PITUITARY CARCINOMAS ARE defined as pituitary tumors

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1 X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(5): Printed in U.S.A. Copyright 2005 by The Endocrine Society doi: /jc CLINICAL REVIEW: Diagnosis and Management of Pituitary Carcinomas Gregory A. Kaltsas, Panagiotis Nomikos, George Kontogeorgos, Michael Buchfelder, and Ashley B. Grossman Department of Endocrinology, St. Bartholomew s Hospital (G.A.K., A.B.G.), London ECIA 7BE, United Kingdom; Department of Neurosurgery, University of Goettingen (P.N., M.B.), Goettingen, Germany; and Department of Pathology, George Gennimatas Hospital (G.K.), Athens, Greece Pituitary carcinomas are rare, making up some 0.2% of all pituitary tumors, but represent a particular challenge to clinical practice. The diagnosis of a pituitary carcinoma requires evidence of metastatic disease, either outside the central nervous system (CNS) or as separate noncontiguous foci within the CNS. They may present as typical pituitary adenomas, which reveal their malignant character only as time progresses, or as peculiarly aggressive tumors ab initio. Recent changes in histopathological classification have clarified many of the features of such tumors, including immunohistochemical staining for Ki-67 and p53, but to date none has been found to be pathognomonic. The majority of carcinomas are secretory, usually arising from corticotroph tumors or PITUITARY CARCINOMAS ARE defined as pituitary tumors with subarachnoid, brain, or systemic metastasis (1, 2). Such tumors are considered to be rare, and information regarding their diagnosis, etiology, therapy, and prognosis is scanty (3 5). However, the collective published experience with these neoplasms has shown them to possess a distinctive profile that differs in a number of respects from that of the much more common benign pituitary adenomas (4 7). In this review, the incidence, etiology, natural history, and prognosis as well as the clinical, endocrinological, and radiological features of pituitary carcinomas are presented. Surgical approaches to pituitary cancer are outlined as well as medical therapies used to control additional tumor expansion and the hypersecretory syndromes that accompany metastatic disease. Because overall prognosis depends to a major extent upon successful resection of the tumor at initial operation, major emphasis is placed upon those features of pituitary carcinomas that help to differentiate them from benign adenomas. Classification of Pituitary Tumors Pituitary tumors are relatively common tumors; approximately 10 20% of normal subjects may harbor such tumors according to either autopsy series and/or on conventional First Published Online March 1, 2005 Abbreviations: CNS, Central nervous system; DI, diabetes insipidus; LI, labeling index; MRI, magnetic resonance imaging; NET, neuroendocrine tumor. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community prolactinomas, but all histological types and secretory patterns are represented. Treatment is by surgery, transsphenoidal wherever possible, and conventional and stereotactic radiotherapy, but ultimately, a plethora of therapies may be required, including various attempts at medical therapy. Chemotherapy in some instances probably prolongs survival, but, in general, their progress from the diagnosis of carcinomatous changes is progressive and inexorable. However, we do not believe there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities. (J Clin Endocrinol Metab 90: , 2005) pituitary magnetic resonance imaging (MRI), although most are clinically insignificant and less than 5 mm in diameter (8, 9). The great majority of pituitary tumors are noninvasive benign pituitary adenomas that either remain within the sella or may exhibit expansive growth to surrounding tissue (4, 10). A number of them, between 45 and 55% depending on the criteria used, can become invasive, infiltrating dura, bone, and/or surrounding tissue (2 6). However, such tumors are not considered to be malignant, and in terms of biological behavior are for the most part clinically benign, even when dural invasion is marked; true carcinomas are defined only by the presence of craniospinal and/or systemic metastases (Table 1) (1, 2, 4). The most clinically useful classification of invasiveness is by demonstrating sphenoid and cavernous sinus extension on pituitary MRI based on Hardy s classification (4). Using such criteria, although invasiveness is not indicative of malignancy, it probably puts the patient at higher risk of developing a pituitary carcinoma (4 6). Incidence Several studies have suggested an incidence of pituitary carcinoma of less than 0.5% of symptomatic pituitary tumors, probably in the region of 0.2% (3, 11). Approximately 92 cases of pituitary carcinoma were reported in an extensive review of the English literature up to 1998 (4); since then, more than 40 cases have been reported, giving an estimated total number of approximately 140 published cases (5). Pituitary carcinomas are usually diagnosed as invasive macroadenomas when first seen, and the great majority are associated with excessive hormonal secretion (4, 5). Pituitary carcinomas de-

