Pathologic Features of Prognostic Significance in Adrenocortical Carcinoma
Lawrence M. Weiss, M.D., L. Jeffrey Medeiros, M.D., and Austin L. Vickery, Jr., M.D.
There are currently no well-established pathologic prog- nostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 patho- logic parameters on survival was investigated in 42 cases of adrenocortical carcinoma. Only one variable, mitotic rate, had a strong statistical association with patient out- come. The 21 patients with carcinomas with >20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with ≤20 mitoses had a median survival of 58 months (p < 0.02). The presence of atypical mitoses, capsular inva- sion, tumor weight >250 g, and size >10 cm each showed a marginal statistical association with poor survival (p < 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or archi- tectural pattern, showed no statistical significance in pre- dicting survival. It is proposed that adrenal cortical car- cinomas with >20 mitoses be designated high grade, whereas tumors with ≤20 mitoses be designated low grade.
Key Words: Adrenocortical carcinoma-Mitosis count- ing-Tumor grading-Endocrine neoplasms.
Am J Surg Pathol 13(3): 202-206, 1989.
Adrenocortical carcinoma is a highly lethal can- cer with a mortality rate of over 50% (5,6,8,10,13). Although many of those who die of the disease do so within the first few years after presentation, oth- ers live much longer before evidence of recurrence or metastasis appears. Although the separation of adrenocortical carcinoma from adenoma can usu- ally be made in a large majority of cases by study of multiple pathologic features (8,18,19), currently no uniformly agreed on pathologic characteristics exist that are helpful in the distinction between low and high grade adrenocortical carcinomas. Some inves- tigators have suggested that a correlation may exist between tumor grade and survival (7,12,13,15,17), whereas others have found no relationship between histologic features and prognosis (2).
If it were possible to separate adrenocortical car- cinomas into tumors with a high probability of rapid progression and early death versus those with a more indolent course, this might afford a rational basis for the selection of patients who might best benefit from postsurgical adjuvant chemotherapy. This separation may well be clinically useful, since the one agent that has been found to be effective in inducing an antitumor response, mitotane, causes significant toxic effects when this drug is used at therapeutic doses (1,9,14,16).
In the current study, a series of adrenocortical carcinomas were examined for various pathologic parameters and their relationship to survival.
MATERIALS AND METHODS
The cases of adrenocortical carcinoma were iden- tified from the pathology files of the Peter Bent Brigham and Brigham and Women’s Hospitals from the period 1959 to 1980 and of the Massachusetts General Hospital from the period 1949 to 1987. The former cases have previously been reported as part
From the Department of Pathology, Stanford University, Stanford, California (L.M.W.), and the Department of Pathol- ogy, Massachusetts General Hospital, Boston, Massachusetts (L.J.M., A.L.V.).
Address correspondence and reprint requests to Lawrence M. Weiss, M.D., Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, U.S.A.
of a comparative study of benign and malignant ad- renocortical tumors (19). All cases chosen for this study met the following criteria: (1) presence of at least three of nine previously proposed microscopic criteria of adrenocortical carcinoma (19): nuclear grade III or IV, mitotic rate >5 per 50 high power fields (hpf), typical mitoses, clear cells constituting ≤25% of the tumor, diffuse architecture, necrosis, invasion of venous structures, invasion of sinusoi- dal structures, and invasion of tumor capsule; (2) absence of a primary carcinoma at another site at the time of diagnosis; and (3) known follow-up in- formation. The definitions relating to the foregoing criteria and representative illustrations of each ap- pear in a previous report (19). Briefly, nuclear grade was assessed according to the criteria of Fuhrman et al. (3). Mitoses were evaluated by counting 10 random hpf in the area of the greatest numbers of mitotic figures on the five slides with the greatest numbers of mitoses. The counts were performed on an American Optical microscope using a ×45 ob- jective with a field 0.47 mm in diameter. Atypical mitoses showed an abnormal distribution of chro- mosomes or an excessive number of mitotic spin- dles. Diffuse architecture was present if greater than one third of the tumor formed patternless sheets of cells; otherwise, the architecture was re- garded as nondiffuse. Necrosis was regarded as present when occurring in at least confluent nests of cells. Invasion of sinusoids (endothelium-lined ves- sels with little supporting tissues) and veins (vessels with smooth muscle in the wall) was accepted only when unequivocal. Capsular invasion consisted of nests or cords of tumor within or penetrating the capsule, with a corresponding stromal reaction. Survival curves were calculated using the actuarial technique of Kaplan and Meier (11). For display, all curves were plotted at yearly intervals. The signif- icance of differences between curves was calcu- lated by the generalized Wilcoxon (Gilbert-Gehan) test, which compares differences along all points of the curves (4). All significance levels are of the two- sided type. In addition to the nine histologic param- eters enumerated, size and weight were also evalu- ated.
