World J. Surg. 16, 663-668, 1992
World Journal of Surgery © 1992by the Soci616 Intemationalede Chirurgie
Adrenal Cortical Carcinoma in Norway, 1970-1984 Jon Arnc Sereide, M . D . , K n u t B r a b r a n d , M . D . , and Steinar 0 . T h o r e s e n , M . D . , Ph.D. bepartment of Surgery, Rogaland Central Hospital, Stavanger, Department of Radiology, Akershus Central Hospital, Nordbyhagen, and Norwegian Cancer Registry, Oslo, Norway Adrenal cortical carcinoma is a rare and highly malignant tumor. This retrospective study includes 99 patients (57 males and 42 females) reported to The Cancer Registry of Norway during the 15 year period from 1970 to 1984. The age adjusted incidence was 1.5 per million per year. Eighty-one patients were diagnosed with adrenal cortical carcinoma When still alive. In 18 cases the diagnosis was first made at autopsy. Median age at diagnosis was 54 years (range 2-88 years) with a slight male Predominance. Information about initial symptoms was available in 67 Patients, of whom 26 patients (18 females and 8 males) presented with clinically functioning tumors, the Cushing syndrome and virilization being most frequently encountered. Only 28 (35%) of 81 patients diag. nOSed when still alive had tumors confined to the adrenals. Half of the Patients had distant metastases, with lungs and liver being the most frequent sites. Sixty-one patients underwent surgery; 51 patients had a radical Or debulking operation and 10 patients had laparotomy with tumor biopsy. After a complete follow-up for at least 6 years (range 6-21 Years), only 9 patients were still alive. Early stage (Stage I and lI) and curative resection had a significant impact on the outcome of this disease. To improve prognosis, early diagnosis and radical surgery, if feasible, are ~eeded.
Adrenal cortical carcinoma (ACC) is a rare malignancy all over the world. The age adjusted incidence has been estimated at 2 Per million population per year [1]. The location of the adrenal glands, deep in the retroperitoneum, make them inaccessible for clinical examination. Most patients with disorders of the adrenal cortex have traditionally presented with either endoCrine disturbances caused by increased secretion of steroid hormones or symptoms related to an abdominal mass [I, 2]. It is obvious from previous studies that most patients with ACC are diagnosed at an advanced clinical stage and, accordingly, the prognosis has been poor [2-5]. The early diagnosis requires a high degree of suspicion by the physician and the surgical Oncologist. Most papers on this rare disease have been based on a rather small number of patients, often from a single or very few institutions. This study comprises all new cases of ACC in the total population of Norway during a time period of 15 years. Based on data from this unique study population, we address Presented at the International Association of Endocrine Surgeons in StOckholm, Sweden, August, 1991. R Reprint requests: Jon Arne SCreide, M.D., Department of Surgery, ogaland Central Hospital, N-4011 Stavanger, Norway.
questions relevant for diagnosis, treatment, and prognosis in patients with ACC.
Materials and Methods
The Norwegian Cancer Registry was established in 1953 and is based on the compulsory reporting of all new cases of cancer in the total population. The Registry receives each year about 70,000 reports on 19,000 new cancer patients. The reports consist of clinical forms as well as cytology, biopsy, and autopsy reports from the pathology laboratories, and finally death certificates from the Central Bureau of Statistics in Norway. An evaluation of this system in 1978 showed a completeness close to 100% [6]. All data in this study were collected from the original reports and reviewed by the authors. In cases of missing data, additional applications were made to institutions in which the patients had been treated to provide information necessary for this study. Complete follow-up data were available for all patients via the Central Bureau of Statistics. The follow-up was closed December 31, 1990. Staging of disease was done retrospectively according to the criteria of McFarlane [7] as modified by Sullivan and coworkers [8] (Table I). We identified I55 malignant adrenal tumors of which 99 were histologically confirmed to originate from the adrenal cortex. Statistical evaluation was generally done by means of nonparametric methods. The log-rank test was used for survival analysis. A p value < 0.05 was considered statistically significant.
