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Metastatic Prolactinoma: Effect of Octreotide, Cabergoline, Carboplatin and Etoposide; Immunocytochemical Analysis of Proto-Oncogene Expression

Department of Medicine (S.J.H., S.F., P.H.B.), Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP; Department of Medicine (P.E.H.), Kings College Medical School, London, SE5 9TJ; Department of Medicine (W.F.K.), Middlesbrough General Hospital, Middlesbrough, TS5 5AZ; and University Department of Pathology (A.M.M.), Glasgow Royal Infirmary, Glasgow, G4 OSF

Address correspondence and requests for reprints to: S.J. Hurel, Department of Medicine, Royal Victoria Infirmary, Queen Victoria Road, Farmington Place, Newcastle-Upon-Tyne, United Kingdom NE1 4LP.

	Abstract

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A 49-yr-old woman presented with an extensive prolactinoma (serum PRL > 10,000 mU/L, normal range <450 mU/L). Over a 5-yr period following transsphenoidal surgery and pituitary irradiation, she became increasingly resistant to high doses of bromocriptine and underwent transfrontal surgery followed by stereotactic radiotherapy. In spite of these treatments, serum prolactin estimations rose progressively to >100,000 mU/L. Magnetic resonance imaging scanning demonstrated a massive cystic tumor invading the temporal lobes, extending into the cervical and thoracic spine, with metastases to cervical lymph nodes. High-dose cabergoline administration resulted in a 30% decrease in serum PRL. Octreotide was administered as a continuous sc infusion with a profound analgesic effect on facial pain but with no effect on tumor progression. She was treated with a course of chemotherapy consisting of carboplatin and etoposide without any noticeable effect. The patient died 6 months following chemotherapy. Immunocytochemical analysis demonstrated positive nuclear staining for WAF-1, Rb protein, c-myc, and p53 both in the original and metastatic tumors. The metastases but not the primary tumor stained for c-jun. Metastatic prolactinoma remains a therapeutic challenge. It is associated with a variable proto-oncogene expression, which may be coincidental or causal. Cabergoline had no advantage over bromocriptine. Octreotide relieved facial pain but did not alter tumor progression. An effective therapy for metastatic prolactinoma remains to be identified.

	Introduction

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PROLACTINOMAS account for approximately 50% of pituitary tumors, the majority of which are microprolactinomas. Macroprolactinomas (>10 mm diameter) are variably benign, slowly proliferating tumors, although they may be locally highly aggressive, particularly in males, and invade the parasellar sinuses. A very small number of macroprolactinomas (<10 in the U.K. and <40 world-wide) develop a much more aggressive phenotype with both intra- and extracranial metastases (1, 2, 3). These metastatic prolactinomas follow an undulating course, and neither surgery, radiotherapy, or noncytotoxic chemotherapy have been shown to significantly alter the natural history of patient death within 4 yr (1, 2, 3). The only cytotoxic regimen reported to date consists of procarbazine, etoposide, and lomustine used in two patients, which may have slowed the progression of the tumor by a few months (1).

The molecular basis for such aggressive tumors is uncertain. A variety of mutations have been associated with pituitary tumors (4). The best characterized genetic change is the gsp mutation, which occurs in 34–40% of somatotroph adenomas (5, 6), although gip mutations have also subsequently been described (7, 8). Mutations in the ras oncogene are relatively rare. A mutation in H-ras has been described in a highly invasive prolactinoma, and H-ras mutations have been described in metastatic deposits of pituitary carcinoma, including a PRL-secreting carcinoma, but not in the primary tumors (9, 10). A point mutation in the isoform of protein kinase C has been described in highly invasive pituitary tumors (11). The p53 tumor suppressor gene mutation is the commonest specific gene alteration associated with major human neoplasia, but abnormal p53 expression appears to occur infrequently in human pituitary adenomas (10, 12) other than corticotrophic adenomas (13). c-myc is overexpressed in a wide variety of pituitary adenomas, and overexpression of c-fos, although occurring much less frequently, may have a pathogenic role in the development of corticotroph adenomas (14). Loss of heterozygosity at the retinoblastoma susceptibility gene (Rb) has been reported in malignant and invasive prolactinomas (15). It remains unknown, however, whether any specific mutation or combination of mutations predispose tumors to develop a particularly aggressive phenotype. We report a case of metastatic prolactinoma, describe the clinical course, treatments employed, and subsequent immunocytochemical analysis.

