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Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing

Abstract

Cutaneous carcinosarcoma (CCS) is an extraordinarily rare neoplasm with a biphasic morphological pattern exhibiting both epithelial and sarcomatoid components. Although its histogenesis and biological aspects remain poorly understood, previous studies have postulated that this tumor may arise from single cancer stem cells which subsequently differentiate into distinct tumor lineages. In this study, we explored a wide array of mutational hot spot regions, through high-depth next-generation sequencing of 47 cancer-associated genes in order to assess the mutational landscape of these tumors and investigate whether the epithelial and mesenchymal components shared the same genetic signatures. Results from this study confirm that despite their striking phenotypic differences, both elements of this infrequent tumor indeed share a common clonal origin. Additionally, CCS appears to embrace a heterogeneous spectrum with specific underlying molecular signatures correlating with the defining epithelial morphotype, with those carcinosarcomas exhibiting a squamous cell carcinoma epithelial component exhibiting diverse point mutations and deletions in the TP53 gene, and those with a basal cell carcinoma morphotype revealing a more complex mutational landscape involving several genes. Also, the fact that our findings involve several targetable gene pathways suggests that the underlying molecular events driving the pathogenesis of CCS may represent future potential targets for personalized therapies.

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References

  1. 1.

    Dawson EK (1972) Carcinosarcoma of the skin. J R Coll Surg Edinb 17:243–246

  2. 2.

    Syme-Grant J, Syme-Grant NJ, Motta L, Howard Stevenson J, Evans AT (2006) Are primary cutaneous carcinosarcomas underdiagnosed? Five cases and a review of the literature. J Plast Reconstr Aesthet Surg 59:1402–1408

  3. 3.

    Brasanac D, Boricic I, Todorovic V (2008) Tomanovic N (2008) Primary cutaneous carcinosarcoma: case report with expanded immunohistochemical analysis. Int J Dermatol 47:496–501

  4. 4.

    Patel NK, McKee PH, Smith NP, Fletcher CD (1997) Primary metaplastic carcinoma (carcinosarcoma) of the skin: a clinicopathologic study of four cases and a review of the literature. Am J Dermatopathol 19:363–372

  5. 5.

    Tran TA, Muller S, Chaudahri PJ, Carlson JA (2005) Cutaneous carcinosarcoma: adnexal vs. epidermal types define high- and low-risk tumors. Results of a meta-analysis. J Cutan Pathol 32:2–11

  6. 6.

    Bigby SM, Charlton A, Miller MV, Zwi LJ, Oliver GF (2005) Biphasic sarcomatoid basal cell carcinoma (carcinosarcoma): four cases with immunohistochemistry and review of the literature. J Cutan Pathol 32:141–147

  7. 7.

    Rose RF, Merchant W, Stables GI, Lyon CL, Platt A (2008) Basal cell carcinoma with a sarcomatous component (carcinosarcoma): a series of 5 cases and a review of the literature. J Am Acad Dermatol 59:627–632

  8. 8.

    Upjohn E, Braue A, Ryan A (2010) Primary cutaneous carcinosarcoma: dermoscopic and immunohistochemical features. Australas J Dermatol 51:26–28

  9. 9.

    Smart CN, Pucci RA, Binder SW, Cassarino DS (2009) Cutaneous carcinosarcoma with myoepithelial differentiation: immunohistochemical and cytogenetic analysis of a case presenting in an unusual location. Am J Dermatopathol 31:715–717

  10. 10.

    Kantrow SM, Boyd AS (2007) Primary cutaneous metaplastic carcinoma: report of a case involving angiosarcoma. Am J Dermatopathol 29:270–273

  11. 11.

    Mc Menamin ME, Goh SG, Poblet E, Gostelow BE, Robson A, Calonje E (2006) Sarcomatoid basal cell carcinoma-predilection for osteosarcomatous differentiation: a series of 11 cases. Am J Surg Pathol 30:1299–1308

  12. 12.

    Luzar B, Perković T (2006) Cutaneous carcinosarcoma-basal cell carcinoma with osteosarcoma. J Cutan Pathol 33:591–592

  13. 13.

    Ram R, Saadat P, Peng D, Vadmal M (2005) Case report and literature review: primary cutaneous carcinosarcoma. Ann Clin Lab Sci 35:189–194

  14. 14.

    Chiyoda T, Tsuda H, Tanaka H, Kataoka F, Nomura H, Nishimura S, Takano M, Susumu N, Saya H, Aoki D (2012) Expression profiles of carcinosarcoma of the uterine corpus-are these similar to carcinoma or sarcoma? Genes, Chromosomes Cancer 51:229–239

  15. 15.

    Ambrosini-Spaltro A, Vaira V, Braidotti P, Rovati MPL, Ferrero S, Bosari S (2006) Carcinosarcoma of the colon: report of a case with morphological, ultrastructural and molecular analysis. BMC Cancer 6:185

  16. 16.

