Role of immunohistochemistry in the diagnosis and staging of cutaneous squamous‑cell carcinomas (Review)

Bălășescu,Elena; Gheorghe,Andreea-Cristina; Moroianu,Andreea; Turcu,Gabriela; Brînzea,Alice; Antohe,Mihaela; Hodorogea,Anastasia; Manea,Lorena; Balaban,Mihaela; Andrei,Răzvan; Hulea,Ionela; Popp,Cristiana Gabriela; Nichita,Luciana; Cioplea,Mirela Daniela; Zurac,Sabina Andrada; Ion,Daniela Adriana; Nedelcu,Roxana Ioana

doi:10.3892/etm.2022.11308

Role of immunohistochemistry in the diagnosis and staging of cutaneous squamous‑cell carcinomas (Review)

Authors:
- Elena Bălășescu
- Andreea-Cristina Gheorghe
- Andreea Moroianu
- Gabriela Turcu
- Alice Brînzea
- Mihaela Antohe
- Anastasia Hodorogea
- Lorena Manea
- Mihaela Balaban
- Răzvan Andrei
- Ionela Hulea
- Cristiana Gabriela Popp
- Luciana Nichita
- Mirela Daniela Cioplea
- Sabina Andrada Zurac
- Daniela Adriana Ion
- Roxana Ioana Nedelcu
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Affiliations: 2nd Clinical Department, Pathophysiology II, National Institute of Infectious Diseases ‘Prof. Dr. Matei Balș’, Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 021105 Bucharest, Romania, Derma 360 Clinic, 011273 Bucharest, Romania, Department of Pathology, Colentina Clinical Hospital, 020125 Bucharest, Romania
Published online on: April 11, 2022 https://doi.org/10.3892/etm.2022.11308
Article Number: 383
Copyright: © Bălășescu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑melanoma skin cancer (NMSC) is the most common type of neoplasm affecting Caucasian individuals, with squamous‑cell carcinoma (cSCC) being the second most common type of NMSC after basal‑cell carcinoma. The immunohistochemical study of cSCC is of particular importance, especially for the diagnosis of its rare forms, for which accurate and early diagnosis is crucial for survival. In the present review of the literature, the potentially significant value of immunohistochemical markers were highlighted to more accurately assess the biological behaviour, the prognosis of cSCC and to optimize case management. The immunohistochemical markers were classified from a pathophysiological point of view in order to present the mechanism by which carcinogenesis occurs with its subsequent evolution and therefore, to develop a more accurate novel risk staging criteria for this type of neoplasm.

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1	Stanganelli I, Spagnolo F, Argenziano G, Ascierto PA, Bassetto F, Bossi P, Donato V, Massi D, Massone C, Patuzzo R, et al: The multidisciplinary management of cutaneous squamous cell carcinoma: A comprehensive review and clinical recommendations by a panel of experts. Cancers (Basel). 14(377)2022.PubMed/NCBI View Article : Google Scholar
2	Parekh V and Seykora JT: Cutaneous squamous cell carcinoma. Clin Lab Med. 37:503–525. 2017.PubMed/NCBI View Article : Google Scholar
3	Lomas A, Leonardi-Bee J and Bath-Hextall F: A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 166:1069–1080. 2012.PubMed/NCBI View Article : Google Scholar
4	Claveau J, Archambault J, Ernst DS, Giacomantonio C, Limacher JJ, Murray C, Parent F and Zloty D: Multidisciplinary management of locally advanced and metastatic cutaneous squamous cell carcinoma. Curr Oncol. 27:e399–e407. 2020.PubMed/NCBI View Article : Google Scholar
5	Roscher I, Falk RS, Vos L, Clausen OPF, Helsing P, Gjersvik P and Robsahm TE: Validating 4 staging systems for cutaneous squamous cell carcinoma using population-based data: A nested case-control study. JAMA Dermatol. 154:428–434. 2018.PubMed/NCBI View Article : Google Scholar
6	Morgado-Carrasco D, Bosch-Amate X, Fusta-Novell X and Garcia-Herrera A: RF-staging cutaneous squamous cell carcinoma: Challenges and questions. Actas Dermosifiliogr (Engl Ed). 111:261–262. 2020.PubMed/NCBI View Article : Google Scholar : (In English, Spanish).