2 3090 J Clin Endocrinol Metab, May 2005, 90(5): Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas TABLE 1. Criteria needed to be fulfilled for the classification of pituitary carcinomas The primary tumor must be identified as a pituitary tumor by histology An alternative primary tumor has to be excluded Discontinuous spread in the form of single or multiple nodular subarachnoid metastatic deposits occasionally invasive of underlying brain or overlying dura Single or multiple systemic deposits broadly similar to and grossly indistinguishable from metastases of carcinomas arising in other organs The structural features or marker expressions of the metastases should correspond or be similar to those of the pituitary tumor Adopted from Refs. 18, 115, and 116. velop with almost equal frequency in both sexes at a mean age of 44 yr, with a latency period of 7 yr after the initial diagnosis of a pituitary tumor is made, although this may vary depending on tumor subtype (3 5). Because a considerable number of metastatic pituitary tumors were only revealed at autopsy, it is probable that some patients with invasive pituitary macroadenomas have clinically silent metastases, and thus the currently reported prevalence may be an underestimate (3, 4, 12). This is also supported by the increased number of cases described over the last few years after improvement in imaging and diagnostic modalities with prolonged follow-up (3 5). Etiology: Molecular Pathogenesis Previous studies have implicated traditional therapeutic modalities, such as transfrontal or transsphenoidal hypophysectomy and/or radiotherapy, in the pathogenesis of pituitary carcinomas; however, clinical and epidemiological evidence has not supported this view (4, 5, 13, 14). Although de novo development cannot be excluded (15, 16), the initial presentation of pituitary carcinomas as macroadenomas (4, 17, 18), the long time interval needed for the progression to carcinoma development (3, 19), and the progressive accumulation of genetic aberrations (20 22) support the view that pituitary carcinomas mainly arise from the transformation of initially large, but benign, adenomas (4, 5, 19). It has been suggested that under the influence of unknown growthenhancing stimuli, an early proliferative stage of polyclonality is followed by monoclonal or multiclonal mutations, leading to selective growth advantage and a state of invasiveness through alterations in the function of oncogenes and/or tumor suppressor genes (4, 23 25). Invasive pituitary tumors and carcinomas exhibit a more protracted sequence of events compared with benign pituitary adenomas, where neoplastic cells acquire the ability to invade surrounding tissues and eventually metastasize (24 26). Although no consistent abnormalities have been identified, chromosomal gains, particularly in 14q, are likely to be involved in pituitary tumor progression and malignant transformation (6, 24, 27). A quantitative immunohistochemical study of p53 expression in pituitary tumors, a tumor suppressor gene mutated in 50 55% of human cancers (28), demonstrated labeling in almost all pituitary carcinomas, and in approximately 15% of invasive adenomas, but not in benign adenomas (3, 29, 30). Deletions of the retinoblastoma gene (31), another tumor suppressor gene that provides a direct connection between cell cycle and cancer (24) and a gene locus in proximity to it, have been documented in the majority of aggressive adenomas and some carcinomas (26, 32). Reduced expression of nm23 protein, which prevents progression of the cell cycle and thus reduces the metastatic potential of the tumor, has been detected in pituitary carcinomas; in addition, the level of nm23 expression has been shown to be inversely related to cavernous sinus invasion (33). A mutated H-ras oncogene has been observed in aggressive pituitary tumors (34) and in metastases from pituitary carcinomas (26), whereas high levels of c-myc oncogene have been found in a variety of aggressive pituitary tumors (24, 35). More recently, additional genetic alterations have been documented, which, although not as extensively studied, are probably involved in pituitary carcinogenesis. Galectin-3, a protein implicated in tumor progression and metastasis, is significantly higher in prolactin- and ACTH-secreting carcinomas (36); the latter may also exhibit a much higher level of immunoreactive chromogranin A peptide fragments compared with ACTH-secreting adenomas (37). The lack or reduced expression of p27 tumor suppressor gene has also been implicated in the development of pituitary adenomas (30, 38), and in the case of carcinomas, this may relate to increased protein jun-activating binding protein-1, which exports p27 from the nucleus (39). Increased telomerase activity, contributing to acquired tumor immortality, has been documented in a prolactin-secreting carcinoma (40). Similarly, the expression of the HER-2/neu protooncogene, which belongs to the epidermal growth factor receptor family, has been identified in the metastases of ACTH- and gonadotropin-secreting pituitary carcinomas (15, 41). In addition, using the chromogen in situ hybridization technique, HER- 2/neu gene amplification was found in 11 of 15 pituitary carcinomas (42). Levels of activated epidermal growth factor receptors are significantly higher in carcinomas, suggesting a role in pituitary tumor progression (43). More recently, increased expression of cyclooxygenase-2, which is involved in pituitary tumor angiogenesis, has been demonstrated in pituitary carcinomas (44). The importance of other genes, such as c-fos, bcl-2, and fibroblast growth factor-2 and -4, is still under investigation (24, 25, 45); pituitary carcinomas exhibit higher apoptotic indices than adenomas (46). Alterations of the multiple endocrine neoplasm type I and Carney genes, commonly found in familial syndromes associated with pituitary tumors, have not been systemically encountered in sporadic benign pituitary tumors and/or carcinomas (47 49). However, a recent study has shown that menin immunoreactivity, the product of the multiple endocrine neoplasm type 1 gene, was significantly decreased in adenomas and was undetectable in a pituitary carcinoma (50). Pathology Pituitary carcinomas, like adenomas, originate from and are composed of adenohypophysial cells (1, 2, 4). Their malignant nature is not usually obvious in terms of their microscopic appearance, and reliable distinction between carcinoma and adenoma is impossible on the basis of standard

