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Endocrinological Oncology |
Department of Internal Medicine and Endocrinology, University Hospital UCL of Mont-Godinne (E.D., J.D.), 5530 Yvoir, Belgium; Laboratoire d’Histologie-Embryologie and INSERM U-369 (J.Tr.), Faculté de Médecine Lyon-RTH Laënnec, 69372 Lyon Cedex 08, France; the Department of Endocrinology and Nutrition, UCL Saint-Luc (D.M.), 1200 Brussels, Belgium; Clinique Endocrinologique de l’Université Claude Bernard, Hôpital de l’Antiquaille (J.T.), 69321 Lyon Cedex 05, France
Address all correspondence and requests for reprints to: Dr. E. Delgrange, Internal Medicine and Endocrinology, University Hospital UCL of Mont-Godinne, 5530 Yvoir, Belgium.
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Abstract |
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Basal PRL levels (mean ± SEM, 2789 ± 573 ng/mL) and mean tumor diameter (26 ± 2 mm) were significantly higher in men than in women (292 ± 74 ng/mL and 10 ± 1 mm, respectively; P < 0.001), but were not correlated to the age at diagnosis or the duration of symptoms. Giant tumors (n = 8) occurred in males only. The frequencies of bromocriptine-resistant tumors (30 vs.5%; P < 0.01) and invasive macroadenomas (52 vs.27%; P < 0.001) were significantly greater in men than those in women. Lastly, macroprolactinomas in males exhibited higher indexes of proliferating cells by Ki-67 immunoreactivity (2.6 ± 1.1% of positive nuclei) than did similar tumors in female patients (0.4 ± 0.2%; P = 0.08).
We conclude that the predominance of large prolactinomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently bromocriptine resistant.
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Introduction |
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The reason for the preponderance of large tumors in men remains to be elucidated. For most researchers, micro- and macroadenomas represent the early and late stages of the same pathological process, and a delay in seeking medical attention explains why tumors are larger in men (12, 13). However, studies comparing the clinical and pathological correlates of growth of these tumors in both sexes are lacking, and a more aggressive course of the disease in men has not been ruled out. To determine whether the preponderance of large tumors in men is due to specific pathological characteristics rather than a delay in diagnosis, we conducted a retrospective study comparing the following data between men and women with a prolactinoma: age at diagnosis; duration of symptoms; PRL levels; tumor size, invasiveness, and response to bromocriptine (BRC) therapy; and immunocytochemical detection of proliferation-associated nuclear antigens [Ki-67 and proliferating cell nuclear antigen (PCNA)], which are potentially useful markers in pituitary adenomas (14).
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Subjects and Methods |
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Between 1976 and 1995, 45 men with PRL-secreting pituitary tumors were diagnosed and followed in 3 centers: the Endocrine Clinic, University Claude Bernard (Lyon, France), and Saint-Luc (Brussels, Belgium) and Mont-Godinne (Yvoir, Belgium) University Hospitals, Louvain Medical School. They were compared to 51 women who presented with prolactinomas at the Endocrine Clinic in Lyon during the same period. Half of the patients (26 men and 22 women) had a diagnosis of pure prolactinoma confirmed by immunocytochemistry. The other patients met the following diagnostic criteria: mean serum PRL levels of at least 50 ng/mL and computed tomography (CT) or magnetic resonance imaging (MRI) scans showing a pituitary tumor of less than 10 mm in diameter for microprolactinomas, and mean serum PRL levels over 200 ng/mL and CT or MRI scans demonstrating a pituitary mass of at least 10 mm in diameter for macroprolactinomas. No patient was taking any medication known to affect PRL levels. The patients with clinical or biological evidence of pituitary mixed tumors (i.e. concomitant GH hypersecretion) were excluded from the study.
Symptoms in men included decreased libido and/or potency (30 of 45 patients), infertility (4 of 45 patients), arrested puberty (3 of 45 patients), gynecomastia and/or galactorrhea (10 of 45 patients), visual abnormalities (19 of 45 patients), and headaches (26 of 45 patients). Five men were eugonadal (defined by a serum testosterone level in the normal range). Fifty of the 51 women presented with amenorrhea and/or galactorrhea. The duration of symptoms was defined as the delay between the first symptom of the disease and the initiation of treatment. This assessment was easier in women and could only be determined precisely in 28 of the 45 men.
Hormone measurements
Hormone measurements were performed in the laboratories of each institution using standard RIA or immunoradiometric assay methods. The upper limit of normal range for PRL was 15 ng/mL for men and 25 ng/mL for women.
