Portuguese Version

Year:  2001  Vol. 67   Ed. 6 - (9º)

Artigo Original

Pages: 819 to 823

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Clinical-pathologic correlation between the presence of microscopic necrosis and evolution of initial laryngeal squamous cell carcinoma

Author(s): Otávio A. Curioni 1,
Marcos R. Magalhães 1,
Marcos B. Carvalho 2,
Abrão Rapoport 3,
Marilene P. Rosa 4.

Keywords: necrosis, squamous cell carcinoma, larynx

Abstract:
Introduction: To analyze the presence of microscopic tumoral necrosis in primary initial laryngeal tumor and to correlate it with clinical characteristics and histopathology to identify the impact in the evolution. Study design: Clinical retrospective. Material and methods: Retrospective study of the medical files and revision of histology sections of 49 squamous cell carcinoma of the larynx staged T1 and T2, treated in the Service of Head and Neck Surgery at Heliópolis Hospital, São Paulo /SP, between January/1978 and December/1997. Results: There was strong association between the presence of microscopic necrosis and the infiltrative characteristic of the primary lesion (p=0.004), lesions in the supraglottic (p=0.021), clinical staging T2 (p=0.04), occurrence of cervical metastasis (p=0.04) and less differentiated lesions (p=0.025). Those cases that presented microscopic necrosis tended to have the best evolution. Conclusion: The information gathered by our study suggested that necrosis itself, as classified by histopathology techniques, may not have exclusive influence or reflex on volume of growth, reflecting the rate of tumoral growth, but it may be related to other tumor factors and/or to a host, such as programmed cellular death.

Introduction

Advances in treatment and cure of cancer, especially of the head and neck, have been made possible by understanding tumor biology and having the capacity to define individual prognosis, leading to the formulation of new and more selective therapeutic strategies for each patient. The likelihood to predict clinical behavior of laryngeal cancer through histopathological studies is in fact one of the objectives of researchers involved in this issue. Metastatic manifestation of cancer in regional lymph nodes has been appointed as the most important prognostic factor for laryngeal cancer1. However, in initial glottic tumors, low incidence of regional metastases is expected and parameters analyzed in histopathological exams of primary tumors are not significant to identify the candidates to local and regional recurrence, and consequently, those who were to benefit from some additional therapy. Among the factors that may indicate tumor aggressiveness, determining worse prognosis, the speed of tumor growth has been considered as an indicative event, depending on the balance between programmed cell death (apoptosis) and cellular proliferation, and any alterations in these factors may be the key to uncontrolled expansion of malignant tumors. Thus, neoplasic cells with high proliferation rates may lead to tumor growth beyond the nourishing capacity of the blood supply, predisposing to necrosis. In view of that, we aimed at conducting a retrospective study to analyze the presence of microscopic tumor necrosis in initial primary laryngeal tumors and correlate them to some clinical and histopathological characteristics in order to identify its impact on evolution.

Material and Method

Based on retrospective analysis of medical files and histological review of surgical piece blocks, the present study aimed at correlating the presence of microscopic tumor necrosis and other clinical-pathological characteristics of 49 patients with laryngeal squamous cell carcinoma treated at the Service of Head and Neck, Complexo Hospitalar Heliópolis, São Paulo/SP, between September 1977 and December 1997. The pre-requirements for inclusion in the study were: not to have being submitted to previous treatment, had undergone surgery, minimum follow-up of 60 months (5 years) and primary neoplasia staged as T1 or T2 (TNM classification - 1997). There were 47 men (95.9%) and two women (4.1%). Ages ranged from 29 to 75 years, mean age of 58 years and median of 59 years.

We collected sections from paraffin blocks of the material obtained from the primary tumor, stained them with hematoxylin-eosin (HE) and reviewed them in details, trying to define the characteristics concerning the following variables: grade of histologic differentiation, presence of angiolymphatic embolization, perineural infiltration, presence of necrosis, invasion pattern in the interface, host tumor and desmoplasia. Slides were revised by one single pathologist.

Descriptive statistical analysis (mean, median, standard deviation) were used for macroscopic variables, TN stages, histologic grade, invasion pattern and microscopic necrosis (Photos 1, 2 and 3).