3 Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas J Clin Endocrinol Metab, May 2005, 90(5): histological criteria (3). Hypercellularity, nuclear pleomorphism, occasional mitotic figures, necrosis, hemorrhage, and even invasion are not reliable indicators of the malignant nature of the tumor (1, 3). Occasionally, GH-secreting adenomas may exhibit marked nuclear pleomorphism and multinucleated tumor cells, whereas ACTH-secreting tumors may also show an unusual number of mitoses; conversely, some carcinomas may show good differentiation and no increased number of mitoses (1, 4, 6). However, on several occasions worsening of these indices has been observed during the progression of adenoma to carcinoma (51). Neuronal metaplasia has also rarely been seen in pituitary carcinoma (18). Dissemination outside the central nervous system (CNS) occurs through lymphatic and vascular spaces, whereas metastases within the CNS axis usually result from invasion into the subarachnoid space, with subsequent tumor seeding along brain and spinal cord surfaces (1, 2); deep metastases within the brain may arise as a result of reverse venous flow (1, 4). Hematogenous dissemination is also possible, probably via the superior petrosal sinus if the cavernous sinus has been invaded by the tumor (1, 52). Natural History of Pituitary Carcinomas Natural history can be defined as the spontaneous course of a disease, which is important for disease management together with establishing the etiology and pathophysiology. Although there is limited information due to the relative paucity of cases of pituitary carcinomas, it seems that there may be two distinct groups of patients with pituitary carcinomas (4, 16, 18, 53). The majority of patients exhibit a variable clinical course, because their behavior is indistinguishable from invasive pituitary adenomas, except that these tumors develop multiple recurrences and eventually metastases (3, 19, 54). Such patients experience a relatively prolonged survival, and most probably represent the group in whom there is a gradual acquisition of tumor genetic alterations; in these patients, proliferative indices and other predictors of biological behavior may overlap, at least initially, with those of benign adenomas (4, 16, 53). Less commonly, pituitary carcinomas can exhibit an early malignant behavior, being highly invasive with multiple recurrences and the early development of metastases (41, 53). Such tumors exhibit the highest proliferative indices and a considerable number of genetic alterations and are associated with a worse outcome (16, 41, 53, 55, 56). Once metastases develop, the mean survival in patients with pituitary carcinomas is less than 4 yr; however, there is wide variation between the different tumor subtypes with corticotroph carcinomas exhibiting the worst survival (3, 4, 19, 57 59). Patients with CNS metastases seem to have a more prolonged survival compared with patients with systemic metastases (3 5). The survival in the group of patients with the more malignant disease is usually less than 1 yr (4, 41, 57). Occasionally longterm survival has been reported (30, 59, 60). It is therefore important to develop means that can predict the subset of tumors with the most aggressive behavior and apply all available treatments early in the course of the disease in an attempt to minimize their metastatic potential. Predictive Factors of Malignancy Because the prognosis of pituitary carcinomas is relatively poor once metastases are demonstrated, efforts have been made to identify parameters that could predict the biological behavior of the pituitary, i.e. neoplasms that are more likely to behave in a malignant manner. Conventional histological analysis and electron microscopy have failed to distinguish benign and invasive adenomas from malignant pituitary tumors, because the latter can exhibit a variable degree of nuclear atypia and cellular pleomorphism (30, 51). However, mitotic indices are consistently higher in progressive and/or metastatic lesions than in benign adenomas (6, 7, 30, 41, 55, 61); although no particular threshold exists (16, 53), brisk mitotic activity is associated with aggressive growth and malignant potential (6, 53). Brain invasion is not as yet considered a criterion of malignancy (6, 62), but this probably requires assessment from a prospective study after a recent report that gross dural invasion may be associated with reduced survival (63). Among the various biological parameters known to affect the invasive potential of pituitary adenomas, their cell proliferation rate, reflected by the degree of cellular proliferation, i.e. number of cells in the S phase of cell cycle, is particularly important (53, 64). Estimation of the cell cycle-specific antigen Ki-67%, using the MIB-1 antibody, has been shown to correlate best with invasiveness and probably prognosis (5, 6, 24, 53). The Ki-67 antigen is expressed in all non-g 0 phases of the cell cycle except for the early G 1 phase (65). Its MIB epitope is highly repetitive and stable after tissue fixation, with formalin facilitating estimation of Ki-67 immunoreactivity in formalin-fixed