| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CASE REPORT |
Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands
(Correspondence should be addressed to M Kars; Email: m.kars{at}lumc.nl)
Abstract
Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedulary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as ‘atypical’ prolactinomas to raise the possibility of future malignant development.
Introduction
Although pituitary tumors are relatively common, occurring in approximately 10–20% of normal subjects on autopsy or magnetic resonance imaging (MRI), the incidence of pituitary carcinoma is extremely low (1). To date, a total of approximately 140 cases have been reported, one third of them being malignant prolactinomas (2). The histological, clinical, and biochemical characteristics are reported to be of minimal utility in distinguishing benign from malignant tumors, unless (distant) metastases have developed. Presently, it is postulated that pituitary carcinomas arise from the transformation of initially large but benign adenomas (1). The arguments are based on observations that the initial presentation is not different from other macroadenomas, the long-duration needed for the transformation into carcinoma, and the increasing accumulation of genetic aberrations (3). We describe a patient with a malignant prolactinoma, whose unusual initial presentation and clinical course prompted us, in retrospect, to make a detailed analysis of the case with respect to the therapeutic interventions and histology. For comparison, we reviewed all published cases of malignant prolactinoma and detailed their epidemiological, clinical, biochemical, and histological characteristics.
Case report
A 63-year-old woman, who presented with diplopia and blurred vision, was diagnosed with a macroprolactinoma in 1998. On neurological examination, ptosis of the right eye was present, together with abducens palsy and impaired convergence. Furthermore, bitemporal hemianopsia was present (Fig. 1
). Prolactin concentration was increased 20-fold: 490 µg/l (normal value < 22 µg/l). MRI showed a pituitary mass with a diameter of 2.5 cm, extending into the right sphenoidal sinus as well as the cavernous sinus and compressing the temporal lobe (Fig. 2). Therapy was initiated with bromocriptine (1.25 mg t.i.d) resulting in normalization of the visual fields and decrease in prolactin levels to 56 µg/l within a few months.
|
|
), 6 months later. Therefore, bromocriptine treatment was switched to quinagolide (up to 300 µg/day). Nonetheless, in January 2000, MRI showed progression of the pituitary tumor with encasement of the internal carotid artery and compression of the optic chiasm. The macroprolactinoma did not react satisfactory to medical treatment, even with cabergoline, which was stopped, since prolactin levels progressively increased in the presence of further progression of tumor growth. Furthermore, she developed progressive anterior pituitary insufficiency (de novo adrenocorticotropic hormone and thyroid-stimulating hormone deficiency) and the visual field defects increased. Therefore, she was operated in April 2000. Decompression of the optic chiasm was performed via transcranial route. Histological investigation of the tumor revealed positive immunostaining for prolactin without mitotic activity, but high Ki-67 (MIB-1) labeling index (10–15%). Fractionated conventional radiotherapy was administered by a linear accelerator (6 MeV) in a total dose of 54 Gray (Gy) in June 2000. Thereafter, prolactin concentrations decreased gradually without dopaminergic therapy from 445 µg/l in June 2000 to a nadir of 33 µg/l in February 2001 (Fig. 3). The effect on tumor volume in response of radiotherapy was evaluated 8 months after radiotherapy with MRI. A slight reduction in tumor volume was noted. Encasement of the internal carotid artery persisted.
|
), which was confirmed with epidepride (dopamine D2 receptor) scintigraphy (Fig. 5). Laminectomy was performed in December 2001 because of compression of the myelum in the sacral region, followed by fractionated radiotherapy (6 x 4 Gy) from L5 to S5 in February 2002. Histological examination confirmed a prolactin-producing metastasis.
|
|
In August 2002, she developed progressive ptosis of the right eye and facial paralysis due to infiltration of the tumor into the orbital cavity. Repeat radiotherapy to the skull (total dose of 25 Gy) was given in September 2002, resulting only in partial improvement of visual disturbances. However, prolactin concentrations continued to increase (Fig. 3
) to a final concentration of 6000 µg/l in May 2003, 1 month before she died at home. Autopsy was not performed.
