BRST5:Inflammatory myofibroblastic tumour

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Primary Author(s)*

Yajuan Liu, PhD, University of Washington

Cancer Category / Type

Mesenchymal tumours of the breast

Cancer Sub-Classification / Subtype

Fibroblastic and myofibroblastic tumors

Definition / Description of Disease

Inflammatory Myofibroblastic Tumor (IMT) of the breast originate from mesenchymal tissue and is composed of both myofibroblastic and fibroblastic spindle cells and is accompanied by an inflammatory infiltrate, which may include plasma cells, lymphocytes, and/or eosinophils. It has intermediate biological potential (low-grade malignant) and rarely metastasizes.  

Essential and desirable diagnostic criteria include loose fascicles of plump spindle cells without substantial atypia or pleomorphism; inflammatory infiltrate of lymphocytes and plasma cells; consistent SMA expression; frequent ALK expression; ALK or other gene rearrangements in some cases.

Synonyms / Terminology

Related terminology: inflammatory pseudotumour (historical, not recommended), inflammatory fibrosarcoma (historical, not recommended); plasma cell granuloma (historical, not recommended)

Epidemiology / Prevalence

Breast IMTs most often affect young to middle-aged females, although the age range is broad.[1][2]

Clinical Features

Signs and Symptoms Breast IMT usually presents as a painless, circumscribed mass.
Laboratory Findings

Sites of Involvement

Breast IMT is rare and fewer than 25 reported cases.[3][4][5][6] IMT shows a wide anatomical distribution, most frequently arising in the respiratory tract, abdominal cavity, and retroperitoneum, followed by the lung, mediastinum, head and neck, gastrointestinal tract, and genitourinary tract (including the bladder and uterus).[1][7][8][9] Unusual locations include somatic soft tissues, pancreas, liver, and CNS.[1][7][10]

Morphologic Features

Most tumors are < 5 cm in size, with white to grey and sometimes yellow cut surfaces.

Loose fascicles of uniform, plump spindle cells with vesicular chromatin, small nucleoli, and pale eosinophilic to amphophilic cytoplasm are typically observed. [1] The stroma may be myxoid or collagenous, usually containing an inflammatory infiltrate dominated by lymphocytes and plasma cells, with fewer eosinophils and neutrophils. Some tumours exhibit a compact, fascicular architecture with minimal stroma. A subset of tumour cells may resemble ganglion cells. Mitotic activity is low and necrosis is usually absent.

Immunophenotype

Essential and desirable diagnostic criteria include loose fascicles of plump spindle cells without substantial atypia or pleomorphism; inflammatory infiltrate of lymphocytes and plasma cells; consistent SMA expression; frequent ALK expression.

Finding Marker
Positive (universal) SMA
Positive (subset) desmin, ALK (~60%),[11][12] ROS1 (~5%)[13] [14]
Negative (universal) keratin
Negative (subset) CD34, S100, SOX10, and EMA

Chromosomal Rearrangements (Gene Fusions)

Confirmation of ALK or other gene rearrangements supports the diagnosis. However, molecular confirmation is not required if ALK immunohistochemistry is definitively positive.[15] Of note, exceptional situations such as inversion of ALK on the same chromosome arm may lead to a false-negative FISH result. [16], and other molecular testing such as RNA-Seq can be used to detect ALK fusions efficiently. In ALK-negative cases, immunohistochemistry for ROS1 and/or molecular tests for non-ALK gene fusions (e.g. NTRK3) may be useful.[17][18][19][14]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(2;var)(p23;var) 5'var::3'ALK

(various 5’partner genes include TPM3, TPM4, CLTC, CARS, ATIC, SEC31L1, PPFIBP1, DCTN1, EML4, PRKAR1A, LMNA, TFG, FN1, HNRNPA1, etc)

der(var) 50-60%[20][21][22][23][24][25][26][27][18] Yes Yes (ALK-negative IMTs may have a higher likelihood of metastasis) Yes IMT with ALK genomic rearrangement features activation and overexpression of the ALK C-terminal kinase region, which is restricted to the neoplastic myofibroblastic component [20][15][11]
t(3;6)(q12.2;q22.1), t(6;17)(q22.1;p13.3) TFG::ROS1, YWHAE::ROS1 der(var) 5-10%[18][13][19][14][17] Yes No Yes
t(12;15)(p13.2;q25.3) ETV6::NTRK3 der(15) >5%[18][14] Yes No Yes Therapy options for NTRK fusions include larotrectinib and entrectinib (clinically approved)
t(5;12)(q32;q13.3) NAB2::PDGFRB der(5) >1%[18] Unknown No Yes
rea(10q11.21) rea(RET) der(10) >1%[14] Unknown No Yes Detected by FISH break-apart probe

Individual Region Genomic Gain / Loss / LOH

NA

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
NA NA
NA NA .