Results
Age and Sex Among the 99 patients there was a slight male predominance, with 57 male and 42 female cases (Fig. 1). All age groups were affected, with an accumulation of patients in the fifth and sixth decade. The median age at diagnosis was 54 years (range 2 to 88 years).
664
World J. Surg. Voi. 16, No. 4, July/Aug. 1992
Table 2. Presenting symptoms and signs in 81 patients with adrenal cortical carcinoma."
Table 1. Staging criteria in adrenal cortical carcinoma.
Staging criteria TI Tumor -< 5 cm, no invasion T2 Tumor > 5 cm, no invasion T3 Tumor any size, locally invading to but not involving adjacent organs T4 Tumor any size, locally invading adjacent organs NO No regional positive lymph nodes N1 Positive regional nodes M0 No distant metastatic disease Distant metastatic disease Mt Staging Stage
Size (cm)
l
1I III IV
Symptom/sign
Nodes
Local invasion
5 Any size Any size
-+ +
-+ +
--+
Metastases
Non-functioning tumors (n = 34) Pain Unspecific gastro-intestinal symptoms Functioning tumors (n = 26) Cushing's syndrome Virilization Feminizing Hypertension Symptoms not reported (n = 21)
I~[~ FemaleIs
25 '
Males
Female (n = 39)
Total (n = 81)
9 14
7 4
16 18
4 1 2 1 11
t1 6 0 1 I0
15 7 2 2 21
al8 patients first diagnosed at autopsy are not included in this table. Table 3. Stage of disease at diagnosis (n = 99).
- - : Absent; +: Present. 30
Male (n = 42)
Stage
Male (n = 57)
Female (n = 42)
No metastases Regional lymph nodes Local invasion of adjacent tissue Distant metastases
17 (30%) 3 (5%) 8 (14%) 29 (51%)
13 (31%) 1 (2%) 6 (14%) 22 (52%)
'~ 20'
Z 10" 5' 0
.
0-9
.
.
.
.
.
.
.
.
10-19 20-29 30-39 40-49 50-59 60-69 70-79 • 80 Age categories
Fig. 1. Age and sex distribution in 99 patients (42 females and 57 males) with adrenal cortical carcinoma.
Diagnosb The radiological studies performed in our series largely reflect the technical development in radiology during this period of time. In the beginning, traditional tests such as intravenous pyelography, retroperitoneal pneumography, nephrotomography, selective arteriography, and venography were performed on an individual basis. The final diagnosis was based on biopsy of the primary tumor in 77 patients. Four patients were diagnosed by biopsy o f distant metastases. A later autopsy verified the diagnosis in 30 cases. In 15 patients the diagnosis o f ACC was first confirmed at autopsy, and in an additional 3 patients the diagnosis was an incidental finding at routine autopsy. The median age for these 18 patients with diagnosis at autopsy was generally higher than for those with diagnosis at biopsy (median age 60 years versus 52 years).
Symptoms Information about initial symptoms and signs was available for 60 patients (Table 2). The most common symptoms were abdominal pain and unspecific gastrointestinal symptoms, oc-
curring in 34 p a t i e n t s . Twenty-six patients (18 females and 8 males) had functioning tumors with hormonal excess causing clinical symptoms such as Cushing's syndrome and virilization (Table 2). The median age o f patients with a functioning tumor was 42 years (range 2-68 years) as compared to 57 years (range 5-88 years) for patients with nonfunctional tumors. Functioning tumors were more commonly found in females (ratio male: female = 1:2).