and paraffin-embedded tissues (66). Malignant and invasive tumors exhibit much higher Ki-67 labeling indices (LI) than benign adenomas, 11.9% vs. 4.66% vs. 1.37%, respectively, according to one study (53). The great majority of invasive tumors have Ki-67 levels of less than 10%, whereas a Ki-67 index of less than 3% exhibits a 97% specificity in distinguishing invasive from noninvasive pituitary tumors (53) (Fig. 1, A C). Pituitary carcinomas have significantly higher mean Ki-67 LI, but there is considerable case to case variability, with measurements ranging from % (53, 64) (Fig. 1D). This suggests that pituitary carcinomas are heterogeneous with respect to proliferative activity, and although assessment of proliferation may be helpful in arousing suspicion as to subsequent tumor invasiveness and/or malignant potential, growth rate is probably not the only major determinant of tumor behavior and carcinogenesis (53, 64). Alternatively, low Ki-67 LI in pituitary carcinomas may be attributed to delayed tissue fixation (67) or suppression of proliferation by previous medical treatment. However, a Ki-67 LI higher than 10% should always raise suspicion about the malignant potential of the tumor (3, 16, 30, 53). Among the previously reported genetic alterations involved in the development of pituitary carcinomas, the quantitative immunohistochemical estimation of p53 expression has been most consistently studied and is thought to be of prognostic significance (28, 29). Although a few cases of pituitary carcinomas with negative p53 immunostaining

4 3092 J Clin Endocrinol Metab, May 2005, 90(5): Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas FIG. 1. A, Immunohistochemistry in a lactotroph adenoma for Ki-67 shows an approximately 3% LI, representing a threshold between ordinary adenomas and atypical adenomas (avidin-biotinperoxidase complex stain; Ki-67; clone MIB-1; magnification, 100). B, This GH-prolactin-producing tumor shows a highly increased Ki-67 labeling index 15%; however p53 yielded negative (avidin-biotin-peroxidase complex stain; Ki-67 clone MIB-1, 100). C, This corticotroph adenoma demonstrates strong and extensive immunoreactivity for p53. Due to a greater than 6% Ki-67 LI, the tumor was designated as an atypical adenoma (avidin-biotin-peroxidase complex stain; p53; clone DO-7; magnification, 80). D, This corticotroph carcinoma shows an approximately 5% Ki-67 LI (avidin-biotin-peroxidase complex technique; Ki-67; clone MIB-1; magnification, 40). have been described (15, 16, 41, 68), most studies have demonstrated either the appearance and/or an increment in subsequent p53 immunostaining during the progression of an adenoma to a carcinoma and in the majority of their metastases (6, 30, 61, 69). Prediction of aggressive and particularly malignant behavior is mainly reflected by the presence of nuclear staining; in such cases, the presence or absence of p53 seems to be of greater biological significance than the extent of staining (29). The predictive value of this method in combination with increased Ki-67% LI is probably superior to either method alone (16). In various types of tumors, microvascular density, a marker of angiogenesis, is related to metastatic potential and may be an independent predictor of patient survival (45). Although microvascular density is much higher in pituitary carcinomas, there is no clear distinction between these tumors and benign or invasive adenomas, and no correlation with Ki-67 labeling indices exists (45, 70). However, the majority of pituitary carcinomas exhibit increased matrix metalloproteinase activity that is related to extracellular matrix degradation promoting angiogenesis and tumor invasion (71). Although microvascular density per se is probably not a prognostic marker on its own, it may be important when other indices point toward an aggressive lesion. As more knowledge is acquired regarding the role of cyclins and inhibitors of the cell cycle, factors controlling apoptosis, and genetic changes in pituitary carcinomas, it may be possible to use the growth potential as part of a multiparametric assessment of pituitary tumors (6, 24, 64). Genetic analysis of pituitary carcinomas using comparative genomic hybridization has revealed a variety of chromosomal gains and losses in particular tumor subtypes (27). Overall, pituitary carcinomas showed an average of 8.8 imbalances/tumor (7.5 gains vs. 1.3 losses), with the most common changes being gains of chromosomes 5, 7p, and 14q (27). It is probable that genetic analysis of invasive pituitary tumors may enable better identification of those tumors designated to undergo malignant progression and thus be associated with a worse prognosis. Diagnosis of Pituitary Carcinomas Clinical features The clinical features of pituitary carcinomas, similar to invasive and noninvasive pituitary adenomas, are due to the pressure effects to surrounding tissues and/or to the effects of excessive hormonal secretion (4, 5). Most cases of pituitary carcinomas have arisen from the malignant transformation of tumors confined to the pituitary initially considered to be benign macroadenomas (3, 19); a case of an ectopic pituitary tumor initially presenting in the nasal cavity, producing FSH and finally developing multiple metastases to the subarachnoid space and the brain, has also been described (55). Symptoms such as visual impairment, presenting either as visual field loss or a reduction in visual acuity and/or cranial nerve palsies, usually dominate the clinical picture (5, 54). The challenge rests upon differentiating pituitary carcinoma from the much more common benign invasive pituitary adenoma, because the morbidity and mortality of pituitary carcinomas are substantial, particularly for the subgroup of pituitary carcinomas that may exert an aggressive course from the initial presentation (4, 16). In several cases the presence of relatively unusual symptoms/signs encountered in benign pituitary tumors, such as hearing loss, ataxia, and/or motor impairment, may direct to the presence of a carcinoma (4, 17, 19, 72). Although diabetes insipidus (DI) has not shown to be a feature at initial presentation in patients with pituitary carcinomas (3, 4), it was present in two cases that

