Malignant prolactinoma: case report and review of the literature

European Journal of Endocrinology (2006) 155 523–534 ISSN 0804-4643 CASE REPORT Malignant prolactinoma: case report and review of the literature Marleen Kars, Ferdinand Roelfsema, Johannes A Romijn and Alberto M Pereira 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: [email protected]) 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 Ki67 and/or p53 immunoreactivity, it may be useful to denote these tumors as ‘atypical’ prolactinomas to raise the possibility of future malignant development. European Journal of Endocrinology 155 523–534 Introduction Case report 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. 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 mg/l (normal value !22 mg/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 mg/l within a few months. The visual field defects recurred and prolactin levels increased to 206 mg/l (Fig. 3), 6 months later. Therefore, bromocriptine treatment was switched to quinagolide (up to 300 mg/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 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02268 Online version via www.eje-online.org 524 M Kars and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Figure 1 Visual field investigation in October 1999, revealing bitemporal hemianopsia. 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 mg/l in June 2000 to a nadir of 33 mg/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. Serum prolactin levels started to rise again in August 2001. MRI of the brain did not reveal progression of the tumor, but the rise in prolactin concentration proved to be due to metastases in the spinal cord (Fig. 4), 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!4 Gy) from L5 to S5 in February 2002. Histological examination confirmed a prolactin-producing metastasis. Subsequently, the patient developed extensive metastases throughout the spinal cord. Therefore, the spinal cord was irradiated with fractionated radiotherapy aimed at C2 to L4 with a total dose of 40 Gy in June 2002 to relieve pain and prevent paralysis from compression of the myelum. In August 2002, she developed progressive ptosis of the right eye and facial paralysis due to infiltration of the www.eje-online.org 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 mg/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 Figure 2 Magnetic resonance image (axial T1-weighted image) obtained in April 1999, demonstrating a pituitary mass of 2.5 cm, invading the right sphenoidal and cavernous sinus (Hardy classification IV-E (47)), and encasement of internal carotid artery. Malignant prolactinoma: a review EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 525 10000 Rt Rt Laminectomy Craniotomy Prolactin (log µg/l) Rt Rt 1000 100 Bromocriptine Quina Cb. 10 0 1 2 3 4 Follow-up (years) Quina.= quinagolide, Cb = cabergoline, Rt= radiotherapy 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. 5 Figure 3 Serum prolactin concentrations from October 1998 to April 2003 (normal value !22 mg/l). 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 Figure 4 MRI (sagittal T1-weighted image) obtained in November 2001, demonstrating spinal lesions (arrows) in the lumbar and sacral region. www.eje-online.org 526 M Kars and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Figure 5 Total-body scintigraphy after [123I] epidepride injection in December 2001. Physiological accumulation of activity in basal ganglia, liver, kidneys, bowel, and urinary bladder. Anterior view (left image): intracranial accumulation of the isotope reflecting the macroprolactinoma (arrow). Posterior view (right image): multiple accumulations of the isotope reflecting multiple metastases in the spine (arrows). 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. Kaltsas et al. described histological and immunohistochemical parameters that predict the biological behavior of pituitary tumors (1, 3). Histological parameters associated with an atypical or aggressive behavior of the adenoma are cellular atypia, nuclear pleomorphism, more than two mitotic figures per ten high-powered fields, a proliferative index of Ki-67 more than 3%, positive p53 immunoreactivity, and invasion. www.eje-online.org They are also called atypical parameters. Histological investigation of the tissue initially obtained by surgery, biopsy, or autopsy of the prolactinoma revealed a benign classification in 37% and an atypical classification in 40% (Table 3). 