Pituitary (2013) 16:515–522 DOI 10.1007/s11102-012-0448-y
Aggressive and malignant prolactin pituitary tumors: pathological diagnosis and patient management Ilyess Zemmoura • Anne Wierinckx • Alexandre Vasiljevic • Michel Jan • Jacqueline Trouillas • Patrick Franc¸ois
Published online: 27 November 2012 Ó Springer Science+Business Media New York 2012
Abstract According to the World Health Organization classification of pituitary tumors, only tumors with systemic metastasis must be considered as carcinomas. Invasive tumors with multiple recurrences are only classified as aggressive tumors or ‘‘atypical adenomas’’. To illustrate the problems encountered in the pathological diagnosis of pituitary carcinoma and in patient management, we present two male patients operated on for an aggressive prolactin pituitary adenoma with and without metastasis. In case 1, 5 surgeries, 3 irradiations, increased doses of dopamine agonists, and trials of temozolomide and carboplatineVP16 failed to control tumor progression and the appearance of metastases which lead to death 16 years after onset. In case 2, based on the initial diagnosis of an aggressiveinvasive adenoma that was resistant to dopamine agonists, I. Zemmoura M. Jan P. Franc¸ois Service de Neurochirurgie, CHU de Tours, Tours, France I. Zemmoura M. Jan P. Franc¸ois Universite´ Franc¸ois Rabelais de Tours, Tours, France I. Zemmoura (&) Service de Neurochirurgie, CHRU Bretonneau, 37000 Tours, France e-mail:
[email protected] A. Wierinckx A. Vasiljevic J. Trouillas Neuro-Oncology and Neuro-Inflammation Team, INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, 69372 Lyon, France A. Wierinckx A. Vasiljevic J. Trouillas Faculte´ de Me´decine Lyon-Est, Universite´ de Lyon, Lyon 1, site Laennec, 69372 Lyon, France A. Vasiljevic J. Trouillas Centre de Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, 69003 Lyon, France
gamma-Knife irradiation was initially performed on the intra-cavernous remnant. Eight years after onset, the remnant remained stabilized and the plasma PRL normalized under dopamine agonist. From these 2 cases alongside other cases found in the literature, we propose that the association of certain clinical signs (male sex, dopamineresistant hyperprolactinemia), radiological signs (invasive macro or giant tumor on MRI) and histological signs (angiogenesis, Ki-67 [ 3 %, p53 positive, mitoses [2 per high power field, vascular invasion, up-regulation of genes related to invasion and proliferation, and allelic loss of chromosome 11) might suggest aggressiveness and be suspicious of malignancy before the appearance of metastasis. The early detection of an aggressive phenotype of a prolactin pituitary tumor should permit the earlier establishment of the optimum therapeutic strategy associating surgery and radiotherapy to delay or inhibit metastasis. Keywords Aggressive pituitary tumor Pituitary carcinoma Prolactinoma Hyperprolactinemia Classification
Introduction According to the literature and the World Health Organization (WHO) classification, pituitary carcinomas are tumors that develop from cells of the anterior pituitary and are accompanied by one or several cerebral, meningeal or systemic metastases [1–4]. Their occurrence is estimated as 0.2 % of pituitary tumors [2, 3, 5–11]. Malignant prolactinomas represent around 30 % [3, 9] of these pituitary carcinomas and occur more frequently in men than in women [12, 13]. These multi-recurrent invasive tumors are resistant to dopamine agonists [12, 13] and generally lead
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to metastases later on though in rare cases they can present an early recurrence with metastasis [7]. Other tumors display clinically aggressive behavior with multiple recurrences but show no obvious metastasis. According to the WHO classification [14], these latter tumors ‘‘showing atypical morphological features suggestive of aggressive behavior such as invasive growth, and other features including, elevated mitotic index, a Ki-67 index[3 % [15] as well as extensive nuclear staining for p53 should be classified as atypical adenomas’’. Recently, other criteria of aggressiveness and malignancy have been suggested such as overexpression of endocan in endothelial cells [16], dysregulated genes revealed by microarrays [17, 18] and/or DNA abnormalities by comparative genomic hybridization (CGH) [19–22]. We report here 2 patients treated by the same neurosurgeon (MJ) and studied by the same pathologist (JT) 13 years apart for aggressive prolactin (PRL) tumors suspected or diagnosed as being malignant. They illustrate the difficulties encountered in the pathological diagnosis and therapeutic management of these tumors. We use these cases to propose some criteria of potential malignancy that would allow an early diagnosis before metastasis and consequently an optimized treatment of these aggressive or malignant pituitary tumors.