5 Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas J Clin Endocrinol Metab, May 2005, 90(5): underwent malignant transformation (73). However, the presence of DI should direct toward a nonpituitary source, because primary pituitary lesions are very seldom associated with DI (4, 74, 75). In cases where a pituitary lesion within the CNS or concomitant peripheral metastases is found without a previous history of pituitary pathology, the possibility of a metastasis from another primary to the pituitary should always be considered (76). The most common clinical presentation of pituitary carcinomas is early recurrence after initial pituitary surgery, followed by repeated operations for rapid local growth and tumor extension (4). Usually at that time the presence of other CNS lesions or distant metastases may suggest a pituitary carcinoma (4) (Fig. 2). Metastases have very rarely dominated the clinical picture in the early stages of the disease, and in several cases were found only at autopsy (19, 77). Metastases can occur in virtually every part of the CNS, but usually involve the cortex, cerebellum, and cerebellopontine angle (4), whereas distant metastases usually involve the liver, lymph nodes, bone, and lung; unusual places, such as the heart, pancreas, eye, ear, ovary, and myometrium, have also been described (4, 5). Systemic metastases seem to be more common than CNS metastases, although a number of carcinomas may exhibit both systemic and CNS metastases (3 5). In some cases the diagnosis of pituitary carcinoma is made in retrospect due to early recurrence, development of distant metastases, and/or findings at autopsy (4, 60). Endocrinological features The great majority of pituitary carcinomas are hormonally active; the predominance of nonhormonally active carcinomas in the oldest series is probably attributed to the lack of hormonal assays and routine use of immunohistochemistry (4 6). This is reinforced by the finding that the Ki-67 LI is significantly higher in secreting than nonsecreting adenomas, possibly explaining their more aggressive nature (2, 30, 78). This may also relate to the presence of galectin-3 in ACTH- and prolactin-secreting tumors (36). The most common pituitary carcinomas are ACTH- and prolactin-secreting FIG. 2. A, MRI (T 1 -weighted coronal image) of the pituitary. A grossly invasive ACTH-secreting pituitary tumor (which proved to be a carcinoma) is demonstrated to occupy the entire pituitary fossa and extend into the sphenoid sinus (posteriorly), beyond the right cavernous sinus into the temporal lobe and the soft tissue (laterally), and into the sphenoid sinus (inferiorly). B, Metastasis from an ACTH-secreting pituitary carcinoma: MRI (T 1 -weighted sagittal image) of the spine in the same patient (A), demonstrating a soft tissue mass (white arrow) at the level of the T4 vertebra. carcinomas, followed by GH-secreting carcinomas (4, 5, 59). The clinical and endocrinological features of currently described pituitary carcinomas have been recently extensively reviewed (4, 5) and generally do not permit differentiation from adenomas. Symptoms related to hormonal hypersecretion usually do not differ from those encountered in patients with benign adenomas and are not considered to exert a major impact on the overall prognosis, except in patients with ACTH-secreting carcinomas (5, 54). In addition, no differences in hormone levels that could differentiate pituitary carcinomas from other invasive and/or noninvasive macroadenomas have been documented (4, 72, 79, 80). However, very high levels of prolactin, ACTH, and/or GH despite apparent surgical clearance of the tumor indicated the presence of metastases as well as worsening of the secretory state due to partial or complete resistance to dopamine agonists and/or somatostatin analogs, in patients with prolactin- and GH-secreting carcinomas (4, 80 83). In a few cases, a sustained elevated -subunit level in patients with TSH- and gonadotropin-secreting carcinomas may be associated with a worse outcome (4, 5, 41). Sudden or progressive reduction of tumor hormonogenesis has also been described and has been attributed to tumor dedifferentiation (4, 84). ACTH-secreting carcinomas are distinct, in that although they constitute the minority of pituitary adenomas, they are found in excess in cases of carcinomas (4, 5, 30, 58, 59, 85, 86). Patients with ACTH-secreting carcinomas exhibit the shortest survival after the diagnosis is made; patients with CNS metastases seem to have a more prolonged survival than patients with systemic metastases (4, 58, 59). Because several ACTH-secreting carcinomas have been described in patients who have undergone bilateral adrenalectomy, it is probable that a reduction in the patient s elevated cortisol level may have stimulated pituitary cells to undergo rapid proliferation and augment tumor transformation (75, 87). More recently, cases of silent ACTH carcinomas have been described that, although not clearly exhibiting any symptoms of Cushing s syndrome, showed a similar prognosis to patients with secretory ACTH-secreting carcinomas (16). Rare cases of a pituitary