Characteristic Chromosomal Patterns

NA

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
NA

Gene Mutations (SNV / INDEL)

NA

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
NA

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

NA

Genes and Main Pathways Involved

IMTs are genetically heterogeneous. About two thirds of inflammatory myofibroblastic tumours harbour receptor tyrosine kinase gene rearrangements, most often involving the ALK locus at 2p23, with diverse fusion partners. [28] Approximately 5% of inflammatory myofibroblastic tumours harbour ROS1 gene fusions; other rare gene fusions involve NTRK3, PDGFRB, and RET. [18][14][17][19][12]

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
ALK fusion; activating rearrangement Kinase fusions, receptor tyrosine kinase/growth factor signaling uncontrolled cell proliferation and survival
ROS1 fusion; activating rearrangement Kinase fusions, receptor tyrosine kinase/growth factor signaling cell growth and differentiation
NTRK3 fusion; activating rearrangement Kinase fusions, receptor tyrosine kinase/growth factor signaling cell differentiation
PDGFRB fusion; activating rearrangement Kinase fusions, receptor tyrosine kinase/growth factor signaling cell growth
RET fusion; activating rearrangement Kinase fusions, receptor tyrosine kinase/growth factor signaling cell growth

Genetic Diagnostic Testing Methods

FISH, RT-PCR, RNA-seq

Familial Forms


Additional Information


Links


References

  1. ↑ 1.0 1.1 1.2 1.3 Coffin, C. M.; et al. (1995-08). "Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases". The American Journal of Surgical Pathology. 19 (8): 859–872. doi:10.1097/00000478-199508000-00001. ISSN 0147-5185. PMID 7611533. Check date values in: |date= (help)
  2. ↑ Makhlouf, Hala R.; et al. (2002-03). "Inflammatory myofibroblastic tumors (inflammatory pseudotumors) of the gastrointestinal tract: how closely are they related to inflammatory fibroid polyps?". Human Pathology. 33 (3): 307–315. doi:10.1053/hupa.2002.32213. ISSN 0046-8177. PMID 11979371. Check date values in: |date= (help)
  3. ↑ Khanafshar, Elham; et al. (2005-06). "Inflammatory myofibroblastic tumor of the breast". Annals of Diagnostic Pathology. 9 (3): 123–129. doi:10.1016/j.anndiagpath.2005.02.001. ISSN 1092-9134. PMID 15944952. Check date values in: |date= (help)
  4. ↑ Haj, Mahmoud; et al. (2003). "Inflammatory pseudotumor of the breast: case report and literature review". The Breast Journal. 9 (5): 423–425. doi:10.1046/j.1524-4741.2003.09516.x. ISSN 1075-122X. PMID 12968967.
  5. ↑ Zhao, Hua-Dong; et al. (2013-01). "Primary inflammatory myofibroblastic tumor of the breast with rapid recurrence and metastasis: A case report". Oncology Letters. 5 (1): 97–100. doi:10.3892/ol.2012.948. ISSN 1792-1074. PMC 3525499. PMID 23255901. Check date values in: |date= (help)
  6. ↑ Kovács, Anikó; et al. (2015). "ALK-Positive Inflammatory Myofibroblastic Tumor of the Nipple During Pregnancy-An Unusual Presentation of a Rare Disease". The Breast Journal. 21 (3): 297–302. doi:10.1111/tbj.12404. ISSN 1524-4741. PMID 25772857.
  7. ↑ 7.0 7.1 Gleason, B. C.; et al. (2008-04). "Inflammatory myofibroblastic tumours: where are we now?". Journal of Clinical Pathology. 61 (4): 428–437. doi:10.1136/jcp.2007.049387. ISSN 1472-4146. PMID 17938159. Check date values in: |date= (help)
  8. ↑ Karnak, I.; et al. (2001-06). "Inflammatory myofibroblastic tumor in children: diagnosis and treatment". Journal of Pediatric Surgery. 36 (6): 908–912. doi:10.1053/jpsu.2001.23970. ISSN 0022-3468. PMID 11381424. Check date values in: |date= (help)
  9. ↑ Tsuzuki, Toyonori; et al. (2004-12). "ALK-1 expression in inflammatory myofibroblastic tumor of the urinary bladder". The American Journal of Surgical Pathology. 28 (12): 1609–1614. doi:10.1097/00000478-200412000-00009. ISSN 0147-5185. PMID 15577680. Check date values in: |date= (help)
  10. ↑ Ramachandra, S.; et al. (1995-10). "Inflammatory pseudotumour of soft tissues: a clinicopathological and immunohistochemical analysis of 18 cases". Histopathology. 27 (4): 313–323. doi:10.1111/j.1365-2559.1995.tb01521.x. ISSN 0309-0167. PMID 8847061. Check date values in: |date= (help)
  11. ↑ 11.0 11.1 Cook, J. R.; et al. (2001-11). "Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study". The American Journal of Surgical Pathology. 25 (11): 1364–1371. doi:10.1097/00000478-200111000-00003. ISSN 0147-5185. PMID 11684952. Check date values in: |date= (help)