    Armstrong AB, Wang M, Eble JN, MacLennan GT, Montironi R, Tan PH, Lopez-Beltran A, Zhang S, Baldridge LA, Spartz H, Cheng L (2009) TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder. Mod Pathol 22:113–118

  17. 17.

    Sung MT, Wang M, MacLennan GT, Eble JN, Tan PH, Lopez-Beltran A, Montironi R, Harris JJ, Kuhar M, Cheng L (2007) Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation. J Pathol 211:420–430

  18. 18.

    Singh RR, Patel KP, Routbort M et al (2013) Clinical validation of a next generation sequencing screen for mutational hotspots in 46 cancer-related genes. J Mol Diagn 15:607–622

  19. 19.

    Routbort M, Patel KP, Singh RR et al (2012) OncoSeek-A versatile annotation and reporting system for next generation sequencing-based clinical mutation analysis of cancer specimens. J Mol Diagn 14:747

  20. 20.

    Xu F, Zou WB, Li XP et al (2013) Multiple carcinosarcomas of the esophagus and stomach. Oncol Lett 5:1017–1021

  21. 21.

    Donnell CA, Pollock WJ, Sybers WA (1987) Thyroid carcinosarcoma. Arch Pathol Lab Med 12:1169–1172

  22. 22.

    Okudela K, Nakamura N, Sano J et al (2001) Thymic carcinosarcoma consisting of squamous cell carcinomatous and embryonal rhabdomyosarcomatous components. Report of a case and review of the literature. Pathol Res Pract 197:205–210

  23. 23.

    Arend R, Doneza JA, Wright JD (2011) Uterine carcinosarcoma. Curr Opin Oncol 5:531–536

  24. 24.

    Haraguchi S, Fukuda Y, Sugisaki Y et al (1999) Pulmonary carcinosarcoma: immunohistochemical and ultrastructural Studies. Pathol Int 10:903–908

  25. 25.

    Wick MR, Swanson PE (1993) Carcinosarcomas: current perspectives and a histological review of nosological concepts. Semin Diagn Pathol 10:118–127

  26. 26.

    El Harroudi T, Ech-Charif S, Amrani M et al (2010) Primary carcinosarcoma of the skin. J Hand Microsurg 2:79–81

  27. 27.

    Biernat W, Kordek R, Liberski PP et al (1996) Carcinosarcoma of the skin: case report and literature review. Am J Dermatopathol 18:614–619

  28. 28.

    Brown TJ, Tschen JA (1999) Primary carcinosarcoma of the skin: report of a case and review of the literature. Dermatol Surg 25:498–500

  29. 29.

    Hanly MG, Allsbrook WC, Pantazis CG et al (1994) Pilomatrical carcinosarcoma of the cheek with subsequent pulmonary metastases. A case report. Am J Dermatopathol 16:196–200

  30. 30.

    McKee PH, Fletcher CD, Stavrinos P et al (1990) Carcinosarcoma arising in eccrine spiradenoma. A clinicopathologic and immunohistochemical study of two cases. Am J Dermatopathol 12:335–343

  31. 31.

    McCluggage WG, Fon LJ, O'Rourke D et al (1997) Malignant eccrine spiradenoma with carcinomatous and sarcomatous elements. J Clin Pathol 50:871–873

  32. 32.

    Meriggi F, Tagliabò R, Morone G et al (1989) The potential malignancy of eccrine spiradenoma. Ital J Surg Sci 19:265–268

  33. 33.

    Mori O, Hachisuka H, Sasai Y (1990) Proliferating trichilemmal cyst with spindle cell carcinoma. Am J Dermatopathol 12:479–484

  34. 34.

    Plumb SJ, Stone MS (2002) Proliferating trichilemmal tumor with a malignant spindle cell component. J Cutan Pathol 29:506–509

  35. 35.

    Quay SC, Harrist TJ, Mihm MC Jr (1981) Carcinosarcoma of the skin. Case report and review. J Cutan Pathol 8:241–246

  36. 36.

    Schaefer IM, Enders C, Polten A et al (2011) Common genomic aberrations in basaloid squamous cell carcinoma and carcinosarcoma of the esophagus detected by CGH and array CGH. Am J Clin Pathol 135:579–586

  37. 37.

    Geyer FC, Weigelt B, Natrajan R et al (2009) Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas. J Pathol 220:562–573

  38. 38.

    Santiago Pérez JT, Pérez Vázquez MR, Rivera Valdespino A et al (2005) Carcinosarcoma of the breast: a tumour with controversial histogenesis. Clin Transl Oncol 7:255–257

  39. 39.

    Paniz Mondolfi AE, Jour G, Johnson M et al (2013) Primary cutaneous carcinosarcoma: insights into its clonal origin and mutational pattern expression analysis through next-generation sequencing. Hum Pathol 44:2853–2860

  40. 40.

