bruey, J.M., Scheerle, J.A., Meloni-Ehrig, A.M., Kelly, J.C., Novick, C., Albitar, M., Exon scanning by reverse transcriptase polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer (2011) Cancer Genet, 204, pp. 45-52; Fletcher, C., Bridge, J.A., Hogendoorn, P.C., (2013) WHO Classification of Tumours of Soft Tissue and Bone, , IARC, Lyon; Graefe, H., Stellmacher, F., Sotlar, K., Wollenberg, B., Gehrking, E., Inflammatory pseudotumor of the hypopharynx: Clinical diagnosis, immunohistochemical findings and treatment of this rare disease (2008) Vivo, 22, pp. 817-820; Nakayama, K., Inoue, Y., Aiba, T., Kono, K., Wakasa, K., Yamada, R., Unusual CT and MR findings of inflammatory pseudotumor in the parapharyngeal space: Case report (2001) AJNR am J Neuroradiol, 22, pp. 1394-1397; Lovly, C.M., Gupta, A., Lipson, D., Otto, G., Brennan, T., Chung, C.T., Borinstein, S.C., Coffin, C.M., Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions (2014) Cancer Discov, 4, pp. 889-895; Cook, J.R., Dehner, L.P., Collins, M.H., Ma, Z., Morris, S.W., Coffin, C.M., Hill, D.A., Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: A comparative immunohistochemical study (2001) Am J Surg Pathol, 25, pp. 1364-1371; Ni, C., Xu, Y.Y., Zhou, S.H., Wang, S.Q., Differential diagnosis of inflammatory myofibroblastic tumour and low-grade myofibroblastic sarcoma: Two case reports with a literature review (2011) J Intern Med Res, 39, pp. 311-320; Soda, M., Choi, Y.L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S., Hatanaka, H., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer (2007) Nature, 448, pp. 561-566; Bridge, J.A., Kanamori, M., Ma, Z., Pickering, D., Hill, D.A., Lydiatt, W., Lui, M.Y., Morris, S.W., Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor (2001) Am J Pathol, 159, pp. 411-415; Cools, J., Wlodarska, I., Somers, R., Mentens, N., Pedeutour, F., Maes, B., De Wolf-Peeters, C., Marynen, P., Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor (2002) Genes Chromosomes Cancer, 34, pp. 354-362; Ma, Z., Hill, D.A., Collins, M.H., Morris, S.W., Sumegi, J., Zhou, M., Zuppan, C., Bridge, J.A., Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor (2003) Genes Chromosomes Cancer, 37, pp. 98-1053; Debiec-Rychter, M., Marynen, P., Hagemeijer, A., Pauwels, P., ALK-ATIC fusion in urinary bladder inflammatory myofibroblastic tumor (2003) Genes Chromosomes Cancer, 38, pp. 187-190; Panagopoulos, I., Nilsson, T., Domanski, H.A., Isaksson, M., Lindblom, P., Mertens, F., Mandahl, N., Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor (2006) Int J Cancer, 118, pp. 1161-1181; Takeuchi, K., Soda, M., Togashi, Y., Sugawara, E., Hatano, S., Asaka, R., Okumura, S., Ishikawa, Y., Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: Reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification (2011) Clin Cancer Res, 17, pp. 3341-3381; Wang, X., Krishnan, C., Nguyen, E.P., Meyer, K.J., Oliveira, J.L., Yang, P., Yi, E.S., Oliveira, A.M., Fusion of dynactin 1 to anaplastic lymphoma kinase in inflammatory myofibroblastic tumor (2012) Hum Pathol, 43, pp. 2047-2052; Mariño-Enríquez, A., Wang, W.L., Roy, A., Lopez-Terrada, D., Lazar, A.J., Fletcher, C.D., Coffin, C.M., Hornick, J.L., Inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK (2011) Am J Surg Pathol, 35, pp. 135-144

PY - 2017

Y1 - 2017

N2 - Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. © 2017, Spandidos Publications. All rights reserved.

AB - Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. © 2017, Spandidos Publications. All rights reserved.

KW - Anaplastic lymphoma kinase

KW - Echinoderm microtubule associated protein like 4

KW - Fusion variants

KW - Inflammatory myofibroblastic tumor

KW - Molecular markers

U2 - 10.3892/ol.2016.5504

DO - 10.3892/ol.2016.5504

M3 - Article

VL - 13

SP - 593

EP - 598

JO - Oncology Letters

JF - Oncology Letters

SN - 1792-1074

IS - 2

ER -