Malignancy grading in squamous carcinoma of uterine cervix treated by surgery.

Some morphological patterns (histological type, vascular invasion, depth of invasion, lymphocytic infiltrate, mode of spread, necrosis) in 125 cases of squamous cervical carcinoma treated by surgery were analysed and graded in order to identify a histoprognostic score. Clinical data on F.I.G.O. stage, modality of surgical treatment, age, hormonal state (pre- or post-menopause) and 5-year survival were known for each patient. Two groups (low and high malignancy) were disclosed, and the difference of survival rate between the 2 was highly significant (P less than 0.001).

In irradiated patients, real differences in survival rate that depend on the cell type may be observed.Large-cell non- keratinizing carcinoma of the cervix treated with radiotherapy appears to be associated with greater survival than keratinizing carcinoma and small-cell car- cinoma (Wentz & Lewis, 1965; Finck &  Denk, 1970; Swan & Roddick, 1973;  Ng & Atkin, 1973).This difference in survival is not seen when the same classification is applied to surgical patients, since other factors probably also influence the prognosis (Sidhu et al., 1970).
Our study concerns some histological patterns which might have a more precise prognostic significance if evaluated to- gether, since we think that prognosis in CCU depends on many factors the evalua- tion of which will give good correlation with survival.

MATERIALS AND METHODS
125 cases of invasive squamous CCU observed at the Obstetric and Gynaecological Clinic of Padua University between 1 Novem- ber 1968 and 31 January 1974 were con- sidered.
Clinical data were recorded for each patient on F.I.G.O.stage and modality of surgical treatment (vaginal hysterectomy and bilateral salpingo -oophorectomy -Schauta -Amreich operation-or abdominal radical hysterectomy-Wertheim or Wertheim-Meigs operation-were used when possible, or anterior or posterior evisceration in more advanced clinical stages).Age, hormonal state (pre-or post-menopause) and 5-year survival were also recorded for each patient.
In each case, the material available included an average of 3 generous histological sections of the primary tumour and adjacent cervix.Specimens were fixed in formalin, and stained with haematoxylin and eosin; sometimes special staining such PAS-methenamine silver, and Weigert's elastic fibre stain was carried out.
Every specimen was reviewed blind by 2 of the authors (C.A.P. and P.D.P.) and the tumours were classified according to the Reagan-Wentz classification.
In addition, the specimens Were scored according to histological type and pattern, as follows: Histological type.-Keratinizingcarcinoma received a score of 1 (Figs 1, 2) and large-cell carcinoma was scored as 2 (Fig. 3) whilst small-cell carcinoma was rated as 3 (Fig. 4).In cases where more than one feature was apparent, the tumour was rated on the basis of the predominant cell type.Vascular invasion.-ofeither the lymphatic or blood vessels was scored 1 when absent, 3 when present.
Depth of invasion.-intothe cervical stroma was scored 1 if it measured less than 5 mm vertically (microinvasion), and 3 if it exceeded 5 mm.
Mode of spread-.wasscored 1 if the tumour extended into the cervical stroma on a broad front ("en bloc") and 2 if the carcinoma cells ;. , 1 1 I .: AL ..i extended in nests and strands, or in single cells ("tentacular").
Necrosis.was scored 1 when focal areas were present in the stroma or an isolated comedo pattern was observed; if no necrosis wNas observed, the score was 2.
On the basis of this scoring, malignant tumour scores range from a minimum of 6 to a maximum of 16 (Table I).