7	Ruiz ES, Karia PS, Besaw R and Schmults CD: Performance of the American joint committee on cancer staging manual, 8th Edition vs. the Brigham and Women's hospital tumor classification system for cutaneous squamous cell carcinoma. JAMA Dermatol. 155:819–825. 2019.PubMed/NCBI View Article : Google Scholar
8	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009.PubMed/NCBI View Article : Google Scholar
9	Micalizzi DS, Farabaugh SM and Ford HL: Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 15:117–134. 2010.PubMed/NCBI View Article : Google Scholar
10	Ribatti D, Tamma R and Annese T: Epithelial-mesenchymal transition in cancer: A historical overview. Transl Oncol. 13(100773)2020.PubMed/NCBI View Article : Google Scholar
11	Gerashchenko TS, Novikov NM, Krakhmal NV, Zolotaryova SY, Zavyalova MV, Cherdyntseva NV, Denisov EV and Perelmuter VM: Markers of cancer cell invasion: Are they good enough? J Clin Med. 8(1092)2019.PubMed/NCBI View Article : Google Scholar
12	Tsai JH and Yang J: Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 27:2192–2206. 2013.PubMed/NCBI View Article : Google Scholar
13	Lewis Kelso R, Colome-Grimmer MI, Uchida T, Wang HQ and Wagner RF Jr: p75(NGFR) immunostaining for the detection of perineural invasion by cutaneous squamous cell carcinoma. Dermatol Surg. 32:177–183. 2006.PubMed/NCBI View Article : Google Scholar
14	Kumar V, Abbas A, Aster JC and Robbins SL: Robbins Basic Pathology, 9th Edition. Elsevier Inc., Philadelphia PA, 2013.
15	Lugano R, Ramachandran M and Dimberg A: Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell Mol Life Sci. 77:1745–1770. 2020.PubMed/NCBI View Article : Google Scholar
16	Hawighorst T: Angiogenesis, lymphangiogenesis, and tumor progression. Zentralbl Gynakol. 124:497–505. 2002.PubMed/NCBI View Article : Google Scholar : (In German).
17	Iatropoulos MJ and Williams GM: Proliferation markers. Exp Toxicol Pathol. 48:175–181. 1996.PubMed/NCBI View Article : Google Scholar
18	Zitvogel L, Tesniere A and Kroemer G: Cancer despite immunosurveillance: Immunoselection and immunosubversion. Nat Rev Immunol. 6:715–727. 2006.PubMed/NCBI View Article : Google Scholar
19	Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C and Fridman WH: Immune infiltration in human tumors: A prognostic factor that should not be ignored. Oncogene. 29:1093–1102. 2010.PubMed/NCBI View Article : Google Scholar
20	Bui JD and Schreiber RD: Cancer immunosurveillance, immunoediting and inflammation: Independent or interdependent processes? Curr Opin Immunol. 19:203–208. 2007.PubMed/NCBI View Article : Google Scholar
21	Strobel SB, Safferling K, Lahrmann B, Hoffmann JH, Enk AH, Hadaschik EN, Grabe N and Lonsdorf AS: Altered density, composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients. Br J Dermatol. 179:405–412. 2018.PubMed/NCBI View Article : Google Scholar
22	Zhao G, Kim KY, Zheng Z, Oh Y, Yoo DS, Lee ME, Chung KY, Roh MR and Jin Z: AXIN2 and SNAIL expression predict the risk of recurrence in cutaneous squamous cell carcinoma after Mohs micrographic surgery. Oncol Lett. 19:2133–2140. 2020.PubMed/NCBI View Article : Google Scholar
23	Toll A, Masferrer E, Hernandez-Ruiz ME, Ferrandiz-Pulido C, Yébenes M, Jaka A, Tuneu A, Jucglà A, Gimeno J, Baró T, et al: Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases. J Dermatol Sci. 72:93–102. 2013.PubMed/NCBI View Article : Google Scholar