Radiology
Pretreatment high resolution CT or MRI scans were available in 33 men and 45 women. Tumor size was evaluated using the maximum craniocaudal diameter obtained in coronal sections. Tumors larger than 40 mm in diameter were called giant tumors. The term invasive was restricted to adenomas showing cavernous sinus invasion at radiological evaluation or at surgery. The radiological criterion used for sinus invasion was visualization of the tumor extending to the lateral margin of the carotid artery and surrounding it.
BRC therapy
Forty men and 41 women received BRC therapy, either as primary treatment or after unsuccessful surgery (9 men and 4 women). Patients who did not reach normal PRL values despite increasing the dose of BRC to 15 mg daily for at least 3 months were called BRC resistant.
Pathological studies
Paraffin blocks containing surgically resected tumoral tissue from 33 patients (17 men and 16 women) were available for morphological and immunocytochemical analyses. All men as well as 9 of the 16 women had macroadenomas. All tumors were studied by the same pathologist (J.Tr.). For immunocytochemical determination of proliferation-related nuclear antigens, two monoclonal antibodies were used: MIB 1 (Immunotech, Marseille, France) to the Ki-67 antigen (dilution, 1:400), and anti-PCNA (Novocastra Laboratories, Newcastle, UK; dilution, 1:400). Immunocytochemistry was performed using the immunoperoxidase method and the streptavidin-biotin complex. Ki-67 immunoreactivity was enhanced by the antigen retrieval technique of heating tissue sections in a microwave oven. Sections from lymph nodes and normal pituitary tissues were processed concomitantly and served as positive and negative controls, respectively. Ki-67 antigen-positive cells were easily detectable, and the staining was identical in tissues fixed in formol or Bouin’s fixative. The interpretation of true positivity in immunocytochemical stains for PCNA appeared more difficult because the intensity of the signal produced was more variable and more dependent on fixation (the PCNA labeling index was generally higher in formol-fixed tissues than with Bouin’s fixative). Thus, to avoid an overestimation of the proliferating cell fractions by PCNA, this method was applied only to tissue sections rapidly fixed in Bouin’s fixative (n = 28; 12 men and 16 women), and labeled nuclei were counted as positive only if the staining was well above background levels. Calculation of the Ki-67 and PCNA indexes was performed at x400 magnification. A total of 500-1000 nuclei were counted for each specimen. Results were expressed as the percentage of labeled nuclei in the total tumor nuclei counted per section.
Statistical analysis
Data are presented as the mean \ SEM unless
otherwise indicated. The nonparametric Wilcoxon two-sample rank sum
test was used to compare the geometric means of the study groups. The
frequency of observations between men and women was compared by
2 test and Fischer’s exact probability where
appropriate. The level of significance was set at P <
0.05.
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Results |
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The mean age at diagnosis was 42 \ 2 yr (range, 17–73;
median, 43) in men and 28 \ 1 yr (range, 16–66; median, 26) in
women (P < 0.001). In men, the occurrence of
PRL-secreting tumor remained at about the same level throughout the
entire life span, whereas there was a marked peak occurrence in women
before the age of 35 yr (Fig. 1). There was no
correlation in either sex between age at diagnosis and tumor size. The
preponderance of large tumors in males was present in each age group,
even in patients between 16–25 yr (28 \ 6 vs.11
\ 2 mm in males and females, respectively; P < 0.001;
Fig. 2).
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The duration of symptoms before diagnosis (5 \ 1 yr in men
vs. 4 \ 1 yr in women; P = NS) was not
predictive of tumor size, which was significantly larger in men than in
women with similar durations of symptoms (Fig. 3). Among
the 26 women who were amenorrheic for less than 2 yr, tumoral diameter
varied from 5–22 mm. On the other hand, 6 of 8 patients with long
standing amenorrhea (>10 yr) had microadenomas, so mean tumor
diameters were similar in women with short and long durations of
disease (respectively, 8 \ 1 and 9 \ 2 mm). A microadenoma
was also found in a man with a 10-yr history of impotence. Of the 14
men with symptoms for less than 2 yr, 13 had macroadenomas, including
those 4 who consulted for endocrine signs. In 3 other male patients,
hyperprolactinemia was discovered in the exploration of a primary
infertility. They were otherwise asymptomatic. All had macroadenomas as
well (12, 25, and 29 mm in diameter).
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The mean pretreatment serum PRL level was significantly higher in
men (2,789 \ 573 ng/mL; range, 62–16,550; median, 1,099) than in
women (292 \ 74 ng/mL; range, 36–2,080; median, 104;
P < 0.001). Pretreatment serum PRL levels were
strongly correlated with tumor size (Fig. 4).
