Pathohistologic diagnosis plays a pivotal role in therapeutic modalities for cancer, and acts as a prognostic factor. The histologic grade is a numeric expression of tumor differentiation and is linked to patient outcome. Broders\u27 scoring system is still widely used in scoring squamous cell carcinomas. New data suggest that in the most invasive parts of a malignant tumor, the morphology and biologic behavior differ from the central and superficial areas of the same tumor. A new invasive cell grading system has been proposed as a better prognostic factor in the multifactorial diagnostic and therapeutic approach to the patient with malignant tumor. Numerous studies performed to date have provided sufficient evidence to propose the invasive cell grading system to be introduced instead of the "old" Broders\u27 scoring system.Patohistološka dijagnoza igra ključnu ulogu u terapijskom pristupu raku te djeluje i kao prognostički čimbenik. Histološki stupanj je brojčani izražaj diferencijacije tumora i vezan je uz prognozu tumorske bolesti u pojedinog bolesnika. Danas je u širokoj uporabi Brodersov sustav histološkog stupnjevanja u karcinomima pločastog epitela. Noviji podatci ukazuju na to da se morfologija i biološko ponašanje stanica u invazivnim dubokim dijelovima malignog tumora razlikuju od središnjih i površinskih dijelova istoga tumora. Novi sustav ICG (invasive cell grading . stupnjevanje invazivnih stanica) predložen je kao bolji prognostički čimbenik u složenom dijagnostičkom i terapijskom pristupu bolesniku s malignim tumorom. Brojna su istraživanja potvrdila da se novi sustav ICG može s dovoljnom sigurnošću rabiti u patohistološkom stupnjevanju malignih tumora umjesto "starog" Brodersovog načina