6 3094 J Clin Endocrinol Metab, May 2005, 90(5): Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas carcinomas cosecreting ACTH, CRH, and the ACTH precursor proopiomelanocortin have also been described (73, 86). Radiological Diagnosis Current neuroimaging modalities, CT and particularly MR scanning, exert high sensitivity in detecting pituitary pathology; in addition, these techniques can be used to demonstrate disease progression elsewhere and thus the presence of metastases even when pituitary pathology has remained stable (4, 87 90). Although pituitary imaging demonstrates pituitary carcinomas to present as invasive macroadenomas, there are no reliable features distinguishing tumors that could behave in a malignant manner from other types of invasive adenomas (4). Several subtypes of pituitary tumors express somatostatin receptors, particularly subtypes 2 and 5, and this property has been used for the detection of pituitary carcinomas and their metastases using scintigraphy with 111 In-labeled octreotide (Octreoscan; Mallinckrodt, Petten, The Netherlands) (4, 90, 91). The application of 111 Inlabeled octreotide has established the diagnosis of a metastatic GH-secreting carcinoma (90) and has revealed additional lesions in an ACTH-secreting carcinoma (88) and/or tumor recurrences at follow-up (92). However, its sensitivity and regular use have not as yet been established (91, 93). Imaging with [ 123 I]meta-iodo-benzyl-guanidine has also been used, but failed to identify metastatic lesions (54, 85). More recently, positron emission tomography scan using 18 F-labeled deoxyglucose as radiolabeled tracer has revealed unsuspected pituitary macroadenomas and also identified metastases from a pituitary carcinoma (85, 94, 95). The introduction of other radiotracers, such as radiolabeled 5- hydroxytryptamine, which are involved in metabolic pathways that are common to a variety of neuroendocrine tumors (NET), is considered to be more sensitive than 18 F-labeled deoxyglucose, at least in gastroenteropancreatic endocrine tumors, and may lead to the recognition of additional lesions (95, 96). As the application of these techniques becomes more widespread, it is probable that the identification of clinically unapparent metastases will lead to an overall increase in the incidence of pituitary carcinomas (4). However, the clinical significance of this remains unclear. A summary of the features that might lead to the suspicion of a pituitary carcinoma is presented in Table 2. It should be noted that the distinction between benign and malignant disease may be extremely difficult when based on clinical and radiological grounds and conventional histopathology. However, it is preferable to have a high index of suspicion for a pituitary carcinoma when relevant features are present than to miss the opportunity of applying aggressive therapy as early as possible that may be associated with improved prognosis. Diagnostic Considerations Although pituitary carcinomas probably develop from preexisting adenomas in the majority of cases, it is important to exclude the presence of a metastatic tumor elsewhere before making the diagnosis of a pituitary carcinoma, because these two distinct entities may coexist (4, 76). Confusion may arise when a carcinoma of unknown primary, which exhibits NET features, metastasizes to the sella where a preexisting adenoma may be present (81, 97). In such cases carcinomatous cell nests may be seen invading the adenoma, but there are clearly two components that have distinct morphology and immunophenotypes. In these cases, immunohistochemical and ultrastructural studies may be helpful in establishing the diagnosis (74, 75). Management of Pituitary Carcinomas The treatment of pituitary carcinomas is similar to that of large and aggressive pituitary tumors and includes surgery (usually via the transsphenoidal route), external beam radiotherapy, and adjuvant medical treatment (4, 5, 80). The treatment of pituitary carcinomas is mainly palliative and may not prolong survival to any major extent (3, 5, 98). However, several reports of long-term survivors after therapy have been published (54, 59, 80), and there are retrospective data suggesting that patients who received aggressive treatment may achieve a better survival rate (4). Surgical Treatment Pituitary carcinomas are large tumors ( 1 cm) presenting as either primary or recurrent pituitary tumors exerting local mass effects that are often the cause of death. Surgical resection is therefore important because it can provide immediate relief of symptoms and aids in the diagnosis (4). Surgical procedures are very rarely curative, because these tumors are largely invasive, infiltrating adjacent and vital TABLE 2. Histological and immunohistochemical parameters commonly employed to predict the biological behavior of pituitary tumors Parameter Pituitary adenoma Atypical adenoma Pituitary carcinoma Size Micro/macroadenoma Micro/macroadenoma Macroadenoma a Cellular atypia Variable Variable Variable b Pleomorphism Variable Variable Variable b Mitotic activity Usually low Variable (2/10 hpf) c Usually high (6/10 hpf) d Proliferative index Ki-67 (%) LI 3 3 (usually 4.7) 3 (usually 10) e p53 positivity Negative Mostly negative Mostly positive f Microvascular density Low Variable Mostly increased g a A case of a microadenoma with metastases to the liver has been described (15). b Ref. 51. c Mitotic figures per high powered field. d Ref. 3. e Ref. 3, 30, and 53. f Ref. 29. g Ref. 70.