24	Kourtidis A, Lu R, Pence LJ and Anastasiadis PZ: A central role for cadherin signaling in cancer. Exp Cell Res. 358:78–85. 2017.PubMed/NCBI View Article : Google Scholar
25	Zhang Y, Liu B, Zhao Q, Hou T and Huang X: Nuclear localizaiton of β-catenin is associated with poor survival and chemo-/radioresistance in human cervical squamous cell cancer. Int J Clin Exp Pathol. 7:3908–3917. 2014.PubMed/NCBI
26	Barrette K, Van Kelst S, Wouters J, Marasigan V, Fieuws S, Agostinis P, van den Oord J and Garmyn M: Epithelial-mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation. Br J Dermatol. 171:1014–1021. 2014.PubMed/NCBI View Article : Google Scholar
27	Vinicius de LV, Scapulatempo C, Perpetuo NM, Mohamed F, de Carvalho TS, de Oliveira AT, Segalla JG and Carvalho AL: Prognostic and risk factors in patients with locally advanced cutaneous squamous cell carcinoma of the trunk and extremities. J Skin Cancer. 2011(420796)2011.PubMed/NCBI View Article : Google Scholar
28	Hesse K, Satzger I, Schacht V, Köther B, Hillen U, Klode J, Schaper K and Gutzmer R: Characterisation of prognosis and invasion of cutaneous squamous cell carcinoma by podoplanin and E-Cadherin expression. Dermatology. 232:558–565. 2016.PubMed/NCBI View Article : Google Scholar
29	Nissinen L, Siljamaki E, Riihila P, Piipponen M, Farshchian M, Kivisaari A, Kallajoki M, Raiko L, Peltonen J, Peltonen S and Kähäri VM: Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ. Exp Dermatol. 26:771–777. 2017.PubMed/NCBI View Article : Google Scholar
30	Clark ES, Whigham AS, Yarbrough WG and Weaver AM: Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res. 67:4227–4235. 2007.PubMed/NCBI View Article : Google Scholar
31	Canel M, Secades P, Garzon-Arango M, Allonca E, Suarez C, Serrels A, Frame M, Brunton V and Chiara MD: Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression. Br J Cancer. 98:1274–1284. 2008.PubMed/NCBI View Article : Google Scholar
32	Munguia-Calzada P, Fernandez-Vega I, Martinez-Camblor P, Díaz-Coto S, García-Pedrero JM, Vivanco B, Osuna CG, Vazquez-Lopez F, Rodrigo JP and Santos-Juanes J: Correlation of focal adhesion kinase expression with nodal metastasis in patients with head and neck cutaneous squamous cell carcinoma. Head Neck. 41:1290–1296. 2019.PubMed/NCBI View Article : Google Scholar
33	Serrels A and Frame MC: FAK goes nuclear to control antitumor immunity-a new target in cancer immuno-therapy. Oncoimmunology. 5(e1119356)2016.PubMed/NCBI View Article : Google Scholar
34	Rose AM, Spender LC, Stephen C, Mitchell A, Rickaby W, Bray S, Evans AT, Dayal J, Purdie KJ, Harwood CA, et al: Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma. Oncotarget. 9:14552–14566. 2018.PubMed/NCBI View Article : Google Scholar
35	Cumsky HJL, Costello CM, Zhang N, Butterfield R, Buras MR, Schmidt JE, Drenner K, Nelson SA, Ochoa SA, Baum CL, et al: The prognostic value of inositol polyphosphate 5-phosphatase in cutaneous squamous cell carcinoma. J Am Acad Dermatol. 80:626–632 e1. 2019.PubMed/NCBI View Article : Google Scholar
36	Maly CJ, Cumsky HJL, Costello CM, Schmidt JE, Butterfield RJ, Zhang N, DiCaudo DJ, Nelson SA, Smith ML, Ochoa SA, et al: Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma. J Am Acad Dermatol. 82:846–853. 2020.PubMed/NCBI View Article : Google Scholar