	Case History

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A 54-yr-old women presented in 1989 to a regional neurosurgical unit with bitemporal hemianopia and oligomenorrhoea. Computerized tomography demonstrated a moderately large pituitary macroadenoma. The serum PRL, measured at the unit, was estimated at >10,000 mU/L (normal range <450 mU/L). She underwent transsphenoidal surgery followed by external beam radiotherapy. Histology demonstrated a PRL-secreting adenoma. Postoperatively her serum PRL remained elevated at 36,310 mU/L, although she had almost a complete return to normal of her visual fields. Following referral to the local endocrinologist, she was prescribed bromocriptine 20 mg/day with a good response, and for 2 yr her PRL remained in the region of 1000 mU/L. In October 1991, she became intolerant to the bromocriptine, which was thus discontinued. She remained well for a further 6 months, at which time she developed diplopia. Computerized tomography demonstrated extension of the tumor into the left cavernous sinus. Dynamic pituitary tests confirmed hypopituitarism. Hydrocortisone followed by T₄ treatment was commenced, and bromocriptine was restarted. Despite this treatment, within 4 months she had developed a left lateral rectus palsy and was referred for a transfrontal debulking resection followed by stereotactic radiotherapy in September 1992. The tumor continued to enlarge, and by March 1993 she had a blind anesthetic left eye with 3rd, 4th, and 6th nerve palsies. In August 1993, an enlarged left submandibular lymph node was removed, and pleomorphic cells consistent with metastatic prolactinoma were identified. The patient’s only complaint was of undulating left facial pain, which had failed to respond to conventional analgesia, high-dose opiates, or carbamazepine. PRL levels gradually increased to 114,000 mU/L, and she was referred to the regional endocrine unit.

A magnetic resonance imaging (MRI) scan demonstrated an extensive tumor invading the ethmoidal sinuses, left orbit, temporal fossa, pons, maxillary antrum, pterygo-palatine fossa, jugular nodal chain, and thoracic bodies (Fig. 1). An In-111 pentetreotide scan showed abnormal uptake in the anterior of skull and the angle of the jaw (Fig. 2). The PRL estimation of 114,000 mU/L was confirmed. Cabergoline was commenced and increased to 8 mg/week in divided doses coincident with a moderate decrease (30%) in her PRL level to 74,000 mU/L. Interestingly, when first treated at this high dose, she developed a transient paranoid delusional state with some features of dermatozoonosis, which resolved within 2 days of decreasing the dose. Octreotide was commenced via a continuous sc infusion and maintained at 800 µg/day. Within 24 h her facial pain resolved completely. She was given three cycles of carboplatin (440 mg infusion over 30 min) and etoposide (100 mg/day orally for 5 days). Serial PRL estimations and MRI scans showed no clear benefit from the treatment. Six months after commencing chemotherapy, following a severe headache presumably caused by tumor infarction or hemorrhage, she died peacefully at home. Autopsy examination was not performed.

View larger version (131K): [in this window] [in a new window]   Figure 1. MRI scan illustrating extensive spread of tumor.

View larger version (28K): [in this window] [in a new window]   Figure 2. Pentetreotide scan of tumor.

	Results

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Paraffin sections obtained from the first hypophysectomy and the lymph node biopsy were immunostained for a range of known proto-oncogenes. Antibodies to RB protein, c-jun, WAF-1, p53, and c-myc were purchased from Novocastro Laboratories (Newcastle, UK). RB protein, c-jun, and WAF-1 were demonstrated using a peroxidase-labeled streptavidin technique, and c-myc was demonstrated using an indirect peroxidase method. Sections underwent microwave pretreatment for RB protein, WAF-1, and c-myc and trypsinization for c-jun. Controls were omission of primary antibody as negative and inclusion of known positives. The results are shown in Fig. 3. Widespread nuclear staining was demonstrated for p53 tumor suppressor gene (50–75%), WAF-1 (40–50%), Rb protein (50–75%), and c-myc (40–60%) in both tissues. There was no positive staining for c-erb-2 in any tissue. The original tumor stained negative for c-jun, but the secondaries were positive. Few cells in the metastatic tumor showed positivity with MIB-1 antibody, which demonstrates ki-67, a nuclear protein expressed during the cell cycle. The lymphoid tissue showed the expected pattern of staining.

View larger version (195K): [in this window] [in a new window]   Figure 3. Immunocytochemistry of tumor. In all figures nuclei had a light hematoxylin stain. a, Immunostaining of original tumor for c-jun shows no nuclear reactivity. b, Immunostaining of recurrent tumor shows variable nuclear immunopositivity for c-jun. c, Immunostaining of recurrent tumor shows variable immunostaining for WAF-1. d, Recurrent tumor shows cytoplasmic positivity for c-myc.

	Discussion

Top Abstract Introduction Case History Results Discussion References

 
Metastatic prolactinomas are rare tumors for which to date no effective therapy has been established. In our case, surgery, radiotherapy, dopamine agonists, octreotide, and chemotherapy failed to control the disease. The patient presented to a neurosurgical unit which proceeded with surgery and radiotherapy before conventional therapy with dopamine antagonists had been tried. It is well established that even very large macroprolactinomas are usually sensitive to dopamine antagonists, and preoperative treatment may have precluded the need for radiotherapy or, indeed, surgery. Two years after her diagnosis, the patient developed increasing resistance to dopamine agonists. This behavior suggests a change in tumor phenotype, which may have been spontaneous or perhaps precipitated by radiotherapy.