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 Ki67 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 Primary treatmenta PA primary tumor Time interval diagnosis – metastases (years) Age/ sex Martin, 1981 31/F Cohen, 1983 70/M U, 1984 63/M Gasser, 1985 28/M Landgraf, 1985 44/F Plangger, 1985 28/M Scheithauer, 1985 52/F Rt, CT, TSS(2x), DA Mitotic figures rare 11 Von Werder, 1985 Muhr, 1988 43/F 14/M CT, Rt, DA CT, Rt Not documented Benign 4 12 Atienza, 1991 34/M DA, CT(2x), Rt, DA No mitotic figures 4 Popovic, 1991 47/M DA, CT(2x), Rt Mitosis 6/HPF 2 56/F TSS, Rt Mitosis 5/10 HPF TSS, Rt, CT, DA, Rt Pleomorphism, rare mitotic figures – No mitotic figuresb Metastatic sites 5.5 Cerebellum 3.5 Cerebellopontine angle Mitosis 3/20 HPF 6 Cerebrum CT, Rt, DA Mitosis, pleomorphism 9 CT, Rt, DA Benign 4 Benign 9 CT, Rt CT, Rt 12 Treatment of metastasesa PA metastases CT Numerous mitotic figures – No mitotic figuresb CT, Rt, DA Mitosis 11/20 HPF, pleomorphic Cerebrum CT, DA, Rt, CT Mitosis, pleomorphism; tumor cells in subarachnoidal space and in venous blood channels Cerebellum, spinal LT, Rt, DA, Benign cord chemo, octapeptidesomatostatin, chemo Cerebrum, subar- CT, Rt, DA, CT Mitotic figure rare achnoid nodules Cerebrum, DA, Rt(2x) Mitotic figure rarec vertebrae, occipital bone, ribs Spinal cord DA, LT, Rt, DA Not documented Cerebellum, fron- Surgery, DA Mitosis tal lobe Spinal cord, DA, Rt, TSS Mitosis 2/10 HPF, pulmonary vascular invanodules sion Dura, cerebrum, CT Mitosis 6/HPF cerebellum Roof fourth ventriCT Mitosis 5/10 HPF cle, cerebrum, spinal cord Cause of death Death due to disease progression Pulmonary edema, circulatory shock Pulmonary embolus Death due to disease progression Death due to disease progression 8.5 3.58 6.25 12 5.5 13.5 5.5 2.02 12.33 527 www.eje-online.org Still alive at publication Death due to disease progression Unknown Still alive at publication Death due to disease progression Gastrointestinal bleeding Acute pulmonary edema, Staphylococcus aureus septicemia Time interval diagnosis – death (years) Malignant prolactinoma: a review Author, year of publication EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Table 1 List of previously published cases of malignant prolactinoma. 528 Author, year of publication Age/ sex Primary treatmenta Berezin, 1992 32/F CT, Rt Figarella, 1992 Kamphorst, 1992 45/M 45/M Petterson, 1992 PA primary tumor Time interval diagnosis – metastases (years) Metastatic sites Treatment of metastasesa 20 Intraorbital TSS, DA, CT(2x) CT, Rt, chemo, Rt Mitosis 1/2 HPF Mitotic figures rare 8 13 Not documented Mitotic figures rareb 40/M CT, Rt, DA Mitotic figures 5 Assies, 1993 63/M CT, Rt, DA Not documented 7 Vertebrae, lung – Pons, medulla – oblongata, spinal cord Encasement caro- CT, DA, CT, tid bifurcation, chemo, CT, retro-orbital chemo space, cerebrum, cerebellopontine angle, nodule vertebral artery Cerebrum Surgery, DA, Rt Kasantikul, 1993 30/F DA Pons, subarachnoid space – No mitotic figuresb CT Mitotic figures in large numbers No mitotic figures Walker, 1993 Long, 1994 Mitosis 3–4/10 HPF, pleomorphism Pleomorphic, invading overlying cerebral tissue Not documented Anorexia, pneumonia, comatose, death due to disease progression Unknown Death due to disease progression Death due to disease progression Death due to disease progression Pneumonia, duodenal ulcer, deep vein thrombosis left leg Still alive at publication Pneumonia 22/M CT, Rt Benign 3 Optic nerves 32/M TSS, Rt, DA, TSS(4x), CT No mitotic figures 5 48/F Rt, DA, TSS No mitotic figures 15 49/M CT, Rt Benign 2 70/M TSS No mitotic figures 6 Sphenoidal and Chemo, TSS, ethmoidal 125 I implansinuses, orbit, tation, TSS, liver, lungs, hilar DA, Octreonods tide, TSS, Rt, Chemp Vertebrae, sacro- DA, Rt, chemo No mitotic figuresc Renal failure iliac joints, femur Mediastinal lymph DA, CT, Rt, No mitotic figures Pulmonary node, lung Octreotide embolus post-operatively after hip replacement Cerebrum CT, Rt, CT, Rt, No mitotic figuresb Still alive at