Discussion
Pituitary carcinomas are considered to arise from the transformation of initially large, but benign, adenomas (1). This notion is based on observations that demonstrate that the initial presentation of pituitary carcinomas does not differ from other (invasive) macroadenomas, the long-duration needed for transformation into a carcinoma, and the progressive accumulation of genetic aberrations (3). The present case of malignant prolactinoma is consistent with many, but not all, of these observations. This gave us an opportunity to compare carefully the data of our patient and review the intriguing features associated with malignant transformation of pituitary prolactinomas.
To date, only 47 cases of malignant prolactinoma have been reported, summarized in Table 1 (4–41). The first report of a patient with malignant prolactinoma was in 1981 by Martin et al. (4). Of the reported cases, 65% were male and the mean age at presentation was 44 years with a range of 14–70 years (Table 2). The presenting symptoms were related to hyperprolactinemia in 35% of the reported cases, including amenorrhea, galactorrhea, impotency, and decreased libido. At presentation, 71% of the patients had symptoms of local compression, such as headache and bitemporal hemianopsia. Only five other patients presented with ptosis (27, 40), diplopia (34), oculomotor paresis (17), or lateral rectus paresis (13). Diabetes insipidus was a feature in only one patient (12). The treatment modalities after diagnosis were transsphenoidal or transcranial surgery (96%), radiotherapy (79%), chemotherapy (2%), and dopamine agonists (DA) in 65% of the cases (Table 3). A study by Isobe et al. shows that, in particular, large prolactinomas are very difficult to control with radiation doses between 50 and 60 Gy (42). Therefore, even benign prolactinomas do not respond very well to radiotherapy. The effect of radiotherapy on malignant prolactinoma has not been systematically documented. Therefore, a small response to radiotherapy, as in our case, cannot be interpreted as an indication of the malignant nature of the tumor. The presentation of our patient with diplopia and blurred vision is a very unusual manifestation of pituitary macroadenoma. Such a presentation is most frequently associated with pituitary apoplexia. In the absence of apoplexia, nerve paralysis is strongly suggestive of compression or infiltration of the nerve, secondary to the high proliferative activity of the tumor. The presentation with diplopia as a result of oculomotor nerve paralysis has been reported previously in only one other case(17). In the present case, oculomotor nerve paralysis was due to tumoral orbital invasion (Fig. 2). Orbital invasion of a pituitary adenoma is very uncommon, being reported in only 16 patients, only 2 of whom manifested diplopia (43). Thus, in retrospect, the initial clinical and radiological presentation was highly indicative for an adenoma with high infiltrative potency.
|
|
|
). In the remaining 23% of cases, no documentation of the histological findings was given. The histological investigation in our case demonstrated a prolactinoma with a high proliferative index, such as nuclear pleomorphism and high Ki-67 labeling index. Estimation of the cell cycle-specific antigen Ki-67, using the MIB-1 antibody, has been demonstrated to correlate best with invasiveness and probably prognosis (1). Malignant and invasive tumors exhibit much higher Ki-67 labeling indices than benign adenomas (11.9 vs 4.66 vs 1.37% respectively) (44), although there is considerable case-to-case variability (1). Others even suggested that an increased Ki-67 labeling index is associated with secondary resistance or escape to DA treatment (45). The time interval between the onset of symptoms at presentation and subsequent metastases in the published cases was highly variable, with a median duration of 7 years, but ranging from 1 month to 20 years. Local recurrence after adenomectomy followed by repeated surgical interventions for local regrowth and extension of the pituitary tumor is frequently observed in malignant prolactinoma. Symptoms of prolactin hypersecretion rarely dominated the clinical picture of metastatic disease. However, symptoms of local compression at the metastatic sites were present in 73% of the cases. In some cases, metastases only manifested during autopsy (14, 18, 20, 21).