    Nelson MA, Einspahr JG, Alberts DS et al (1994) Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers. Cancer Lett 85:23–29

  41. 41.

    Brash DE (2006) Roles of the transcription factor p53 in keratinocyte carcinomas. Br J Dermatol 154:8–10

  42. 42.

    Xie J, Aszterbaum M, Zhang X et al (2001) A role of PDGFR alpha in basal cell carcinoma proliferation. Proc Natl Acad Sci U S A 98:9255–9259

  43. 43.

    Yang CM, Hsieh HL, Yao CC et al (2009) Protein kinase C-delta transactivates platelet-derived growth factor receptor-alpha in mechanical strain-induced collagenase 3 (matrix metalloproteinase-13) expression by osteoblast-like cells. J Biol Chem 284:26040–26050

  44. 44.

    Yang CM, Chien CS, Yao CC et al (2004) Mechanical strain induces collagenase-3 (MMP-13) expression in MC3T3-E1 osteoblastic cells. J Biol Chem 279:22158–22165

  45. 45.

    Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312

  46. 46.

    Donovan J, Abraham D, Norman J (2013) Platelet-derived growth factor signaling in mesenchymal cells. Front Biosci (Landmark Ed) 18:106–119

  47. 47.

    Athar M, Tang X, Lee JL et al (2006) Hedgehog signalling in skin development and cancer. Exp Dermatol 15:667–677

  48. 48.

    Daja-Grosjean L, Couvé-Privat S (2005) Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett 225:181–192

  49. 49.

    Li C, Chi S, He N et al (2004) IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene 23:1608–1617

  50. 50.

    Kaur P, Mulvaney M, Carlson JA (2006) Basal cell carcinoma progression correlates with host immune response and stromal alterations: a histologic analysis. Am J Dermatopathol 28:293–307

  51. 51.

    Lin N, Moroi Y, Uchi H et al (2007) Significance of the expression of phosphorylated-STAT3, −AKT and -ERK-1/2 in several tumors of the epidermis. J Dermatol Sci 48:71–73

  52. 52.

    Hafner C, Landthaler M, Vogt T (2010) Activation of the PI3K/AKT signaling pathway in non-melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations. Exp Dermatol 19:e222–e227

  53. 53.

    Hafner C, Houben R, Baeurle A et al (2012) Activation of the PI3K/AKT pathway in Merkel cell carcinoma. PLoS One 7:e31255

  54. 54.

    Hafner C, López-Knowles E, Luis NM et al (2007) Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci U S A 104:13450–13454

  55. 55.

    Groesser L, Herschberger E, Landthaler M et al (2012) FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis. Br J Dermatol 166:784–788

  56. 56.

    Miranda LQ, Fracaroli TS, Fonseca JC et al (2013) Analysis of mutations in the PIK3CA and FGFR3 genes in verrucous epidermal nevus. An Bras Dermatol 88:36–38

  57. 57.

    Matsuda S, Nakanishi A, Wada Y et al (2013) Roles of PI3K/AKT/PTEN pathway as a target for pharmaceutical therapy. Open Med Chem J 7:23–29

  58. 58.

    Almendro V, Marusyk A, Polyak K (2013) Cellular heterogeneity and molecular evolution in cancer. Annu Rev Pathol: Mech Dis 8:277–302

  59. 59.

    Gerlinger M, Rowan AJ, Horswell S et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Eng J Med 366:883–892

  60. 60.

    Polyak K (2011) (2011) Heterogeneity in breast cancer. J Clin Invest 121:3786–3788

  61. 61.

    Bonavia R, Inda MM, Cavenee WK (2011) Heterogeneity maintenance in Glioblastoma: a social network. Cancer Res 71:4055–4060

  62. 62.

    Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805:105

  63. 63.

    Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39:305–318

  64. 64.

    Iwatsuki M, Mimori K, Yokobori T et al (2010) Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101:293–299

  65. 65.

    Yanhia H, Xinchun J (2007) The role of epithelial-mesenchymal transition in oral squamous cell carcinoma and oral submucous fibrosis. Clin Chim Acta 383:51–56

  66. 66.

    Smith A, Teknos TN, Pan Q (2013) Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol 49:287–292

  67. 67.

    Jeanes A, Gottardi CJ, Yap AS (2008) Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27:6920–6929

  68. 68.

    Hugo H, Ackland ML, Blick T et al (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383

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Conflict of interest

The authors declare no conflict of interest.

Author information

Correspondence to Alberto Paniz-Mondolfi.

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Paniz-Mondolfi, A., Singh, R., Jour, G. et al. Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing. Virchows Arch 465, 339–350 (2014). https://doi.org/10.1007/s00428-014-1628-0

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Keywords

  • Carcinosarcoma
  • Cutaneous
  • Mutations
  • Next-generation sequencing
  • Stem cells
  • Histogenesis