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Prolactinomas were significantly larger in men than in women. The ratios of microprolactinoma to macroprolactinoma were 1:8 in men and 2.4:1 in women. Macroadenomas were more frequently invasive in men (21 of 40) than in women (4 of 15; P < 0.001), and giant prolactinomas were only present in males (8 of 45; P < 0.01). In 1 male patient, the development of spinal cord metastases with positive anti-PRL immunostaining led to the diagnosis of malignant prolactinoma.
Response to BRC therapy
BRC therapy resulted in normalization of PRL levels in 26 of 40 men and in 35 of 41 women. Treatment could not be increased to 15 mg daily because of intolerance in 3 men and 4 women. The remaining patients (11 men and 2 women) were resistant to BRC. One of the two BRC-resistant women was a 17-yr-old girl with a macroadenoma, and the other had multiple endocrine neoplasia type I. Among the men, 10 of the 11 patients had invasive macroadenomas, and the last subject had a recurrent tumor. Four of these patients were particularly young (17, 24, 25, and 26 yr). Resistance developed during therapy in 1 man, but he experienced a subsequent fall in his serum PRL level after treatment with another dopamine agonist, CV 205–502. Another BRC-resistant male patient developed PRL-secreting spinal cord metastases 6 yr after the original diagnosis of prolactinoma. In a third man, we observed tumor growth and PRL increment despite an increase in the BRC dose to 30 mg daily.
Pathological studies
The mean proliferating cell indexes determined by Ki-67 and PCNA immunoreactivity were 1.7 \ 0.6% (range, 0–15.6; median, 0.8) and 4.2 \ 1.1% (range, 0–23.0; median, 2.6), respectively. The Ki-67 and PCNA labeling indexes did not correlate with tumor size and were similar in women with macroadenomas (n = 9) and microadenomas (n = 7). Considering macroprolactinomas, no significant difference was found between invasive (n = 10) and noninvasive (n = 13) tumors (Ki-67 expression, 2.3 \ 1.5% and 1.2 \ 0.7% in invasive and noninvasive adenomas, respectively; PCNA expression, 4.0 \ 2.8% and 4.7 \ 1.3% in invasive and noninvasive adenomas, respectively).
Patients treated with BRC at the time of surgery (n = 12) had proliferation-related antigen expression similar to that of patients who had never been treated with this drug (n = 16). However, in the first group, the proliferation activity was higher in BRC-resistant prolactinomas (four male patients) than in tumors responsive to this drug (four men and four women). In BRC-resistant prolactinomas, the mean percentage of positive nuclei was 4.7% (range, 0.9–15.6%) for Ki-67 and 10.6% (range, 4.0–23.0%) for PCNA. By contrast, all but one of the tumors responsive to BRC had Ki-67 and PCNA labeling indexes less than 1%.
Prolactinomas in males tended to exhibit higher indexes of
proliferating cell by Ki-67 and PCNA immunoreactivity than did similar
tumors in female patients (Table 2). Although not
reaching statistical significance, the difference in Ki-67 expression
between men and women was more obvious when considering macroadenomas
only \[2.6 \ 1.1% in men (n = 16) and 0.4 \ 0.2% in
women (n = 9); P = 0.08\]. Twelve of the 28
adenomas were positive for both markers (7 of 12 in men and 5 of 16 in
women; P = 0.25; Table 2).
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Discussion |
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As far as microprolactinomas are concerned, these findings are in keeping with the data obtained from untreated female patients followed for long periods; the risk for tumor growth is very low, averaging 6.9% in a recent meta-analysis (15). In men, the natural history of microprolactinomas is unknown, probably because of their rarity and the fear of a more aggressive course of disease leading to systematic treatment (18). However, they may also remain small, as a long history of impotence \[20 yr in the literature (13) and 10 yr in our series\] is still consistent with the discovery of microprolactinoma.
Regarding macroprolactinomas, wide variations in growth rate are likely, and these tumors may enter a static phase at some stage of their development so that the duration of disease is not predictive of tumor size. The growth potential of macroprolactinomas seems greater in men than in women, given a male preponderance of aggressive forms of the disease (i.e. giant, invasive, and malignant prolactinomas) despite the overall increased prevalence of prolactinomas in women (19). Giant prolactinomas are rare and almost exclusively seen in men of all ages. Nine of 10 cases included in the largest series reported are men (20), as well as our 8 patients. To our knowledge, data comparing the invasiveness of macroprolactinomas between sexes are lacking. We found that invasive growth was significantly more frequent among men. Finally, a review of the literature (21, 22, 23) shows that 11 of the 17 reported cases of PRL-secreting pituitary carcinomas occurred in men, and our patient with a carcinoma was also a man.