publication DA Time interval diagnosis – death (years) 25 13.02 8 8 0.17 9.5 15.5 3.5 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Benign No mitotic figuresb CT, enucleation left eye and retroorbital mass, Rt PA metastases Cause of death M Kars and others www.eje-online.org Table 1 Continued Age/ sex O’Brien, 1995 48/M CT, Rt, DA Benign Gollard, 1995 33/F TSS, DA, TSS biopsy, Rt No mitotic figures Saeger, 1995 59/M DA, TSS(2x), Rt Mitotic figures Rockwell, 1996 50/M TSS, CT, Rt, DA Benign Bayindir, 1997 32/F Hurel, 1997 49/F Pernicone, 1997 44/F DA, TSS TSS, Rt, DA TSS, Rt DA, Rt, TSS 5 12 5 16 Metastatic sites Cerebrum Cheek pouch, cerebrum, pelvis, ovaries Liver Treatment of metastasesa PA metastases CT Mitoses frequent DA, surgery, Rt, hysterectomy, salpingooophorectomy, chemo Chemo, DA Mitosis 1–3/HPF Pleomorphicc Spinal intradural Mitoses and necroses, pleomorphic 0.08 Benign, p53 positive 5 Not documented 3 Not documented 3 Gamma-knife Mitotic figures radiosurgery, LT, Rt, DA Oculomotor nerve, CT, LT, CT Mitoses and the optic foranecroses men, encasement carotid artery, cerebrum, spinal cord Ethmoidal Pleomorphic, p53 CT, Rt, DA, sinuses, orbita, positive, Ki-67 Octreotide, temporal fossa, positive chemo pons, maxillary antrum, submandibular node Oral submucosa, Surgery, Rt, Not documented ovaries, myochemo, DA metrium, pelvic nodes Vertebrae, femur Rt Not documented CT, Rt Not documented 3 Cerebellum Rt, DA, Surgery Not documented 54/F TSS Not documented 1 Spinal subarachnoid Rt, DA, chemo Not documented 37/M TSS(2x) Not documented 6 Lymph nodes Rt Not documented 64/M TSS Not documented 6 Occipital lobe, tentorium Unknown Not documented Time interval diagnosis – death (years) Still alive at publication Still alive at publication Pulmonary embolus Still alive at publication 6 Death due to disease progression 0.25 Tumor infarction or hemorrhage, coma 7 Still alive at publication Death due to disease progression Death due to disease progression Death due to disease progression Death due to disease progression Still alive at publication 4 11 3 7 529 www.eje-online.org 62/M Cause of death Malignant prolactinoma: a review 34/M Primary treatmenta PA primary tumor Author, year of publication Time interval diagnosis – metastases (years) EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Table 1 Continued 530 Primary treatmenta PA primary tumor Time interval diagnosis – metastases (years) Age/ sex Popadic, 1999 51/M CT, DA, Rt Invasive prolactinoma, pleomorphism, no mitotic figures 4 Spinal cord Arias, 2000 32/M DA, CT, Rt Mitosis 1 Petrossians, 2000 43/M CT, TSS(2x), DA Not documented 7 Medulocerebral angle, vertebrae, spinal epidural space Spinal cord, rib, mediastinum, femur Sironi, 2002 45/M TSS, CT, TSS, Rt, Sandostatin Mitosis 1/20 HPF 9 Vaquero, 2003 40/M Not documented 14 Winkelmann, 2002 53/M DA, TSS, CT, Rt Pleomorphism, Ki-67 positive 6 Harinarayan, 2004 Lamas, 2004 26/M 14/M CT, DA TSS, DA, Rt, CT Benign Pleomorphism, numerous mitotic figures 7 6 Noda, 2004 52/F TSS, CT, Rt, DA Benign 7 Uum Van, 2004 20/F CT(2x), DA Not documented 13 Vaishya, 2004 55/F CT, Rt, DA Benign 10 Crusius, 2005 47/M CT, Rt TSS, CT, Rt, DA Ki-67 2.80% and 4.40% 6 Metastatic sites Cerebrum, spinal cord Cerebrum Treatment of metastasesa PA metastases Cause of death Pleomorphism Still alive at with rare mitotic publication figures, tumor cells in nervous and fibrous tissue CT, Rt Mitosis; tumor Pneumonia cells in subarachnoid space and in venous blood channels CT, Rt, DA, Not documented Death due to gamma-knife disease proradiosurgression gery(4x), CT(2x), Rt CT(2x), Rt Mitosis 5–25/10 Pulmonary HPF, Ki-67 embolism positive, pleomorphic Surgery Ki-67 ! 