Case reports Clinical, radiological and biological data Case 1 (Figs. 1, 2) A 54-year-old man presented with bitemporal hemianopsia, reduced libido and hyperprolactinemia (PRL: 8,300 mUI/L; normal values: 53–360 mUI/L). MRI (Fig. 1-1) showed a macroadenoma with invasion of the right cavernous sinus. The first intervention by a transrhinoseptal approach allowed what appeared to be a complete removal of the tumor leading to visual improvement and MRI normalization; however, prolactinemia remained elevated despite increasing doses of bromocriptine (5 9 2.5 mg/day). MRIs and CT (Fig. 1-2) showed a gradual increase in tumor volume over 4 years when visual trouble began to reappear and levels of PRL had reached 24,000 mUI/L. The second surgical intervention was again followed by visual improvement though this time also by a moderate decrease of prolactinemia. The patient was given quinagolide (300 lg/day). Fractionated stereotactic irradiation was performed (50–1.8 Gy per session). Follow-up examinations revealed high levels of PRL and MRI revealed tumor progression (Fig. 1-3) leading to radiosurgery (18 Gy).
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Over the next 4 years, tumor growth was associated with high PRL levels and invasion of the right cavernous sinus, clivus and prepontine cistern (Fig. 1-4) leading to a third intervention. The tumor continued to spread despite fractionated stereotactic irradiation (45 Gy) (Fig. 1-5) leading to the fourth surgical intervention followed by two therapeutic trials with temozolomide (200 mg/m2 5 days a month for 5 months) followed by its association with carboplatine-VP16 (2 sessions). Control MRI showed continued growth of the tumor (Fig. 1-6). A fifth intervention by transcranial approach allowed a transient visual improvement. PET scan revealed left jugulo-carotid lymph node metastasis and MRI frontal and temporal meningeal metastases (Fig. 2). The patient died 16 years after onset at home. The patient’s family refused to provide consent for an autopsy. Case 2 (Fig. 3) A 46-year-old man presented with impotence and loss of libido. MRI showed a pituitary macroadenoma invading the right cavernous sinus. Treatment by cabergoline (0.5 then 1 mg/week) was imposed. Levels of PRL rose progressively from 10,280 to 22,900 mUI/l. MRI remained the same (Fig. 3-1). The patient was operated by a transnasal approach. PET scan was normal. At the 6-month follow-up, PRL levels were 6,968 mUI/L associated with a tumor residue in the right cavernous sinus (Fig. 3-2). Cabergoline was consequently increased to 2 mg/week. Based on pathological diagnosis, gamma knife irradiation was performed (30 Gy) on the tumor residue. Six months later the patient was working and leading a normal life with no sexual disorder. Under cabergoline (1 mg/week), the level of PRL had been normalized at 206 mUI/L. Several follow-up evaluations up until the most recent (Fig. 3-3, 4) showed the same picture under low dose of cabergoline 8 years after the surgery. Pathological data (Table 1; Fig. 4) Fragments of tumor removed following each surgical intervention were fixed in Bouin-Hollande fixative. Paraffin sections were stained with hematoxylin-phloxine-saffron and Herlant’s tetrachrome. An immunoperoxidase reaction was performed using antibodies against PRL, GH, bFSH, bLH, ACTH, bTSH, and endocan (clone MEP08, 1/200, Lunginnov, Lille France). Also performed was the detection of cell cycle markers: Ki-67 (Mib1, 1/50, Dako, Glostrup, Denmark), PTTG (clone 18-0278; 1/200, Zymed Laboratories Inc., San-Francisco, CA USA) and p53 (clone DO-7, 1/200, Novocastra Laboratories, Newcastle-upon-Tyne, UK), by immunostaining both manually with microwave
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Fig. 1 Case 1: evolution of plasma prolactin (PRL) levels (normal values: 53–360 mUI/L), tumor imaging by MRI and CT, and treatment during the 18 years of follow-up
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Fig. 2 Case 1: a PET-scan revealing metastasis in the left jugulocarotid lymph node, b MRI showing temporal metastasis, c frontal metastasis