7 Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas J Clin Endocrinol Metab, May 2005, 90(5): tissues, although there have been cases where repeated transcranial surgery has been associated with complete excision of secondary deposits (4); however, in the majority of cases, incomplete resection results in recurrent disease. Overall disease control also relies on the use of other therapeutic modalities, although repeated surgery may be necessary to achieve local control and decompression of vital structures (4). There seems to be no benefit in terms of prognosis when transcranial, rather than transsphenoidal, surgery is advocated, although the transcranial approach may be necessary when there is extension to the anterior or posterior fossa or to other vital structures (4). However, extended transsphenoidal approaches along the skull base are also being employed. In selected cases, resection of isolated distant metastases may result in clinical and/or biochemical remission, at least temporarily (4) Radiation Therapy Radiotherapy has extensively been used in the past for prevention of tumor regrowth in large or partially excised pituitary tumors and for the local control of expanding tumors and/or metastatic deposits (4, 54). Observational studies have shown that radiotherapy, when administered to expanding lesions that were later proven to be carcinomas, was effective in achieving, at least temporarily, local control (4), but was less successful when given for the control of proven carcinomas (12, 17, 88). In a small number of patients sequentially studied, a trend toward a lower proliferative index in recurrent tumors that were treated with postoperative irradiation was found compared with untreated ones (99). Radiotherapy to CNS metastases has been shown to prevent additional tumor growth and even induce partial remission; it can also be administered to patients in whom surgical excision is not possible or to patients unable to undergo a surgical procedure (17, 79). However, there are no data to suggest that radiotherapy may improve the prognosis of these patients (3 5). Radiotherapy has also been applied to the local control of mainly bony and/or occasionally visceral metastases with variable results, mainly showing only temporary or partial control (12, 80). Focused radiotherapy (radiosurgery) in the form of either stereotactic multiarc radiotherapy or -knife, has the advantage that it can be applied to a much smaller area than conventional radiotherapy, reducing the risk of radiation-induced damage to surrounding tissue (4, 100). This form of radiotherapy can also be given to patients who have already had conventional radiotherapy and have developed a recurrence or metastases (100). However, experience with these modalities has been limited to a few case reports, usually demonstrating only palliative effects (4, 12, 30, 101). Another emerging therapeutic modality that has been applied to other NET bearing somatostatin receptors is treatment with radiolabeled somatostatin analogs (102). This technique involves the delivery of a toxic dose of radioactivity, using various radiation-delivering agents, specifically to tumor tissue, thus attempting to avoid damage to nearby healthy tissue (93). Although this form of treatment has not been applied as yet to malignant pituitary tumors expressing somatostatin receptors, it has caused considerable objective tumor responses in a number of other NET refractory to biotherapy and/or chemotherapy (103, 104). However, treatment with radiolabeled somatostatin analogs has to be weighed against potential toxicity to surrounding normal brain tissue and should only be employed after careful dosimetry has been performed, using a variety of radiationemitting agents with different penetrations, such as 111 In, 90 Y, and/or 177 Lu (93, 104). Medical Treatment Directed against Hypersecretory Syndromes Dopamine agonists have successfully been used for the treatment of prolactin-secreting tumors with an overall success rate of approximately 80% in macroprolactinomas (98). Patients with malignant prolactinomas may present with dopamine agonist resistance from the beginning (105), may develop resistance during the course of treatment, or may even escape treatment after an early response (3). Sudden and marked elevations in prolactin levels may reflect tumor recurrence with extensive invasive spread and/or development of additional metastases (105). Although partial biochemical (57) or even objective tumor responses (106) to treatment with dopamine agonists have been described, the great majority of reports have demonstrated either lack of response or tumor progression after treatment with bromocriptine (80) or newer dopamine agonists, such as quinagolide and cabergoline (4, 80 82). These medications should be employed early in the course of the disease to achieve as much biochemical control as possible, particularly because it seems that there is a latent period until additional growth and metastases develop (4, 57, 79, 81, 105). Tamoxifen has also been given to achieve a synergistic effect, although the results are generally disappointing (80). Bromocriptine has been tried in patients with malignant GH-secreting tumors; however, after initial partial biochemical or objective tumor responses, all of these patients died from progression of the disease (19, 52, 107). Dopamine agonists have been used in ACTH-secreting (54, 87) and TSH-secreting (84) carcinomas, but with only minimal benefit; however, a drug such as cabergoline is always worth a therapeutic trial (4). Somatostatin analogs, such as octreotide and lanreotide, that bind with high-affinity pituitary tumors expressing subtype 2 and 5 somatostatin receptors have been used to control the hypersecretory syndrome in GH- and TSH-secreting pituitary carcinomas with variable success (4, 83, 84, 107, 108). These agents, including their slow release formulations, have also been used in the therapy of ACTH- and prolactin-secreting carcinomas, although, again, the results have often been disappointing (80, 85, 88). In patients with malignant GH-secreting tumors and difficult to control acromegaly, the use of the novel GH receptor antagonist, pegvisomant, may be helpful in normalizing IGF-I levels, but this would have to be weighed against the theoretical possibility of the enhancement of tumor growth, and its use must be carefully considered in this situation (109). It is hoped that the recently developed longer-acting somatostatin analogs that also exhibit a higher affinity for the majority of somatostatin receptors, such as SOM230 (Novartis, Basel, Switzerland), may show a more potent therapeutic effect (110).