The association between variables was made through chi-square test of hypothesis or Fisher exact test for frequencies, depending on the sample, at a 5% significance level.

Photo 1.



Photo 2.



Photo 3.

Results

Out of 8 cases in which there was necrosis in the primary tumor, seven had infiltrating aspect in the lesion and only one had vegetating aspect - statistically significant correlation (Table 1).

The presence of necrosis in the primary tumor found in 16.3% of the cases showed significant distribution when compared to the primary site (Table 2).

When correlated with categories T and N, necrosis presented positive association with more advanced lesions, that is, T2 N+ (Table 3).

Tumor necrosis, when correlated to angiolymphatic neoplasic embolization, did not present statistically significant correlation (Table 4).

The presence of tumor necrosis tended to concentrate on less differentiated lesions (Table 5).

The pattern of tumor invasion, when correlated with the presence of necrosis, did not present statistical correlation (Table 6).

The number of alive patients with no evidence of disease (VSED), patients who died of laryngeal cancer (MOCA), patients who died of other causes rather than laryngeal cancer (MOAS) and rate of second lesion up to the end of the present study were also identified (Table 7).

Table 1.



Table 2.



Table 3.



Table 4.



Table 5.



Table 6.



Table 7.

Discussion

Conceptually, necrosis and apoptosis are two morphological expressions of cellular death, representative of a spectrum of morphological alterations that follow after the cellular death of a living tissue. Necrosis results, in most part, from the progressive action of enzymes on the lethally affected cell. Two essentially competitive processes take to alterations of necrosis: enzymatic cell digestion and protein denaturation 2. Apoptosis is another morphological pattern of cellular death caused by varied noxious stimulus capable of causing necrosis. The alteration may be a result of mild thermal lesion, radiation, anti-cancer cytotoxic drugs, and possibly, hypoxia. Its function is to delete cell from the normal development, organogenesis, immune functioning and tissue growth, but it may also be induced by pathological stimuli3. Cell retraction and formation of apoptotic bodies are quick and fragments are quickly phagocytosed, degraded or eliminated by light; a considerably serious apoptosis may affect tissues before they become apparent in histologic sections. In addition, apoptosis, differently from necrosis, does not stimulate inflammation, hindering more and more histologic detection4. Inappropriate blood supply, caused by imperfectly formed vascular canals in cancer tissues may predispose to insufficient nutrition and less removal of dead tumor tissue. Cells with high proliferation rates may lead to growth beyond the nourishing capacity of the blood supply5, or alternatively, provide the necessary conditions for a higher neoplasic progression rate, by means of acquisition of autonomic properties, resulting in metastasis and drug-resistance. Neoplasic growing cells obviously need blood supply; however, vascular connective stroma is reduced and, in fact, less differentiated tumors and/or anaplastic tumors with central areas suffer ischemic necrosis.

Necrosis normally affects solid tumors. Folkman6 demonstrated that cultured tumor cells may grow in the absence of vascularization, up to nodules in the range of 1 to 2mm in diameter. When implanted in tissues, there is more growth because of the development of blood supply in host tissues. Careful examination normally reveals that the necrotic region is parallel to the tumor blood vessel, and separated from it by a 1 to 2mm zone of viable tumor cells. Theoretically, this 1-2mm zone around blood vessels represents the maximum distance through which the oxygen and other nutrients may be distributed. Therefore, it is supposed that the presence of tumor microscopic necrosis may be indicative of lesions that have higher aggressive potential, in which the faster growing pace of neoplasic cells would not provide the blood supply to the corresponding tumor, causing an area of ischemic necrosis. According to our results, we noticed strong correlation between presence of microscopic necrosis and infiltrating characteristics of the primary lesion, supraglottic lesions, T2 clinical staging, occurrence of cervical metastases and less differentiated lesions. Although there was no statistical confirmation, the presence of tumor necrosis was more incident in lesions of patients up to 59 years of age.

Although the studies have shown that the presence of necrosis in the tumor causes hemorrhage, which would facilitate the neoplasic invasion of blood and lymphatic vessels7, we did not find such a correlation.