37	Florence ME, Massuda JY, Brocker EB, Metze K, Cintra ML and Souza EM: Angiogenesis in the progression of cutaneous squamous cell carcinoma: An immunohistochemical study of endothelial markers. Clinics (Sao Paulo). 66:465–468. 2011.PubMed/NCBI View Article : Google Scholar
38	Ciortea CD, Jung I, Gurzu S, Kovecsi A, Turdean SG and Bara T: Correlation of angiogenesis with other immunohistochemical markers in cutaneous basal and squamous cell carcinomas. Rom J Morphol Embryol. 56 (2 Suppl):S665–S670. 2015.PubMed/NCBI
39	Toll A, Gimeno-Beltran J, Ferrandiz-Pulido C, Masferrer E, Yébenes M, Jucglà A, Abal L, Martí RM, Sanmartín O, Baró T, et al: D2-40 immunohistochemical overexpression in cutaneous squamous cell carcinomas: A marker of metastatic risk. J Am Acad Dermatol. 67:1310–1318. 2012.PubMed/NCBI View Article : Google Scholar
40	Gulseren D, Gokoz O, Karahan S and Karaduman A: Podoplanin expression in cutaneous squamous cell carcinomas and its relationship to histopathological prognostic factors. J Histotechnol. 43:147–152. 2020.PubMed/NCBI View Article : Google Scholar
41	Takahara M, Chen S, Kido M, Takeuchi S, Uchi H, Tu Y, Moroi Y and Furue M: Stromal CD10 expression, as well as increased dermal macrophages and decreased Langerhans cells, are associated with malignant transformation of keratinocytes. J Cutan Pathol. 36:668–674. 2009.PubMed/NCBI View Article : Google Scholar
42	Yun JH, Roh JY, Park SH and Lee JR: CD10 expression in cutaneous squamous cell carcinoma and its precursor lesions: Evaluation using tissue microarray. Ann Dermatol. 25:515–517. 2013.PubMed/NCBI View Article : Google Scholar
43	Kreuter A, Gambichler T, Pfister H and Wieland U: Diversity of human papillomavirus types in periungual squamous cell carcinoma. Br J Dermatol. 161:1262–1269. 2009.PubMed/NCBI View Article : Google Scholar
44	Marinescu A, Stepan AE, Margaritescu C, Marinescu AM, Zăvoi RE, Simionescu CE and Niculescu M: P53, p16 and Ki67 immunoexpression in cutaneous squamous cell carcinoma and its precursor lesions. Rom J Morphol Embryol. 57 (2 Suppl):S691–S696. 2016.PubMed/NCBI
45	Oh ST, Eun YS, Yoo DS, Park HJ, Kim TY, Cho BK, Stark A and Reichrath J: Expression of insulin-like growth factor-1 receptor in conventional cutaneous squamous cell carcinoma with different histological grades of differentiation. Am J Dermatopathol. 36:807–811. 2014.PubMed/NCBI View Article : Google Scholar
46	Canueto J, Cardenoso E, Garcia JL, Santos-Briz Á, Castellanos-Martín A, Fernández-López E, Blanco Gómez A, Pérez-Losada J and Román-Curto C: Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma. Br J Dermatol. 176:1279–1287. 2017.PubMed/NCBI View Article : Google Scholar
47	Chen MK, Cai MY, Luo RZ, Tian X, Liao QM, Zhang XY and Han JD: Overexpression of p300 correlates with poor prognosis in patients with cutaneous squamous cell carcinoma. Br J Dermatol. 172:111–119. 2015.PubMed/NCBI View Article : Google Scholar
48	Sellheyer K: Basal cell carcinoma: Cell of origin, cancer stem cell hypothesis and stem cell markers. Br J Dermatol. 164:696–711. 2011.PubMed/NCBI View Article : Google Scholar