Intracranial metastases were reported in the frontal lobe (7, 9, 12, 18, 19, 22, 23, 27, 33, 34), parietal–occipital lobe (6, 22, 29), temporal lobe (10, 18, 24, 28, 33), cerebellum (4, 8, 12, 14, 29, 38), cerebello–pontine angle (5, 18, 31), brainstem (17, 20, 28, 38), and subarachnoid space (9, 14, 20). Less commonly involved areas were the cranial nerves (20, 27) and the orbital space (15, 18, 28, 35). Extracranial metastases within the central nervous system involved the spinal cord (8, 11, 13, 14, 17, 26, 27, 29, 30–33, 35, 38, 39). Approximately 40% of the malignant prolactinomas were associated with systemic metastases in bone (10, 16, 21, 29, 32, 35, 37), lymph nodes (18, 21, 28, 29, 31, 37), lung (13, 16, 21, 31, 37), liver (21, 25, 31, 36), and, rarely, ovaries (24, 29).
Treatment of metastatic disease consisted of surgery in 69%, radiotherapy in 54%, and chemotherapy in 21% of cases. There is a case-to-case variability of the effect of chemotherapy on prognosis. At publication, three out of ten patients were still alive. Survival time of the remaining seven patients after being diagnosed with metastases was 2.1 years compared with 1.9 years for the whole cohort of patients. The mean time interval of diagnosis until death was 7.8 years compared with 8 years in all reported cases. Although, these data involve only a limited number of cases, we conclude that chemotherapy does not improve prognosis of malignant prolactinoma. In addition, 60% of the patients were treated with dopamine agonists. Only a minority of the patients was treated with octreotide (8, 21, 28, 36) or gamma-knife radiosurgery (26, 32, 35, 38). Survival in these patients was not different from the other patients.
Histological investigation of the metastatic lesions showed more often tissue with atypical parameters, compared with the results obtained from the primary tumor. Atypical features were present in 62% in the metastatic lesions versus 40% in the primary tumor.
The prognosis of malignant prolactinoma is poor. Survival after the onset of initial symptoms of prolactinoma is approximately 8 years, although there are patients who have survived for as long as 25 years. Only 60% of reported cases with a prolactin-secreting pituitary carcinoma survive more than 1 year after the development of metastases. It is presently difficult to estimate long-term survival in all patients since long-term follow-up has not been reported in most of these patients.
Another feature indicative of a non-benign clinical course is the disappearance of prolactin-suppressive effects of treatment with DA. DA resistance, or an escape to the prolactin-suppressive effects, during treatment of prolactinoma is rare, but has been reported in the majority of patients with malignant prolactinomas (Table 3). Only six patients, however, including our case, were treated with cabergoline. When non-compliance is ruled out, this phenomenon is associated with dedifferentiation of the tumor and thus of malignant transformation. In our case, it is certainly remarkable because we found positive visualization of the pituitary tumor and the metastases by the epidepride scan (Fig. 5). Apparently, the tumor still expressed the D2 receptors because [123I] epidepride binds with high affinity to dopamine D2 receptors (46). Epidepride scintigraphy was only performed in our case and one previously reported case by Petrossians, et al. (32). Scintigraphy in the latter detected metastases in the spine, rib, mediastinum, and right femur. The metastases were treated with radiotherapy. In general, it is currently unclear how to translate these results in only two patients to the diagnostic value of this procedure in benign and malignant prolactinomas. The development of pituitary insufficiency within a time frame of several weeks is also consistent with tumor dedifferentiation and growth. The occurrence of pituitary insufficiency within such a short time interval is exceptional in pituitary adenoma.
In conclusion, malignant prolactinoma can present with unusual and atypical clinical manifestations. In the case of an invasive macroprolactinoma, these features, together with the development of resistance to dopamine agonists, should prompt the clinician to obtain histological information. In the presence of atypical indices, such as nuclear pleomorphism, numerous mitosis, and increased Ki-67 labeling index, the prolactinoma could be termed atypical to denote the potential of malignant transformation.
References
This article has been cited by other articles:
|
|
 |
|
  G. Vlotides, O. Cooper, Y.-H. Chen, S.-G. Ren, Y. Greenman, and S. Melmed Heregulin Regulates Prolactinoma Gene Expression Cancer Res., May 15, 2009; 69(10): 4209 - 4216. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