RESULTS
Tumor Characteristics
Of 87 adrenocortical tumors with known clinical follow-up and absence of another primary carci- noma, 42 exhibited three or more of the defined histologic criteria for carcinoma and were included in the current study. None of the 45 cases with
fewer than three criteria showed evidence of recur- rence or metastasis, including 33 cases with a min- imum follow-up time of 5 years.
The gross and histologic features of the 42 carci- nomas are summarized in Table 1. No one patho- logic finding was found in all cases. Grade III to IV nuclei were present in 88% of cases. A mitotic rate of >5 per 50 hpf was observed in about three fourths of cases, with atypical mitoses present in all but three of those cases. Three cases had no ob- servable mitotic figures. The architecture of the car- cinomas was predominantly diffuse in 71% of cases, and necrosis was observed in 90% of cases. Ve- nous, sinusoidal, and capsular invasion was seen in 50%, 57%, and 57% of cases, respectively. The weights of the carcinomas ranged from 38 to 4000 g,
| Feature | Number of cases | Percentage |
|---|---|---|
| Nuclear grade | ||
| 1 | 0/42 | 0 |
| II | 5/42 | 12 |
| III | 16/42 | 38 |
| IV | 21/42 | 50 |
| Mitotic rate (per 50 hpf) | ||
| 0-5 | 10/42 | 24 |
| 6-20 | 11/42 | 26 |
| 21-50 | 16/42 | 38 |
| >50 | 5/42 | 12 |
| Atypical mitoses | ||
| Absent | 13/42 | 30 |
| Present | 29/42 | 70 |
| Cytoplasm | ||
| 26-100% clear | 4/42 | 10 |
| 0-25% clear | 38/42 | 90 |
| Architecture of tumor | ||
| Nondiffuse | 12/42 | 29 |
| Diffuse | 30/42 | 71 |
| Necrosis | ||
| Absent | 4/42 | 10 |
| Present | 38/42 | 90 |
| Invasion of venous structures | ||
| Absent | 21/42 | 50 |
| Present | 21/42 | 50 |
| Invasion of sinusoidal structures | ||
| Absent | 18/42 | 43 |
| Present | 24/42 | 57 |
| Invasion of capsule | ||
| Absent | 18/42 | 43 |
| Present | 24/42 | 57 |
| Weight (g) | ||
| 0-100 | 2/29ª | 7 |
| 101-250 | 7/29 | 24 |
| 251-1,000 | 13/29 | 45 |
| >1,000 | 7/29 | 24 |
| Size (cm) | ||
| 0-5 | 2/38b | 5 |
| 6-10 | 11/38 | 29 |
| 11-20 | 21/38 | 55 |
| >20 | 4/38 | 11 |
a Weight recorded in 29 cases.
b Size recorded in 38 cases.
with a median weight of 528 g in the 29 tumors in which weights were recorded. In size the carcino- mas ranged from 4 to 28 cm with a median size of 12 cm for the 38 tumors for which measurements were available.
Patient Characteristics
The median age of the 42 patients with adrenal cortical carcinoma was 47 years, with a range from 6 to 70 years. Twenty-three tumors were located on the left side, and 19 tumors were present on the right. Twenty-six patients (62%) had evidence of endocrine disease on presentation: 12 with Cush- ing’s syndrome, nine with virilization, two with Conn’s syndrome, two with gynecomastia, and one with mixed Cushing’s syndrome and virilization. Sixteen patients (38%) presented without clear ev- idence of an endocrine syndrome.
Thirty-four of the 42 patients (81%) developed distant metastases, including 14 patients with me- tastases evident at initial diagnosis. Four additional patients (10%) had local disease recurrences. Thirty-three of the 38 patients (87%) with metasta- sis or recurrence were followed until their death. Four of the 42 patients (10%) had no evidence of disease at follow-up periods of 19, 61, 96, and 366 months. The median disease-free survival for all pa- tients was 8 months, and the median survival was 29 months (Figs. 1 and 2).