Location and Stage A slight left-sided prevalence was found, with the primary tumor localized on the left side in 51 patients and on the right side in 44 patients. Bilateral tumors were present in 4 patients. The stage distribution at the time of diagnosis is listed in Table 3 and 4. Only 30 patients were without metastases, and the majority of the patients had advanced disease (Stage Ill/IV, see Table 1 for definition). The stage distribution was equal for both sexes (Table 3). Twelve (46%) of 26 patients with functioning tumors and 8 (24%) of 34 patients with nonfunctioning tumors had no metastases, indicating a less advanced disease among patients in the functioning tumor group (Table 4) (p = 0.05, F i s h e r ' s exact test, two-sided). In 55 patients with extra-adrenal disease (Table 3), the most frequent sites of metastases were liver (55%) and lungs (35%). L y m p h node metastases or local extension o f tumor into adjacent tissues were also commonly found. In some cases metastases to pleura, pancreas, kidneys, bone, brain, spleen, and skin were present. Multiple metastatic sites could be found in 39 (71%) patients with extra-adrenal disease.
J,ASerei . deetal.:AdrenalCorticalCarcinoma Table 4. Stage of disease at diagnosis according function o f the adrenal cortical a d e n o m a (n = 81). a
Stage
--.._.,_
No metastases Regional lymph nodes ocal invasion to adjacent tissues Distant metastases
--.-...
665 to
endocrine
I00'
Symptoms
80"
Functioning (n = 26) 12 1 1
Nonfunctioning (n = 34) 8 2 7
not reported (n = 21) 8 1 3
12
17
9
.~.
6o"
~
40. 20"
"18 patients diagnosed at autopsy are not included in this table. Years Fig. 2. Survival rates by stage o f disease at diagnosis. The follow-up
Table 5. Surgical procedures in 61 patients."
--,-...
Surgical procedure
-..-...
time was 6 years or more. p < 0.01 ; log rank test. No. of pts. (%)
Adrenalectomy
28 (46)
Adrenalectomy + Nephrectomy L~aparotomy + Biopsy
23 (38) 10 (16)
100-~,
[
8
~38 patients did not undergo surgical procedures; 18 patients were first diagnosed at autopsy, 20 patients were offered non-surgical treatment without surgical exploration.
o
'
t>------ .¢~54yrs. I
~
'~ 40
Treatment 20"
Surgery. Various primary surgical procedures were performed on 61 patients (Table 5). Twenty-three patients underwent rather extensive surgery including radical adrenalectomy and nephrectomy. In several patients lymph nodes and surrounding tumor tissues were removed. None of the patients died within the first 30 days following surgery. Seventeen of 26 patients With hormone producing tumors underwent surgery. In general, the patients who underwent surgery tended to be younger than Patients treated with non-surgical options.
0
0
Radiation Therapy. In a few patients, irradiation therapy was given as a palliative measure. Details concerning this therapeutic option were not recorded.
i
i
2
3 Years
* ..................
4
5
6
Fig. 3. Survival rates by age (median age 54 yrs for the study population), No statistically significant difference was found.
Systemic Therapy. In 26 patients medical treatment was given either as single agent or combination systemic chemotherapy. In this group, 14 patients received o,p'DDD[l,l,dichloro-2(OChlorophenyl)-2(P-chlorophenyl)ethane] either as a single drug, or in combination with drugs such as doxyrubicin, cyclophosPhamide, cisplatin, streptozotocin, or others. Medical treatment was given both as adjuvant treatment after surgery in SOme patients, or as the only treatment option in patients not Undergoing surgery. Treatment schedules, dose given, sideeffects, and response rates to systemic treatment were not reported in sufficient detail for this study.
;
80'
"-
6o.
\\
1 +
\\
DYb~ki"g~rg°~ i
20" 0
•
0
~
•
1
,
.
r
.
T
•
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•
",
2
3 4 5 6 Years Fig. 4. Survival rates after various surgical treatment options in patients with a complete fol!ow-up for at least 6 years. Curative resection vs. debulking surgery: p = 0.02. Debulking surgery vs. not operated: not significant; log rank test.