Hrvoje Čupić

Livije Kalogjera

Mirko Ivkić

Vladimir Bedeković

Željko Ferenčić

English

Hrčak - Portal of scientific journals of Croatia

Ivkiæ M. et al. Invasive cell grading in squamous cell caercinomaActa clin Croat, Vol. 41, No. 3, 2002 233Acta clin Croat 2002; 41:233-236 ReviewINVASIVE CELL GRADING  AN OVERVIEW*Mirko Ivkiæ1, Vladimir Bedekoviæ1, Livije Kalogjera1, Hrvoje Èupiæ2 and eljko Ferenèiæ31Department of Otorhinolaryngology and Head and Neck Surgery, 2Ljudevit Jurak University Department of Pathology, Sestremilosrdnice University Hospital; 3Pliva Pharmaceuticals Inc., Research Division, Laboratory of Histopathology, Zagreb, CroatiaCorrespondence to: eljko Ferenèiæ, M.D., Pliva Pharmaceuticals Inc.,Research Division, Laboratory of Histopathology, Baruna Filipoviæa 25,HR-1000 Zagreb, CroatiaE-mail: zeljko.ferencic@pliva.hrReceived March 25, 2002, accepted in revised form July 3, 2002*Paper presented at the International Symposium Head and Neck Tu-mors  Cancer of the Larynx and Hypopharynx, Zagreb, Croatia, No-vember 16-17, 2001SUMMARY  Pathohistologic diagnosis plays a pivotal role in therapeutic modalities for cancer, and acts asa prognostic factor. The histologic grade is a numeric expression of tumor differentiation and is linked topatient outcome. Broders scoring system is still widely used in scoring squamous cell carcinomas. New datasuggest that in the most invasive parts of a malignant tumor, the morphology and biologic behavior differfrom the central and superficial areas of the same tumor. A new invasive cell grading system has beenproposed as a better prognostic factor in the multifactorial diagnostic and therapeutic approach to thepatient with malignant tumor. Numerous studies performed to date have provided sufficient evidence topropose the invasive cell grading system to be introduced instead of the old Broders scoring system.Key words: Carcinoma  diagnosis; Carcinoma  pathology; Carcinoma  prognosisIntroductionPathohistologic diagnosis is fundamental in the studyof many diseases, tumors in particular. Therapeutic mo-dalities for cancer can often rely upon diagnostic data pro-vided by pathologists. Apart from the routine diagnosticprocedure, histologic examination of the surgical specimenyields valuable data on the biologic behavior of the tumor.On histopathologic assessment, many tumors are notgraded or scored because sufficient information is associ-ated with a specific diagnostic label. For example, cutane-ous basal cell carcinomas are not graded because the diag-nostic label and assessment of whether the lesion is excisedare the only data required for the referring clinician to treatthe patient.In the majority of malignant tumors, the relation be-tween the biologic behavior and the extent of differentia-tion is known for more than a century1. Subsequent obser-vations on the characteristics of aggressive cancers had ledto the histologic grade concept, i.e. numeric expressionof differentiation, which was linked to patient outcome.Broders studies established a simple grading method forsquamous cell carcinomas that is still widely used to thepresent2-4. By his grading method, tumors are assigned oneof the four grades according to the percentage of tumorshowing incomplete differentiation.A grading or scoring system usually produces a singlelabel that may be alphabetic or numeric. If the latter, it isimportant to recognize the attributes of the respectivenumber. In most cases, the numeric label is an ordinal cat-egorical label rather than a real number. This means thatthe label assigns the case to a particular group, and thisgroup has a specific position in relation to other groups(e.g., grade 2 lies in-between grades 1 and 3). The major-ity of scoring systems combine several different featuresinto a single score. In many cases, such summation reduc-es the amount of information valuable to the clinician re-ceiving the report.Many scoring and grading systems have been suffi-ciently well established and familiar to clinicians receiv-ing histopathology reports, which they use extensively onmaking decisions on patient management. Several grad-ing systems have been subsequently developed for tumorsIvkiæ M. et al. Invasive cell grading in squamous cell caercinoma234 Acta clin Croat, Vol. 41, No. 3, 2002of various sites, just to mention some of the well estab-lished: Gleason score for prostatic carcinoma5, Daumas-Duport grading for astrocytomas6, International Federationof Gynecology and Obstetrics scoring method for endome-trial cancer7, Bloom and Richardson histologic grading ofbreast carcinoma8, etc. In all their variations and modifi-cations for specific site, the degree of differentiation isconsidered in relation to tumor biologic behavior.It is a known fact that tumor morphology in the mostinvasive parts of a malignant tumor often is different fromthe central and superficial areas of the same tumor. At theinvasive front, the tumor frequently shows a lower degreeof differentiation and higher grade of cellular dissociationthan the remaining areas of the tumor. This phenomenonis frequently observed in squamous cell carcinomas, ma-lignant melanomas, and various adenocarcinomas (gastric,colorectal and prostatic).The development of modern techniques in molecularpathology has confirmed that tumor cells at the invasivefront of carcinomas differ substantially from the rest oftumor cells in a variety of human cancers9,10. Various mo-lecular events of importance in tumor spread, such as thegain and loss of adhesion molecules, secretion of proteolyticenzymes, increased cell proliferation, and initiation ofangiogenesis, occur at the tumor  host interface (invasivefront).Invasive Cell GradingThe features at the tumor  host interface have beensummarized and simplified by Bryne et al.11,12, proposing anew simple multifactorial malignancy grading system, i.e.invasive cell grading (ICG). Each of the morphological fea-tures: (a) degree of keratinization; (b) nuclear polymor-phism; (c) number of mitoses per high-power field; (d)pattern of tumor invasion; and (e) lymphoplasmacytic in-filtration, is given a score of 1 to 4 (score 4 being the worstfeature). To increase the reproducibility of the scoringsystem in their subsequent modification, the counting ofmitoses has been omitted13.Tumor cell characteristics are solely graded within thelowest differentiated parts of the most invasive 3-6 celllayers at the advancing front of the tumor. An average of 4fields (magnification X100) are recorded as the score foreach parameter. When the sum (total score) is achieved,the system recognizes three prognostic groups, i.e. good,moderate, and poor.The grading is performed on routine H&E stainedsections. No special stain is needed. The time needed forgrading of one section is 1-3 minutes for a trained pathol-ogist.DiscussionIn the last three decades, a number of studies haveraised the question of the prognostic value of Brodersscoring system, as it takes into account the whole tumorarea with no particular interest in the invasive front. It hasresulted in the emergence of new scoring systems concen-trating only on the tumor invasive front, scoring the fea-tures at the tumor  host interface14-16.The growing evidence that the invasive front gradingsystem represents the prognosis better than Broders sys-tem in head and neck tumors has been even more convinc-ingly confirmed when combined with other methods. Inoral squamous cell carcinoma, the argyrophilic nucleolarorganizer regions-associated protein (AgNOR) content ofinvading tumor cells and the multiparametric histopatho-logic tumor front grade were found to be significantly andindependently associated with tumor-related death, irre-spective of the conventional Broders grade and clinicalstage of the tumors17. Strict correlation was found betweenthe frequency and density of Ki67/p53 immunoreactivityaccording to ICG scores and poor patient prognosis18. His-tologic characteristics of the deep invasive front have alsoproved to be a better indicator of prognosis than the T-category (size of tumor). The pattern of invasion and de-gree of keratinization were the strongest prognostic fac-tors in multivariate analyses19. Broders method of gradingwas compared with ICG grading system. Cox multivari-ate survival analyses showed this new grading at the inva-sive sites to have a highly significant prognostic value,whereas Broders grading had no prognostic value at all14.The usefulness of the deep invasive front grading systemwas also demonstrated for small lingual carcinoma20.The results of DNA analysis (2c deviation index, DNAmalignancy grade) along with the morphologic tumor frontgrading and Ki67 score were closely related to prognosis(p<0.01). No correlation was found for Broders gradingor any other clinical parameter21.All these studies have shown that there are some moresensitive predictors of outcome in cancer patients (flowcytometry DNA analysis, use of molecular markers, immu-nohistochemistry, and other technologic procedures).However, compared with these methods, invasive frontgrading has established itself as an easily adopting, prov-en prognostic factor with practical advantages22.Ivkiæ M. et al. Invasive cell grading in squamous cell caercinomaActa clin Croat, Vol. 41, No. 3, 2002 235Clinicians and pathologists who prefer the simplerBroders system could argue that there is no point in pro-ducing more categories than there are treatment optionsavailable. But there is a more important counterpoint. Ifthe response to treatment varies with a continuous featuresuch as differentiation, it is important to define as manygrades of differentiation as possible in order to determinethe precise relationship.There must be a dialogue between the histopatholo-gist and the clinician so that the role of the grade or scorein patient management is understood and the clinician isaware of the degree of reproducibility of the system. Thefirst duty of the pathologist is to extract as much informa-tion as possible from the surgical material and pass it onto the clinician.The introduction and testing of such a new system istime-consuming but must be performed to ensure thathistopathologists are transmitting real information in theirreports, and not irrelevant noise, trying to help cliniciansin making important therapeutic decisions.The simple invasive cell grading has proved to be ofhigh prognostic