The various pathologic features were analyzed with respect to patient outcome. Mitotic rate showed a strong correlation with survival. The 21 patients with carcinomas with >20 mitotic figures per 50 hpf had a median survival of 14 months, whereas the 21 patients with carcinomas with ≤20 mitotic figures had a median survival of 58 months (generalized Wilcoxon test p < 0.02) (Fig. 3). In
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addition, similar statistically significant separation into two prognostic groups was achieved when 3 (p < 0.04), 5 (p<0.02), and 15 (p<0.03) mitoses per 50 hpf were used as cutoffs, and marginal signifi- cance separating the cases into two prognostic groups was achieved when 10 (p < 0.09) and 30 (p < 0.06) mitoses per 50 hpf were used as cutoffs, im- plying that mitotic activity showed a strong nega- tive correlation with survival. However, absence of mitotic activity did not necessarily imply a com- pletely benign course, as two of the three cases with no observable mitoses showed progression of dis- ease over the time of follow-up.
The individual presense of atypical mitoses, cap- sular invasion, tumor weight greater than 250 g, and size greater than 10 cm showed a marginal statisti- cal association with decreased actuarial survival (all p < 0.06) (Figs. 4-7). Multivariate analysis to ex- plore the possible prognostic value of combining more than one of the diagnostic criteria was not feasible owing to the small number of cases and the strong correlation of one variable (mitotic rate) with survival. None of the other pathologic features showed a statistically significant correlation with survival.
No pathologic feature showed a statistically sig- nificant effect on disease-free interval. Despite the strong correlation of mitoses with survival, mitotic rate was a poor predictor of time to recurrence or metastasis.
DISCUSSION
The results of our study suggest that mitotic ac- tivity is the most important pathologic determinant of survival in patients with adrenocortical carci- noma. Separation of adrenocortical carcinomas into those with >20 mitotic figures per 50 hpf and those
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with ≤20 per 50 hpf fortuitously yielded two groups of equal size with a significantly different prognosis. Other pathologic parameters, including nuclear grade, showed only a weak or no significant asso- ciation with patient outcome. It is, therefore, pro- posed that adrenocortical carcinomas with >20 mi- toses per 50 hpf be designated high grade and those with ≤20 be considered low grade. In the present series, patients with high grade tumors had a me- dian survival of 14 months, versus 58 months for patients with low grade neoplasms. However, it must be kept in mind that several other divisions of mitotic rate also achieved statistically significant separation of the patients into two prognostic groups; that is, there was a negative linear correla- tion of mitotic activity with survival. A cutoff of 20 mitoses per 50 hpf is recommended to create two
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grades because it separates the patients into two large groups with distinct survival curves.
In the current study, and in a previous study by one of the present authors (19), the mitotic rate of adrenocortical carcinomas was found to be some- what higher than that reported by Hough and col- leagues (8). In the present study, 76% of the carci- nomas had a mitotic rate of >5 per 50 hpf, which was true for only 57% of the metastasizing tumors of Hough et al. (8). The current study method con- sisted of counting 10 random hpfs in the area of the greatest numbers of mitotic figures on the five his- tologic sections with the greatest number of mitoses for a total of 50 hpf; in contrast, Hough et al. de- scribe counting 100 hpf, presumably at random.
Analysis of the adrenocortical neoplasms evalu- ated for this study provided a validation of the pre- viously described histologic criteria proposed by
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Weiss (19). In that report, analysis of 9 histologic features (summarized in the Methods of this study) were found to provide discrimination between ade- noma and carcinoma, since 18 of 19 patients with tumors exhibiting four or more histologic criteria had evidence of metastasis or disease recurrence whereas none of 18 patients with tumors with two or fewer histologic criteria showed disease progres- sion. In addition, we have lowered the threshold for malignancy from four to three histologic criteria on the basis of a new case from the current series, a patient whose tumor satisfied three criteria and who developed a local recurrence at 55 months and eventually died of disease at 116 months. Twenty- three newly studied tumors had at least three of nine histologic criteria of malignancy; 20 of the pa- tients in this group have died of disease and only three had no evidence of disease at last follow-up examination at 19, 61, and 366 months. In contrast, all 24 patients with tumors newly reviewed satisfy- ing fewer than three criteria of malignancy (and therefore not included in the statistical analyses) had no evidence of recurrence or metastasis, in- cluding 12 with a follow-up period of 5 or more years.
This study also highlights the dismal prognosis of adrenocortical carcinoma when properly separated from adrenocortical adenoma. The overall survival
rate was just under 10%, with a median survival time of 29 months. Even the large majority of pa- tients with low grade carcinomas have an overall poor survival rate (14% in our series), although pro- gression to death may take many years in this group of patients. ☐
Note added in proof: The correlation coefficient (r) for the association between mitotic rate and clinical outcome in the 42 patients is - 0.66 (p < 0.01).
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