Survival The Overall 6 year and 10 year survival in the 81 patients diagnosed while alive, were 16% and 4.6%, respectively. SurVival data analyzed according to stage demonstrate that Stage I and II patients had a significantly better prognosis than Stage III and IV patients (p < 0.01; log rank) (Fig. 2). The median SUrvival for Stage III and IV patients was
World Journal of Surgery © 1992by the Soci616 Intemationalede Chirurgie
Adrenal Cortical Carcinoma in Norway, 1970-1984 Jon Arnc Sereide, M . D . , K n u t B r a b r a n d , M . D . , and Steinar 0 . T h o r e s e n , M . D . , Ph.D. bepartment of Surgery, Rogaland Central Hospital, Stavanger, Department of Radiology, Akershus Central Hospital, Nordbyhagen, and Norwegian Cancer Registry, Oslo, Norway Adrenal cortical carcinoma is a rare and highly malignant tumor. This retrospective study includes 99 patients (57 males and 42 females) reported to The Cancer Registry of Norway during the 15 year period from 1970 to 1984. The age adjusted incidence was 1.5 per million per year. Eighty-one patients were diagnosed with adrenal cortical carcinoma When still alive. In 18 cases the diagnosis was first made at autopsy. Median age at diagnosis was 54 years (range 2-88 years) with a slight male Predominance. Information about initial symptoms was available in 67 Patients, of whom 26 patients (18 females and 8 males) presented with clinically functioning tumors, the Cushing syndrome and virilization being most frequently encountered. Only 28 (35%) of 81 patients diag. nOSed when still alive had tumors confined to the adrenals. Half of the Patients had distant metastases, with lungs and liver being the most frequent sites. Sixty-one patients underwent surgery; 51 patients had a radical Or debulking operation and 10 patients had laparotomy with tumor biopsy. After a complete follow-up for at least 6 years (range 6-21 Years), only 9 patients were still alive. Early stage (Stage I and lI) and curative resection had a significant impact on the outcome of this disease. To improve prognosis, early diagnosis and radical surgery, if feasible, are ~eeded.
Adrenal cortical carcinoma (ACC) is a rare malignancy all over the world. The age adjusted incidence has been estimated at 2 Per million population per year [1]. The location of the adrenal glands, deep in the retroperitoneum, make them inaccessible for clinical examination. Most patients with disorders of the adrenal cortex have traditionally presented with either endoCrine disturbances caused by increased secretion of steroid hormones or symptoms related to an abdominal mass [I, 2]. It is obvious from previous studies that most patients with ACC are diagnosed at an advanced clinical stage and, accordingly, the prognosis has been poor [2-5]. The early diagnosis requires a high degree of suspicion by the physician and the surgical Oncologist. Most papers on this rare disease have been based on a rather small number of patients, often from a single or very few institutions. This study comprises all new cases of ACC in the total population of Norway during a time period of 15 years. Based on data from this unique study population, we address Presented at the International Association of Endocrine Surgeons in StOckholm, Sweden, August, 1991. R Reprint requests: Jon Arne SCreide, M.D., Department of Surgery, ogaland Central Hospital, N-4011 Stavanger, Norway.
questions relevant for diagnosis, treatment, and prognosis in patients with ACC.
Materials and Methods
The Norwegian Cancer Registry was established in 1953 and is based on the compulsory reporting of all new cases of cancer in the total population. The Registry receives each year about 70,000 reports on 19,000 new cancer patients. The reports consist of clinical forms as well as cytology, biopsy, and autopsy reports from the pathology laboratories, and finally death certificates from the Central Bureau of Statistics in Norway. An evaluation of this system in 1978 showed a completeness close to 100% [6]. All data in this study were collected from the original reports and reviewed by the authors. In cases of missing data, additional applications were made to institutions in which the patients had been treated to provide information necessary for this study. Complete follow-up data were available for all patients via the Central Bureau of Statistics. The follow-up was closed December 31, 1990. Staging of disease was done retrospectively according to the criteria of McFarlane [7] as modified by Sullivan and coworkers [8] (Table I). We identified I55 malignant adrenal tumors of which 99 were histologically confirmed to originate from the adrenal cortex. Statistical evaluation was generally done by means of nonparametric methods. The log-rank test was used for survival analysis. A p value < 0.05 was considered statistically significant.