49	Xu R, Cai MY, Luo RZ, Tian X, Han JD and Chen MK: The expression status and prognostic value of cancer stem cell biomarker CD133 in cutaneous squamous cell carcinoma. JAMA Dermatol. 152:305–311. 2016.PubMed/NCBI View Article : Google Scholar
50	Farshchian M, Nissinen L, Siljamaki E, Riihilä P, Piipponen M, Kivisaari A, Kallajoki M, Grénman R, Peltonen J, Peltonen S, et al: Tumor cell-specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma. Oncotarget. 8:45825–45836. 2017.PubMed/NCBI View Article : Google Scholar
51	Ko CJ, McNiff JM and Glusac EJ: Squamous cell carcinomas with single cell infiltration: A potential diagnostic pitfall and the utility of MNF116 and p63. J Cutan Pathol. 35:353–357. 2008.PubMed/NCBI View Article : Google Scholar
52	Alomari AK, Glusac EJ and McNiff JM: p40 is a more specific marker than p63 for cutaneous poorly differentiated squamous cell carcinoma. J Cutan Pathol. 41:839–845. 2014.PubMed/NCBI View Article : Google Scholar
53	Yanofsky VR, Mercer SE and Phelps RG: Histopathological variants of cutaneous squamous cell carcinoma: A review. J Skin Cancer. 2011(210813)2011.PubMed/NCBI View Article : Google Scholar
54	Morgan MB, Purohit C and Anglin TR: Immunohistochemical distinction of cutaneous spindle cell carcinoma. Am J Dermatopathol. 30:228–232. 2008.PubMed/NCBI View Article : Google Scholar
55	Dotto JE and Glusac EJ: p63 is a useful marker for cutaneous spindle cell squamous cell carcinoma. J Cutan Pathol. 33:413–417. 2006.PubMed/NCBI View Article : Google Scholar
56	Hall JM, Saenger JS and Fadare O: Diagnostic utility of P63 and CD10 in distinguishing cutaneous spindle cell/sarcomatoid squamous cell carcinomas and atypical fibroxanthomas. Int J Clin Exp Pathol. 1:524–530. 2008.PubMed/NCBI
57	Gleason BC, Calder KB, Cibull TL, Thomas AB, Billings SD, Morgan MB, Hiatt KM and Smoller BR: Utility of p63 in the differential diagnosis of atypical fibroxanthoma and spindle cell squamous cell carcinoma. J Cutan Pathol. 36:543–547. 2009.PubMed/NCBI View Article : Google Scholar
58	Ha Lan TT, Chen SJ, Arps DP, Fullen DR, Patel RM, Siddiqui J, Carskadon S, Palanisamy N and Harms PW: Expression of the p40 isoform of p63 has high specificity for cutaneous sarcomatoid squamous cell carcinoma. J Cutan Pathol. 41:831–838. 2014.PubMed/NCBI View Article : Google Scholar
59	Mühleisen B, Petrov I, Gachter T, Kurrer M, Schärer L, Dummer R, French LE and Hofbauer GF: Progression of cutaneous squamous cell carcinoma in immunosuppressed patients is associated with reduced CD123+ and FOXP3+ cells in the perineoplastic inflammatory infiltrate. Histopathology. 55:67–76. 2009.PubMed/NCBI View Article : Google Scholar
60	Pettersen JS, Fuentes-Duculan J, Suarez-Farinas M, Pierson KC, Pitts-Kiefer A, Fan L, Belkin DA, Wang CQ, Bhuvanendran S, Johnson-Huang LM, et al: Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. J Invest Dermatol. 131:1322–1330. 2011.PubMed/NCBI View Article : Google Scholar
61	Sandvik LF, Skarstein K, Krynitz B, Volchenkov R, Sviland L, Leivestad T, Jonsson R and Appel S: Peritumoral dermis of squamous cell carcinomas in renal transplant recipients contains less CD11c+ myeloid dendritic cells and FoxP3+ T cells compared to immunocompetent controls. J Eur Acad Dermatol Venereol. 29:2128–2135. 2015.PubMed/NCBI View Article : Google Scholar