pretreatment and automatically with Benchmark XT, Ventana Medical System, Tucson, AZ, USA on all the fragments of the tumors of both cases at the same time. Ki-67 and p53 labeling was expressed as a maximum percentage and mitotic index by the absolute number of mitoses. In both cases, the initial tumor was a pituitary adenoma with diffuse arrangement and signs of angiogenesis (Fig. 4a), with a strong expression of endocan in the endothelial cells of many vessels (Fig 2c in ref [16]). The cells were agranular with large nuclei and prominent nucleoli. By immunocytochemistry, all the cells were immunostained with anti-PRL antibodies (Fig. 4a–c) and showed strong cytoplasmic immunoreactivity with the antiPTTG antibody. Numerous normal (arrow) and abnormal (double arrow) mitotic cells (Fig. 4b) with high Ki-67 were observed in the initial tumor of both cases and in the 4 recurrent tumors of case 1 (Table 1). Nuclear expression of p53 was also observed in both cases and its index varied in the recurrent tumors of case 1. The detection of vascular invasion of PRL-immunopositive cells was observed in the initial tumor of case 2 and in the fragments from the last surgical intervention in case 1 (Fig. 4c). The diagnosis of
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carcinoma was only made in case 1 based on the presence of metastatic lymph nodes on PET scan (Fig. 2). In case 2, while the high number of mitoses with abnormalities and vascular invasion suggested a malignancy, in absence of obvious metastasis, the diagnosis was ‘‘atypical adenoma’’ [14] or aggressive-invasive adenoma [17, 18]. Fragments of tumors of both cases were frozen for molecular study. Unfortunately, only fragments of the third surgical intervention of case 1 were available for microarray and CGH. Both the technique and results have partly been published in two series of PRL tumors (case 3 in Raverot [17] and case 4 in Wierinckx [22]). The results were reanalyzed in comparison with four non-aggressive tumors and two other PRL carcinomas. Among the upregulated genes, 11 genes were considered as interesting in view of their involvement in the normal and/or cancer cell cycle (PTTG, E2F2, E2F4, ERB2, ASK, CCNB1, AURKB, and CENPE), in invasion (ADAMTS6, CRMP1), and in cell transformation (Twist1). Three genes (TGFbR1, PTX2 and AIP) were dramatically down regulated. Moreover, an allelic loss of the whole chromosome 11 was revealed by CGH, as in the two other PRL carcinomas.
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Fig. 3 Case 2: Evolution of plasma prolactin (PRL) levels, tumor imaging by MRI and treatment during the 5 years of follow-up
Discussion A high level of PRL was found in both cases however this parameter cannot be used alone to predict the malignant evolution of prolactinomas [3]. Imaging suggested giant or invasive prolactinomas for both cases with no signs of malignancy [7]. In case 1, tumor progression was unavoidable and similar to that of pituitary carcinomas. Neither a change of
drugs nor increasing dose helped to delay the hypersecretion of PRL, thus confirming the resistance to dopamine agonists [7, 23–26]. The attempt to treat with chemotherapy using temozolomide, as proposed by certain authors [27–30], as well as the trial of antimitotic agents (carboplatine, VP16) failed to stop tumor progression. The patient died 16 years after initial presentation, which was notably longer than the average of 7 years [26] and 4.7 years [10] reported previously.
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Table 1 Pathological data and treatment of 2 aggressive-invasive prolactin tumors Angiogenesis
Cellular atypia
Vascular invasion
Mitoses (Nb)
Year 0
?
0
0
8
Year 4
???
?
0
15
??
?
0
8
Ki-67 (%)
p53 (%)
Treatment
7
1
Bromocriptin
2.5
0
Bromocriptin
3
0
Case 1
Year 5–9 Year 13
Radiotherapy
Year 14
Cabergolin Radiosurgery
Year 15
???
???
0
Year 16
???
???
??
19
7
–
Cabergolin
9
21
1
Temozolomide Carboplatine
Case 2 Year 0
?
?
?