Results
Age and Sex Among the 99 patients there was a slight male predominance, with 57 male and 42 female cases (Fig. 1). All age groups were affected, with an accumulation of patients in the fifth and sixth decade. The median age at diagnosis was 54 years (range 2 to 88 years).
664
World J. Surg. Voi. 16, No. 4, July/Aug. 1992
Table 2. Presenting symptoms and signs in 81 patients with adrenal cortical carcinoma."
Table 1. Staging criteria in adrenal cortical carcinoma.
Staging criteria TI Tumor -< 5 cm, no invasion T2 Tumor > 5 cm, no invasion T3 Tumor any size, locally invading to but not involving adjacent organs T4 Tumor any size, locally invading adjacent organs NO No regional positive lymph nodes N1 Positive regional nodes M0 No distant metastatic disease Distant metastatic disease Mt Staging Stage
Size (cm)
l
1I III IV
Symptom/sign
Nodes
Local invasion
5 Any size Any size
-+ +
-+ +
--+
Metastases
Non-functioning tumors (n = 34) Pain Unspecific gastro-intestinal symptoms Functioning tumors (n = 26) Cushing's syndrome Virilization Feminizing Hypertension Symptoms not reported (n = 21)
I~[~ FemaleIs
25 '
Males
Female (n = 39)
Total (n = 81)
9 14
7 4
16 18
4 1 2 1 11
t1 6 0 1 I0
15 7 2 2 21
al8 patients first diagnosed at autopsy are not included in this table. Table 3. Stage of disease at diagnosis (n = 99).
- - : Absent; +: Present. 30
Male (n = 42)
Stage
Male (n = 57)
Female (n = 42)
No metastases Regional lymph nodes Local invasion of adjacent tissue Distant metastases
17 (30%) 3 (5%) 8 (14%) 29 (51%)
13 (31%) 1 (2%) 6 (14%) 22 (52%)
'~ 20'
Z 10" 5' 0
.
0-9
.
.
.
.
.
.
.
.
10-19 20-29 30-39 40-49 50-59 60-69 70-79 • 80 Age categories
Fig. 1. Age and sex distribution in 99 patients (42 females and 57 males) with adrenal cortical carcinoma.
Diagnosb The radiological studies performed in our series largely reflect the technical development in radiology during this period of time. In the beginning, traditional tests such as intravenous pyelography, retroperitoneal pneumography, nephrotomography, selective arteriography, and venography were performed on an individual basis. The final diagnosis was based on biopsy of the primary tumor in 77 patients. Four patients were diagnosed by biopsy o f distant metastases. A later autopsy verified the diagnosis in 30 cases. In 15 patients the diagnosis o f ACC was first confirmed at autopsy, and in an additional 3 patients the diagnosis was an incidental finding at routine autopsy. The median age for these 18 patients with diagnosis at autopsy was generally higher than for those with diagnosis at biopsy (median age 60 years versus 52 years).
Symptoms Information about initial symptoms and signs was available for 60 patients (Table 2). The most common symptoms were abdominal pain and unspecific gastrointestinal symptoms, oc-
curring in 34 p a t i e n t s . Twenty-six patients (18 females and 8 males) had functioning tumors with hormonal excess causing clinical symptoms such as Cushing's syndrome and virilization (Table 2). The median age o f patients with a functioning tumor was 42 years (range 2-68 years) as compared to 57 years (range 5-88 years) for patients with nonfunctional tumors. Functioning tumors were more commonly found in females (ratio male: female = 1:2).