Even though tumor necrosis has been significantly associated with poor prognosis of breast cancer, it was not correlated with lymph node status and revealed its influence in treatment failure, regardless of the size of the tumor4, 8, 9.

Despite the limited number of patients included in the present study, the results suggested that tumor microscopic necrosis be may associated to lesions that have better evolution trend from the local control point of view, since the groups of patients in which there was necrosis of the primary tumor, the rate of second lesion was higher. In other words, as described by the literature10, 11, the rate of development of a new tumor in the digestive tract is increased at a rate of 10% a year if there is local regional control of the first lesion.

Information collected to our study suggested that necrosis per se, as classified by the histopathologic techniques, may not represent exclusive influence or reflex of the volumetric growth, reflecting the rate of tumor growth, but it may be related to other tumor factors and/or to host factors (apoptosis mechanisms). New studies, including those with head and neck tumors, should be developed to target this analysis. In summary, the findings of tumor necrosis could be taken into account considering the detailed follow-up the patient should be submitted. New studies approaching the histopathologic manifestation of tumor necrosis, biological markers involved, apoptosis mechanisms and mediators and cellular proliferation markers, especially in initial lesions, should be performed.

References

1. STELL, P.M. - Prognosis in laryngeal carcinoma: tumor factors. Clin. Otolaryngol., 15:69-81, 1989.
2. MANJO, G. - Cellular death and necrosis: chemical, physical and morphologic changes in rat liver. Virchows Arch., 333:421, 1960.
3. CARSON, B. A.; RIBEIRO, D. M. - Apoptosis and disease. Lancet, 341:1251, 1993.
4. WYLLIE, A.H. - Apoptosis and regulation of cell numbers in normal and neoplastic tissue: An overview. Cancer Metastasis Ver., 11:95, 1992.
5. GILCHRIST, K.W.; GRAY, R.; FOWBLE, B.; TORMEY, D.C.; TAYLOR, S.G. - Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node - positive breast cancer: A 10 - year follow-up study of 728 Eastern Cooperative Oncology group patients. J. Clin. Oncol., 11:1929-35, 1993.
6. FOLKMAN, J. - Tumor angiogenesis. In Holland, J.F., et al. (eds.): Cancer Medicine. 3rd ed. Philadelphia, Lea & Febiger, 1993, p.153.
7. WEISS L. - Principles of Metastasis. Orlando F. L.: Academic Press, 1985.
8. FISHER, E.R.; PALEKAR, A.S.; GREGORIO, R.M.; REDMOND, C.; FISHER, B. - Pathological findings from the National Surgical Adjuvant Breast Project. Significance of tumor necrosis. Hum. Pathol., 9:523?30, 1978.
9. ROSES, D.F.; BELL D.A.; FLOTE T.J.; TAYLOR R; RATECH, H.; DUBIN, N. - Pathologic predictor of recurrence in stage 1 breast cancer. Am J Clin Pathol. 78:817-20,1982.
10. BATSAKIS, J.G. - Synchronous and metachronous carcinomas in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 10:2163-72, 1984.
11. BLACK, B.J.; GLUCKMAN J.L.; SHUMRICK, D.A. - Multiple primary tumors of the upper aerodigestive tract. Clin. Otolaryngol. 8:277?80, 1983.

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1 Assistant Physician, Service of Head and Neck Surgery, Hospital Heliópolis, São Paulo /SP.
2 Head of the Service of Head and Neck Surgery, Hospital Heliópolis, São Paulo /SP.
3 Coordinator of the Post-Graduation Course on Head and Neck Surgery, Hospital Heliópolis, São Paulo /SP.
4 Assistant Physician, Service of Pathology, Hospital Heliópolis, São Paulo /SP.

Study conducted at the Service of Head and Neck Surgery, Hospital Heliópolis, São Paulo /SP.
Address correspondence to: Prof. Dr. Abrão Rapoport - Praça Amadeu Amaral, 47 - cj. 82 - Paraíso
01327-010 - São Paulo /SP.

Tel: (55 11) 289-6229 / 287-4347. E-Mail: cpgcp.hosphel@attglobal.net

Article submitted on May 10, 2001. Article accepted on May 30, 2001.

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