2% Still alive at publication Renal failure, DA, gammaPleomorphic, Kib lung edema, knife radio67 positive death due to surgery(2x) disease progression Unknown DA, Octreo Benignc c Still alive at Chemo, DA Mitotic figures publication Time interval diagnosis – death (years) TSS, LT, Rt, DA Orbita, foramen magnum, medulla oblongata, spinal cord, vertebrae Liver, gastric Cerebrum, skull, pulmonary hilum, nodules lungs, ribs, pelvis, spine Cerebellum, Gamma-knife Pleomorphism, Ki- Respiratory arrest medulla oblonradiosurgery, 67 positivec gata, spinal cord Rt, DA Leptomeningeal LT, DA Low mitotic index Still alive at publication Encasement TSS, DA Mitosis 2/10 HPF, Death due to internal carotis vascular invadisease proartery, sphenoid sion, Ki-67 gression sinus positive Cardiac arrest Cerebrum Ki-67 4.45%c 3 15 10.42 7 9 11 6.02 EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Author, year of publication M Kars and others www.eje-online.org Table 1 Continued M, male; F, female; Chemo, chemotherapy; CT, craniotomy; DA, dopamine agonist; F, female; HPF, high powered field; LT, laminectomy; M, male; PA, pathological anatomic investigation; Octreo, octreotide; Rt, radiotherapy; TSS, transsphenoidal surgery. Numbers in parentheses indicate number of treatments. b Pathological anatomic findings on autopsy. c Pathological anatomic findings on biopsy. a 5 Mitosis 6/HPF, Ki- Death due to 67 positive disease progression LT, Rt(3x) Sinus sphenoidales, encasement internal carotis artery, spinal cord, vertebrae 3.5 No mitotic figures, Ki-67 10–15% 62/F Kars, 2006 DA, CT, Rt Age/ sex Author, year of publication Table 1 Continued Primary treatmenta PA primary tumor Time interval diagnosis – metastases (years) Metastatic sites Treatment of metastasesa PA metastases Cause of death Time interval diagnosis – death (years) EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Malignant prolactinoma: a review 531 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 longterm follow-up has not been reported in most of these patients. www.eje-online.org 532 M Kars and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 Table 2 Summary of clinical features of malignant prolactinoma presented between 1981 and 2005. nZ48 Gender, male (%) Age, years Most prevailing symptomatology, number (%) Hyperprolactinemia Local compression Metastatic sites (%) Intracranial Extracranial Extramedullary Mean time interval diagnosis – metastases (years) Mean time interval metastases – death (years) Mean time interval diagnosis – death (years) Alive at publication (%) 65 43.6 (range 14–70 years) Primary tumor 17 (35) 34 (71) Metastases 1 (2) 35 (73) 75 33 40 6.9 (range 1 month–20 years) 1.9 (range I week–8 years) 8.0 (range 2 months–25 years) 29 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 noncompliance 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. Table 3 Histological, biochemical and therapeutic characteristics of the primary pituitary tumor and metastases. References nZ48, number (%) Histological classification Typical Atypical Not documented Response to DA DA resistance Cabergoline Others DA escape Cabergoline Others Therapy Surgery Radiotherapy Surgery and radiotherapy Chemotherapy Dopamine agonist DA, dopamine agonists. www.eje-online.org Primary tumor Metastases 18 (37) 19 (40) 11 (23) 8 (17) 30 (62) 10 (21) Overall 15 (31) 2 (13) 13 (87) 25 (52) 4 (16) 21 (84) 46 (96) 38 (79) 38 (79) 33 (69) 26 (54) 20 (42) 1 (2) 31 (65) 10 (21) 29 (60) 1 Kaltsas GA, Panagiotis N, Kontogeorgos G, Buchfelder M & Grossman AB. Clinical review: diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism 2005 90 3089–3099. 2 Ragel BT & Couldwell WT. Pituitary carcinoma: a review of the literature. Neurosurgical Focus 2004 16 1–9. 3 Kaltsas GA & Grossman AB. Malignant pituitary tumours. Pituitary 1998 1 69–81. 4 Martin NA, Hales M & Wilson CB. Cerebellar metastasis from a prolactinoma during treatment with bromocriptine. Journal of Neurosurgery 1981 55 615–619. 5 Cohen DL, Diengdoh JV, Thomas DGT & Himsworth RL. An intracranial metastasis from a PRL secreting pituitary tumour. Clinical Endocrinology 1983 18 259–264. 6 U SH & Johnson C. Metastatic prolactin-secreting pituitary adenoma. Human Pathology 1984 15 94–96. 7 Gasser RW, Finkenstedt G, Skrabal F, Twerdy K, Grunert V, Mayr U, Frommhold H, Zur Nedden D, Feichtinger J & Hofstaedter F. Multiple intracranial metastases from a prolactin secreting pituitary tumour. Clinical Endocrinology 1985 22 17–27. 8 Landgraf R, Rieder G, Schmiedek P, Clados D, Bise K & Von Werder K. Hormone-active intradural spinal metastasis of a prolactinoma: a case report. Klinische Wochenschrift 1985 63 379–384. EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 9 Plangger CA, Twerdy K, Grunert V & Weiser G. 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