Location and Stage A slight left-sided prevalence was found, with the primary tumor localized on the left side in 51 patients and on the right side in 44 patients. Bilateral tumors were present in 4 patients. The stage distribution at the time of diagnosis is listed in Table 3 and 4. Only 30 patients were without metastases, and the majority of the patients had advanced disease (Stage Ill/IV, see Table 1 for definition). The stage distribution was equal for both sexes (Table 3). Twelve (46%) of 26 patients with functioning tumors and 8 (24%) of 34 patients with nonfunctioning tumors had no metastases, indicating a less advanced disease among patients in the functioning tumor group (Table 4) (p = 0.05, F i s h e r ' s exact test, two-sided). In 55 patients with extra-adrenal disease (Table 3), the most frequent sites of metastases were liver (55%) and lungs (35%). L y m p h node metastases or local extension o f tumor into adjacent tissues were also commonly found. In some cases metastases to pleura, pancreas, kidneys, bone, brain, spleen, and skin were present. Multiple metastatic sites could be found in 39 (71%) patients with extra-adrenal disease.
J,ASerei . deetal.:AdrenalCorticalCarcinoma Table 4. Stage of disease at diagnosis according function o f the adrenal cortical a d e n o m a (n = 81). a
Stage
--.._.,_
No metastases Regional lymph nodes ocal invasion to adjacent tissues Distant metastases
--.-...
665 to
endocrine
I00'
Symptoms
80"
Functioning (n = 26) 12 1 1
Nonfunctioning (n = 34) 8 2 7
not reported (n = 21) 8 1 3
12
17
9
.~.
6o"
~
40. 20"
"18 patients diagnosed at autopsy are not included in this table. Years Fig. 2. Survival rates by stage o f disease at diagnosis. The follow-up
Table 5. Surgical procedures in 61 patients."
--,-...
Surgical procedure
-..-...
time was 6 years or more. p < 0.01 ; log rank test. No. of pts. (%)
Adrenalectomy
28 (46)
Adrenalectomy + Nephrectomy L~aparotomy + Biopsy
23 (38) 10 (16)
100-~,
[
8
~38 patients did not undergo surgical procedures; 18 patients were first diagnosed at autopsy, 20 patients were offered non-surgical treatment without surgical exploration.
o
'
t>------ .¢~54yrs. I
~
'~ 40
Treatment 20"
Surgery. Various primary surgical procedures were performed on 61 patients (Table 5). Twenty-three patients underwent rather extensive surgery including radical adrenalectomy and nephrectomy. In several patients lymph nodes and surrounding tumor tissues were removed. None of the patients died within the first 30 days following surgery. Seventeen of 26 patients With hormone producing tumors underwent surgery. In general, the patients who underwent surgery tended to be younger than Patients treated with non-surgical options.
0
0
Radiation Therapy. In a few patients, irradiation therapy was given as a palliative measure. Details concerning this therapeutic option were not recorded.
i
i
2
3 Years
* ..................
4
5
6
Fig. 3. Survival rates by age (median age 54 yrs for the study population), No statistically significant difference was found.
Systemic Therapy. In 26 patients medical treatment was given either as single agent or combination systemic chemotherapy. In this group, 14 patients received o,p'DDD[l,l,dichloro-2(OChlorophenyl)-2(P-chlorophenyl)ethane] either as a single drug, or in combination with drugs such as doxyrubicin, cyclophosPhamide, cisplatin, streptozotocin, or others. Medical treatment was given both as adjuvant treatment after surgery in SOme patients, or as the only treatment option in patients not Undergoing surgery. Treatment schedules, dose given, sideeffects, and response rates to systemic treatment were not reported in sufficient detail for this study.
;
80'
"-
6o.
\\
1 +
\\
DYb~ki"g~rg°~ i
20" 0
•
0
~
•
1
,
.
r
.
T
•
";'
•
",
2
3 4 5 6 Years Fig. 4. Survival rates after various surgical treatment options in patients with a complete fol!ow-up for at least 6 years. Curative resection vs. debulking surgery: p = 0.02. Debulking surgery vs. not operated: not significant; log rank test.
Survival The Overall 6 year and 10 year survival in the 81 patients diagnosed while alive, were 16% and 4.6%, respectively. SurVival data analyzed according to stage demonstrate that Stage I and II patients had a significantly better prognosis than Stage III and IV patients (p < 0.01; log rank) (Fig. 2). The median SUrvival for Stage III and IV patients was