RESULTS
At diagnosis the mean age of patients was 52-8 + 9-7 years.Five-year age dis- tribution and hormonal state are reported in Fig. 5.In this series of 125 cases, 85 patients (68.000) were alive after 5 years, and 40 (3200%) were dead.
Age at first diagnosis Fin. 5. Distribution of cervical cancer according to age at first diagnosis and hormonal state (pre-an(l post-menopausal).
Table II reports survival in the 125 cases of invasive squamous carcinoma with respect to clinical stage and histological type.Patients in Stages I and II show better survival rates than patients in Stages III and IV, but there is no sig- nificant difference between one cell type and another.according to Since keratinizing carcinoma has a somewhat better prognosis, it was scored 1. Whilst small-cell carcinoma had a higher survival rate than large-cell car- cinoma, it was scored 3 because there were 9 cases of microinvasive carcinoma in the group, that modified the overall group survival (Table III).
Vascular invasion has a significant in- fluence on the prognosis (P < 0001; Table IV) and this explains a score of 1 and 3 to its absence and presence, respectively.The same holds true for depth of invasion, since survival is much better when the depth is less than 5 mm (Table V).
It was observed that mode of spread and necrosis have no real prognostic significance and thus were scored 1 or 2    (Tables VI and VII).On the other hand a statistically significant difference (P < 0 01 ) between markedly present and absent periand intra-tumoral lymphocytic in- filtrate was observed, as well as between moderate and absent (P < 0 05; Table VIII).The total score distribution of the cases is reported in Fig. 6.The scores in most cases range from 9 to 12.It may also be noticed that survivors and non-sur- vivors have an opposite distribution, the boundary line falling between scores 12 and 13.We thus considered a score be- tween 6 and 12 as indicating low malignancy, and a score between 13 and 16 as indicating high malignancy.
The 5-year survival rate decreases in the high-grade group, and between the 2 malignancy grades there is a statistic- ally sigonificant difference (P < 0 001; Table IX); this difference is especially significant in Stages I and II, while it is not so in Stages III and IV (Table X).P<0-001.

DISCUSSION
In our retrospective analysis, it was found that some histological patterns correlated well with survival.Vascular invasion has prognostic significance since it indicates a tendency to metastases (Friedell & Parsons, 1962; Friedell et al.,  1967; Gusberg & Herman, 1968; Sidhu  et al., 1970; Gusberg et al., 1971; van  Nagell et al., 1977, 1978) and the prognosis of patients with this pattern is less favourable than that of patients without vascular invasion (Table IV).
Classification of cell type in surgical cases gives no useful information (Table II).Survival rates in irradiated patients depend on cell type, and are probably due to the different radiosensitivity of the tumoral cells (Finck & Denk, 1970;  Gunderson et al., 1974).
In surgical patients, however; other parameters influence the prognosis.It was found that the depth of invasion was a significant indicator, and carcinomas < 5 mm have a better survival than those > 5 mm (Table V; Sidhu et al., 1970).The cure rate in microinvasive carcinoma is quite good, and only 1 of our 15 cases did not survive beyond 5 years.
Lymphocytic infiltration is also a mean- ingful pattern (Table VI).The immune response to tumour antigens represents an attempted defence against tumoral spread, so a good response indicates a blocking action against the tumour (Reagan et al., 1969; Ng & Atkin, 1973;  van Nagell et al., 1977, 1978).This is further shown by the poor prognosis in our cases without lymphocytic-plasmacellular stromal infiltrate.
Recognition of the mode of spread is very important because tentacular spread usually requires a more aggressive therapy for complete extirpation of the tumour.Nevertheless, in our series, mode of spread and necrosis are not prognostically significant.However, since other workers (Mitani et al., 1962; Reagan et al., 1969;   Ng & Atkin, 1973;Fisher et al., 1978).report useful indications from these pat- terns, further studies into these aspects may clarify their prognostic significance.
As illustrated in Table IX, our cases can be divided into 2 groups: one with low- TABLE X.-Relation of histological scores to survival of 125 cases of infiltrating squamous grade malignancy, and one with a high grade.
The survival rate in the 2 groups is very different.It appears that cases of squamous CCU may be best resolved by evaluating all these histological patterns together.The fuller information thus obtained may give a better indication of the various factors influencing the prog- nosis.
microinvasive cases: all 8 cases in Stage I alive; of 7 Stage II cases, 6 alive, 1 dead.
FiG.6.-Distribution of 125 cases of infiltrating squamous cervical carcinoma according to scores.

TABLE I .
-Scores of histological features of

TABLE II .
-Five-year survival of 125 cases of infiltrating squamous CCU histological type and clinical staye

TABLE V .
-Five-year survival of 125 cases

TABLE VI .
-Five-year survival of 125 cases

TABLE VIII
P < 0.05 between moderate and absent.