  12. ↑ 12.0 12.1 Pickett, Justine L.; et al. (2017-10). "Inflammatory Myofibroblastic Tumors of the Female Genital Tract Are Under-recognized: A Low Threshold for ALK Immunohistochemistry Is Required". The American Journal of Surgical Pathology. 41 (10): 1433–1442. doi:10.1097/PAS.0000000000000909. ISSN 1532-0979. PMC 5598906. PMID 28731868. Check date values in: |date= (help)
  13. ↑ 13.0 13.1 Hornick, Jason L.; et al. (2015-05). "Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 28 (5): 732–739. doi:10.1038/modpathol.2014.165. ISSN 1530-0285. PMC 5874150. PMID 25612511. Check date values in: |date= (help)
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Antonescu, Cristina R.; et al. (2015-07). "Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement". The American Journal of Surgical Pathology. 39 (7): 957–967. doi:10.1097/PAS.0000000000000404. ISSN 1532-0979. PMC 4465992. PMID 25723109. Check date values in: |date= (help)
  15. ↑ 15.0 15.1 Coffin, C. M.; et al. (2001-06). "ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 14 (6): 569–576. doi:10.1038/modpathol.3880352. ISSN 0893-3952. PMID 11406658. Check date values in: |date= (help)
  16. ↑ Haimes, Josh D.; et al. (2017-06). "Uterine Inflammatory Myofibroblastic Tumors Frequently Harbor ALK Fusions With IGFBP5 and THBS1". The American Journal of Surgical Pathology. 41 (6): 773–780. doi:10.1097/PAS.0000000000000801. ISSN 1532-0979. PMID 28490045. Check date values in: |date= (help)
  17. ↑ 17.0 17.1 17.2 Yamamoto, Hidetaka; et al. (2016-07). "ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours". Histopathology. 69 (1): 72–83. doi:10.1111/his.12910. ISSN 1365-2559. PMID 26647767. Check date values in: |date= (help)
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 Lovly, Christine M.; et al. (2014-08). "Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions". Cancer Discovery. 4 (8): 889–895. doi:10.1158/2159-8290.CD-14-0377. ISSN 2159-8290. PMC 4125481. PMID 24875859. Check date values in: |date= (help)
  19. ↑ 19.0 19.1 19.2 Alassiri, Ali H.; et al. (2016-08). "ETV6-NTRK3 Is Expressed in a Subset of ALK-Negative Inflammatory Myofibroblastic Tumors". The American Journal of Surgical Pathology. 40 (8): 1051–1061. doi:10.1097/PAS.0000000000000677. ISSN 1532-0979. PMID 27259007. Check date values in: |date= (help)
  20. ↑ 20.0 20.1 Bridge, J. A.; et al. (2001-08). "Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor". The American Journal of Pathology. 159 (2): 411–415. doi:10.1016/S0002-9440(10)61711-7. ISSN 0002-9440. PMC 1850566. PMID 11485898. Check date values in: |date= (help)
  21. ↑ Chen, Sung-Ting; et al. (2008-12). "An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features". Human Pathology. 39 (12): 1854–1858. doi:10.1016/j.humpath.2008.04.016. ISSN 1532-8392. PMID 18701132. Check date values in: |date= (help)
  22. ↑ Debelenko, Larisa V.; et al. (2003-09). "Identification of CARS-ALK fusion in primary and metastatic lesions of an inflammatory myofibroblastic tumor". Laboratory Investigation; a Journal of Technical Methods and Pathology. 83 (9): 1255–1265. doi:10.1097/01.lab.0000088856.49388.ea. ISSN 0023-6837. PMID 13679433. Check date values in: |date= (help)
  23. ↑ Griffin, C. A.; et al. (1999-06-15). "Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors". Cancer Research. 59 (12): 2776–2780. ISSN 0008-5472. PMID 10383129.
  24. ↑ Lawrence, B.; et al. (2000-08). "TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors". The American Journal of Pathology. 157 (2): 377–384. doi:10.1016/S0002-9440(10)64550-6. ISSN 0002-9440. PMC 1850130. PMID 10934142. Check date values in: |date= (help)
  25. ↑ Takeuchi, Kengo; et al. (2011-05-15). "Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 17 (10): 3341–3348. doi:10.1158/1078-0432.CCR-11-0063. ISSN 1557-3265. PMID 21430068.
  26. ↑ Yamamoto, Hidetaka; et al. (2006-10). "Absence of human herpesvirus-8 and Epstein-Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene". Pathology International. 56 (10): 584–590. doi:10.1111/j.1440-1827.2006.02012.x. ISSN 1320-5463. PMID 16984614. Check date values in: |date= (help)
  27. ↑ Inamura, Kentaro; et al. (2017-11). "A novel fusion of HNRNPA1-ALK in inflammatory myofibroblastic tumor of urinary bladder". Human Pathology. 69: 96–100. doi:10.1016/j.humpath.2017.04.022. ISSN 1532-8392. PMID 28504207. Check date values in: |date= (help)
  28. ↑ Mariño-Enríquez, Adrian; et al. (2013-11). "ALK as a paradigm of oncogenic promiscuity: different mechanisms of activation and different fusion partners drive tumors of different lineages". Cancer Genetics. 206 (11): 357–373. doi:10.1016/j.cancergen.2013.07.001. ISSN 2210-7762. PMID 24091028. Check date values in: |date= (help)


Notes

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