value and sufficient evidence exists topropose its introduction in clinical practice.10. RIVIERE A, WILKENS C, LÖNING T. Expression of c-erbB2 andc-myc in squamous epithelia and squamous cell carcinomas of thehead and neck and lower female genital tract. J Oral Pathol Med1990;19:408-13.11. BRYNE M, KOPPANG HS, LILLENG R, STENE T, BANG G,DABELSTEEN E. New malignancy grading is a better prognosticindicator than Broders grading in oral squamous cell carcinomas. JOral Pathol Med 1998;18:432-7.12. BRYNE M, KOPPANG HS, LILLENG R, KJERHEIM Å. Malig-nancy grading of the deep margins of oral squamous cell carcinomashas high prognostic value. J Pathol 1992;166:375-81.13. BRYNE M, BOYSEN M, ALFSEN CG, ABELER VM, SUDBØ J,NESLAND JM, KRISTENSEN GB, PIFFKO J, BANKFALVI A.The invasive front of carcinomas. The most important area for tu-mour prognosis? Anticancer Res 1998;18:4757-64.14. JAKOBSSON PÅ, ENEROTH C-M, KILLANDER D, MOBERG-ER G, MÅRTENSSON B. Histologic classification and grading ofmalignancy in carcinoma of the larynx. Acta Radiol Ther Phys Biol1973;12:1-8.15. LUND C, JØRGENSEN K, HJELM-HANSEN M, ANDERSENAP. Laryngeal carcinoma III. Treatment results in relation to micro-scopic score. Acta Radiol Oncol 1979;18:497-508.16. SALA O, FERLITO A. Morphological observations of immunobi-ology of laryngeal cancer. Evaluation of the defensive activity ofimmunocompetent cells present in tumour stroma. Acta Otolaryn-gol 1976;81:353-63.17. PIFFKO J, BANKFALVI A, OFNER D, BRYNE M, RASCH D,JOOS U, BOCKER W, SCHMID KW. Prognostic value of histobio-logic factors (malignancy grading and AgNOR content) assessed atthe invasive tumour front of oral squamous cell carcinomas. Br JCancer 1997;75:1543-6.18. SILVESTRI F, BUSSANI R, PAVLETIC N, MANNONE T, BO-SATRA A. From epithelial dysplasia to squamous cell carcinoma ofthe head and neck region: evolutive and prognostic histopatholog-ical markers. Acta Otolaryngol 1997;527 (Suppl):49-51.19. BRYNE M, JENSSEN N, BOYSEN M. Histological grading in thedeep invasive front of T1 and T2 glottic squamous cell carcinomashas high prognostic value. Virchows Arch 1995;427:277-81.20. ODELL EW, JANI P, SHERRIFF M, AHLUWALIA SM, HIBBERTJ, LEVISON DA, MORGAN PR. The prognostic value of individ-ual histologic parameters in small lingual squamous cell carcinomas.The importance of the pattern of invasion. Cancer 1994;74:789-94.21. WELKOBORSKY HJ, HINNI M, DIENES HP, MANN WJ. Pre-dicting recurrence and survival in patients with laryngeal cancer bymeans of DNA cytometry, tumor front grading, and proliferationmarkers. Ann Otol Rhinol Laryngol 1995;104:503-10.22. FERENÈIÆ , PETRIC V, IVKIÆ M, BEDEKOVIÆ V, TARA-BARIÆ D. Klinièko znaèenje Brodersove i ICG klasifikacije plano-celularnih karcinoma laringohipofarinksa (Abstract). Medicina1994;30 (Suppl 2):24-5.References1. HANSEMANN D. Über assymetrische Zellteilung in Epithelkreb-sen und deren biologische Bedeutung. Virchows Arch A Pathol AnatHistopathol 1890;299-326.2. BRODERS AC. Squamous cell epitheliomas of the lip. JAMA1920;656-64.3. BRODERS AC. Squamous cell epithelioma of the skin. Ann Surg1921;73:141-60.4. BRODERS AC. Carcinoma: grading and practical applications. ArchPathol Lab Med 1926;2:376-81.5. GLEASON DE, MELLINGER GT, and the Veterans Administra-tion Cooperative Urological Research Group. Prediction of progno-sis for prostatic adenocarcinoma by combined histological gradingand clinical staging. J Urol 1974;111:58-64.6. DAUMAS-DUPORT C, SCHEITHAUER B, OFALLON J,KELLY P. Grading of astrocytomas: a simple and reproducible meth-od. Cancer 1988;62:2152-65.7. MIKUTA JJ. International Federation of Gynecology and Obstet-rics staging of endometrial cancer 1988. Cancer 1993;71:1460-3.8. BLOOM HJG, RICHARDSON WW. Histological grading and prog-nosis in breast cancer. Br J Cancer 1957;11:359-77.9. KEARSELY JH, FURLONG KL, WATERS MJ. An immunohis-tochemical assessment of cellular proliferation markers in head andneck squamous cell cancers. Br J Cancer 1990;61:821-7.Ivkiæ M. et al. Invasive cell grading in squamous cell caercinoma236 Acta clin Croat, Vol. 41, No. 3, 2002SaetakSTUPNJEVANJE INVAZIVNIH STANICA  PREGLEDM. Ivkiæ, V. Bedekoviæ, L. Kalogjera, H. Èupiæ i . FerenèiæPatohistoloka dijagnoza igra kljuènu ulogu u terapijskom pristupu raku te djeluje i kao prognostièki èimbenik. Histolokistupanj je brojèani izraaj diferencijacije tumora i vezan je uz prognozu tumorske bolesti u pojedinog bolesnika. Danas je u irokojuporabi Brodersov sustav histolokog stupnjevanja u karcinomima ploèastog epitela. Noviji podatci ukazuju na to da se morfologijai bioloko ponaanje stanica u invazivnim dubokim dijelovima malignog tumora razlikuju od sredinjih i povrinskih dijelova istogatumora. Novi sustav ICG (invasive cell grading  stupnjevanje invazivnih stanica) predloen je kao bolji prognostièki èimbenik usloenom dijganostièkom i terapijskom pristupu bolesniku s malignim tumorom. Brojna su istraivanja potvrdila da se novi sustavICG moe s dovoljnom sigurnoæu rabiti u patohistolokom stupnjevanju malignih tumora umjesto starog Brodersovog naèina.Kljuène rijeèi: Karcinom  dijagnostika; Karcinom  patologija; Karcinom  prognoza

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