The specific DA2 antagonist cabergoline appeared to have no advantage over bromocriptine; although serum PRL estimations decreased by 30%, which may represent dedifferentiation, there was no decrease in tumor size. Cabergoline did, however, precipitate an acute paranoid crises in the form of dermatozoonosis, i.e. a sensation of animals crawling over the skin. This interesting monosymptomatic hypochondriasis was first described by Ekbom (16) as a consequence of presenile neuronal degeneration and was subsequently seen in association with high doses of bromocriptine (5). In this latter case, as in ours, the psychotic symptoms resolved on reduction in the dose of dopamine agonist.

Despite the presence of somatostatin receptors, as demonstrated by the positive pentetreotide scan, octreotide had no significant effect on disease progression. This agrees with previous observations that tumor growth suppression may not occur with octreotide despite a high level of uptake when using radiolabeled ligand (17). However, octreotide did have a rather favorable effect on the patient’s facial pain. Somatostatin messenger RNA has been identified in high density within the pain-modulating caudal region of the spinal trigeminal nucleus and in the substantia gelatinosa of the dorsal horns within both the cervical and lumbar regions (18). This has led to the suggestion that spinal injections of somatostatin analogs may be of benefit in the management of intractable pain of malignancy (19). In humans, intraarticular injection of somatostatin has been shown to reduce painful osteoarthritis of the knee (20). We have seen a similar phenomenon in a patient with a malignant phaeochromocytoma that also had large uptake of octreotide. There was no reduction in tumor size, but a dramatic analgesic effect occurred with octreotide therapy. Furthermore, octreotide is well recognized as having a rapid analgesic effect on headache in acromegalic patients. Despite the lack of effect of octreotide, pentetreotide scanning may still have a role in determining the extent of local and metastatic spread in patients with prolactinomas.

Walker et al. (1) treated three patients with procarbazine, etoposide, and lomustine, resulting in dramatic reductions in serum PRL concentration suggestive of either response to treatment or dedifferentiation with tumor progression. There was, however, no clear benefit in terms of life expectancy. After consultation with our local oncologists, it was felt that carboplatin and etoposide offered the best chance of success with the minimum of adverse effects in our patient. It seems unlikely, however, that they had any real benefit on the progression of disease.

We demonstrated immunocytochemical staining for c-myc, p53, WAF-1, and Rb protein in both the primary and secondary tumor. The original pituitary tumor did not stain for c-jun, but the recurrent tumor was positive. We have subsequently carried out further studies on genomic DNA but have identified no mutations other than loss of heterozygosity within the Rb region as described previously (15). The underlying oncogenic mechanisms occurring in pituitary neoplasia are poorly understood. X-chromosome inactivation has demonstrated that most pituitary tumors are monoclonal, implying the occurrence of an initial genetic event (21). The best-characterized genetic change occurring in pituitary adenomas is in the gsp oncogene (5, 6), although no mutations were present in our case. Positive nuclear staining for p53 cannot normally be detected because of its short half-life. The presence of WAF-1, however, suggests that there is functional p53 present in these cells. It may be that this reflects mechanisms of p53 inactivation other than mutation, resulting in loss of control of cell proliferation and apoptosis function. It is interesting that c-jun activating protein-1 protein was increased in the tumor metastases but not in the primary tumor. These data suggest that the activating protein-1 proteins c-myc and c-jun may have had a specific role in progression to metastatic spread similar to that suggested for H-ras (10). Pei et al. (15) reported allelic loss in the region of the Rb gene in 13 aggressive pituitary tumors, seven of which were metastatic. Immunohistochemical analysis did, however, reveal the presence of Rb protein (which may not reflect functional protein), and it appears that loss of heterozygosity in the Rb region of chromosome 13q may provide a marker for other tumor suppression factor(s) that are of central importance in the development of metastatic pituitary tumors. Overall, the data point to multiple potential oncogenic mutations in the development of this tumor. Increased numbers of mutations, perhaps secondary to radiotherapy (22, 23), in particular loss of heterozygosity, appear to be associated with increasingly aggressive tumor behavior. It may be that particular mutations, e.g. ras or jun are associated with malignant transformation.

In summary, the management of pituitary carcinoma remains very unsatisfactory. Specific oncogenic mutations may be associated with the progression of the disease, and in the future gene therapy may be possible to correct for the loss of tumor suppressor function.

Received April 10, 1997.

Revised May 28, 1997.

Accepted June 3, 1997.

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