The rarity of prolactinomas in women after the age of 45 yr (with an inversion in the sex ratio) may also reflect the less aggressive behavior of these tumors in females; the endocrine signs of PRL-secreting tumor disappear after the menopause, and the tumor, if present, stays silent in women, whereas men develop symptoms of a pituitary mass.
Conventional cytological characteristics have proven unreliable for assessing the growth potential of pituitary tumors, and the incidence of mitosis is generally too small for drawing conclusions concerning tumor growth (14). The availability of monoclonal antibodies to proliferation-related nuclear antigens Ki-67 and PCNA has provided a simple method for the identification of proliferating cells, but the usefulness of this marker as a predictor of the clinical behavior of pituitary tumors is still under evaluation. PCNA and Ki-67 indexes seem useful to predict tumor recurrence (24, 25), but, on the other hand, immunostaining for Ki-67 failed to demonstrate any difference between ACTH-secreting adenomas and carcinomas (21). There is no correlation between Ki-67 expression and the sizes of various types of pituitary adenomas (14, 25, 26). However, unlike Ki-67, the PCNA index is higher in macro- than microadenomas (24). Regarding PRL-secreting pituitary adenomas, this is in keeping with the benign clinical course of microadenomas. Microscopic (26, 27), but not macroscopic (25, 27, 28), invasiveness correlates with Ki-67 and/or PCNA indexes, but the prognostic and therapeutic significance of microinvasion remains a matter of debate. In PRL-secreting pituitary tumors, higher Ki-67 indexes were found in males by some (29), but not all (26), researchers. These studies did not distinguish between macro- and microprolactinomas. Our results indicate that prolactinomas in males have higher proliferative indexes than similar tumors in females. The difference does not reach statistical significance, probably because the number of tumors studied is small, and our pathological series is not representative of the usual intrasellar microadenoma encountered in female patients. Indeed, we rarely propose pituitary surgery as a primary therapeutic modality, and only 7 of the 16 resected tumors were microprolactinomas, including an unusual tumor invading the cavernous sinus. By contrast, in a series of 14 female microprolactinomas referred directly to surgical centers, all but 2 tumors showed only occasional Ki-67- or PCNA-positive nuclei (<1%) (Trouillas, J., unpublished data).
BRC has been reported to inhibit DNA synthesis and to delay the cell cycle (25). Some investigators showed that Ki-67 expression was significantly lower in patients treated with BRC at the time of surgery than in patients who had never been treated with this drug (14). We found such a difference when considering BRC-responsive adenomas only, whereas we observed high proliferating cell indexes in four male patients with BRC-resistant adenomas. Proliferation-related nuclear antigens have recently been detected in a rapidly growing invasive prolactinoma resistant to dopamine agonists (30). In addition, these BRC-resistant tumors have been recognized to have a particularly severe clinical course (31), and we found that they were significantly more frequent in males. A retroanalysis of the data published by Brue et al. (31) concerning BRC-resistant prolactinomas confirms our finding, as resistance to BRC occurred in 9 of 37 men (24%) and in 18 of 224 women (8%; P < 0.01). This sex difference is not directly explained by the predominance of large tumors in men, as the tumor size (or the pretreatment serum PRL level) is not predictive of the response to BRC therapy (32, 33), and microadenomas have been reported to be even less sensitive to BRC than macroadenomas (34). Prolactinomas resistant to BRC may respond to newer dopamine agonists, CV 205–502 (31) or cabergoline (35).
In conclusion, the predominance of large prolactinomas in men is not due to a longer delay in diagnosis, but, rather, to the greater proliferative potential of the tumors, which are more frequently invasive and less responsive to BRC therapy. The molecular basis of these differences remains to be determined. Our findings justify a more aggressive therapeutic approach to PRL-secreting tumors in men than in women. Given the high frequency of resistance to BRC, primary treatment with new dopamine agonists (cabergoline or CV 205–502) should be considered in men. In the case of resistance to medical therapy, surgery is mandatory in view of the risk of tumor growth. Measurement of proliferation activity by Ki-67 and PCNA indexes could then provide an additional tool for the decision to use postoperative radiation therapy.
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Acknowledgments |
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Footnotes |
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Received January 23, 1997.
Revised March 20, 1997.
Accepted March 26, 1997.
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