For case 2, the clinical course differed greatly due to an altered management strategy. The patient was initially treated with cabergoline and instantly revealed a resistance to dopamine agonists. Following surgical intervention and considering the pathological suspicion of malignancy, radiosurgery was performed on the tumor residue. Clinical signs then disappeared under dopamine agonist treatment, the residue stabilized and levels of PRL remained normalized until the last consultation on October 2012, 8 years after the onset. Pituitary carcinoma was confirmed only in case 1 in accordance with the WHO classification [4] when jugular lymph node metastases were found on a PET scan performed due to the detection of vascular invasion on histology. For case 2, the above diagnosis was suggested by the presence of such vascular invasion. In addition, numerous mitotic cells and high Ki-67 and p53 indexes suggested an unusual proliferative rate for a pituitary adenoma. These tumors would today be classified as atypical adenomas [14] or aggressive-invasive adenomas [17, 18]. This diagnosis was delayed in patient 1 because Ki-67 and p53 detection was not systematically performed until 2007. As has already been suggested, such adenomas may in fact be carcinomas without metastasis [17, 18, 22]. To date, the question as to whether pituitary carcinomas arise de novo from normal adenohypophysial cells or by the transformation of a preexisting adenoma remains unanswered. The tumor presented here in case 1, became clinically aggressive only 10 years after onset and pathological signs of malignancy were only obvious 13 years after the initial surgery. At the first surgical intervention, the tumor was invasive and exhibited signs of high proliferation and would today still be classified as an atypical adenoma or an aggressive-invasive tumor. The evolution of the pathological signs, with increasing Ki-67 indexes and the appearance of vascular invasion at the end of the
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14
2.3
1.4
Cabergolin (Year 0–8) Gamma knife
evolution alongside the increased chromosomal imbalance in recurrent pituitary adenomas and metastases [20, 21] seem to favor the transformation from an aggressive tumor rather than a benign adenoma. Indeed, in our experience [22] chromosomal alterations do not accumulate between non-aggressive and aggressive tumors, contrary to that portrayed by the clonal genetic model of tumor progression. We thus propose that benign and aggressive PRL tumors arise from different mechanisms and follow two distinct tumor progression routes. Our comparisons of human PRL tumors with our animal model (SMtTW model) have also led us to postulate that aggressive-invasive tumors are in fact malignant tumors without metastasis [18]. The early identification of these potentially malignant tumors may allow the use of precocious and optimal treatment as demonstrated here for case 2. Indeed this tumor, which was at first resistant to dopamine agonists, was very similar histologically to the tumor of case 1. After radiosurgery, which probably destroyed the most proliferative cell clones, the tumor became sensitive to dopamine agonists and was then stabilized showing no recurrence 8 years after surgery. In light of these findings and the frequency of certain signs in previous pathological series of pituitary carcinomas (4, 10, 11), we believe that the criteria used to diagnose pituitary carcinomas need redefining. For prolactinomas, a potential malignancy could reasonably be suspected based on the association of the following clinical and pathological signs: male sex, hyperprolactinemia resistant to dopamine agonists, invasive macroprolactinoma with at least 2 of 3 cell cycle markers (mitoses [ 2 per 10 fields at 9400, Ki67 [ 3 %, p53 positive). Angiogenesis, vascular invasion, abnormal mitoses, very high index of Ki-67 [ 10 %, and p53 [ 5 % and allelic loss of chromosome 11 might be considered as criteria of malignancy. However, these signs could be absent in metastatic pituitary carcinomas and the
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We believe this management should increase the chances of stabilizing the tumor progression and prevent systemic metastases. Acknowledgments We thank G. Raverot for helpful criticism, Emily Witty from Angloscribe for help with the translation into English. This work was supported by grants from the Ministe`re de la Sante´ (Programme Hospitalier de Recherche Clinique National no 27-43: HYPOPRONOS), from the Institut National de la Sante´ et de la Recherche Me´dicale and la Ligue Contre le Cancer Rhoˆne-Alpes. Conflict of interest The authors declare having no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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Fig. 4 Pathological features of an aggressive-invasive PRL tumor with suspected malignancy. All the cells are strongly positive with PRL antibody and angiogenesis is also observed (a); numerous normal (arrow) or abnormal (double arrow) mitoses, with elevated Ki-67 index [ 3 % (Case 1, 0–16th year) (b); vascular invasion (arrow) of PRL immunoreactive cells (Case 1, 16th year) (c). Immunoperoxidase reaction with PRL antibody (a, c) and Ki-67 antibody (b)
cut-offs of the cell cycle markers must be confirmed in large series of pituitary carcinomas. In conclusion, early diagnosis of malignancy, before the appearance of metastases, should lead to an optimum treatment comprising the removal of the maximum amount of the tumor followed by irradiation of the residual volume.
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