8 3096 J Clin Endocrinol Metab, May 2005, 90(5): Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas Medical Treatment Directed against Tumor Growth Biotherapy (nonchemotherapy-based regimens) Somatostatin analogs have successfully been used to control hormone secretion and substantially reduce the size of GH- and TSH-secreting pituitary tumors (111). However, administration of octreotide sc and/or slow release octreotide and lanreotide have, in general, failed to control tumor growth in a variety of hormone-secreting pituitary carcinomas (4, 85, 90). This could be due to a lack of expression of somatostatin receptor types 2 and 5 or to posttranscriptional effects and might be improved with the introduction of the newer somatostatin analogs, such as SOM-230, that bind to more somatostatin receptors and exhibit a higher affinity (110). A potent antihormonal effect of interferon- on cultured pituitary adenoma cells has been demonstrated, suggesting a possible role for this drug in the treatment of patients with highly invasive adenomas resistant to dopamine and/or somatostatin analogs (112). However, the few patients in whom interferon was used did not show any substantial improvement (54, 85). Chemotherapy Several different therapeutic regimens have been used, and occasional sporadic, although usually short-lasting, responses have been reported (4, 80). However, there have not been any randomized studies, and the patients entrance criteria are poorly defined. Experience with the use of chemotherapy in pituitary carcinomas has been reviewed (4, 54). Some observational data have suggested that those patients with extra-cns metastases who exhibited prolonged survival had received some form of chemotherapy (4). It has therefore been suggested that early application of chemotherapy may be useful in patients with highly aggressive and recurrent tumors after maximum therapy with surgery and radiotherapy if biological predictors indicate that it is likely to be highly aggressive and there is a change in malignant transformation (4). The experience of others, particularly with poorly differentiated NET exhibiting high proliferative indices, has shown that cis-platinum and etoposide-based chemotherapy may be associated with considerable, although variable, responses (54, 103, 113). However, these FIG. 3. A histopathologically based diagnostic and therapeutic approach for invasive pituitary tumors. *, Tumors with Ki-67 greater than 10% should be regarded as atypical adenoma. **, Atypical adenoma. ***, Suggested imaging modalities for follow-up., Ref. 112;, Refs. 4, 12, 83, 100, and 101;, Ref. 54;, Ref. 104.

9 Kaltsas et al. Diagnosis and Management of Pituitary Carcinomas J Clin Endocrinol Metab, May 2005, 90(5): issues would ideally need to be assessed in a prospective study. To improve response rates and find novel chemotherapeutic regimens for other NET, new agents with antitumor activity are under investigation, including paclitaxel (103). Because a number of pituitary carcinomas may express somatostatin receptors, cytotoxic hybrid compounds between the somatostatin analog vapreotide and doxorubicin can increase, at least in animal studies, the dose and effect of doxorubicin without increasing toxicity (114). Because the overall response to currently used chemotherapeutic agents is relatively poor, it is hoped that the administration of new agents will improve the response rate. In the long term, definition of the precise molecular derangements in pituitary carcinomas should allow for a targeted approach using drugs specific for the abnormal signaling or receptor pathways, or specific gene therapy may become available. Diagnostic and Therapeutic Consideration (Fig. 3) In keeping with the recent World Health Organization classification of endocrine neoplasms, primary endocrine tumors that exhibit a high mitotic activity, an increased ( 3%) Ki-67% LI, and/or p53 immunoreactivity should be termed atypical adenomas to denote their aggressive potential and the possibility of future malignant transformation (18). Our current practice is to routinely perform Ki-67 immunostaining in all invasive macroadenomas. Tumors with a Ki-67 LI greater than 3% also have p53 immunostaining performed. Atypical tumors and those with Ki-67% LI greater than 10%, regardless of p53 immunostaining, are treated with radiotherapy and are followed up for early recurrence and/or development of metastases. When the clinical suspicion is high, imaging with [ 111 In]octreotide and/or positron emission tomography may be considered for the detection of indolent metastases. Multidisciplinary Approach The increasing number of investigative procedures and therapeutic options for the diagnosis and treatment of pituitary carcinomas is best dealt with by a multidisciplinary team. Such a team should include physicians with a special interest in pituitary tumors, such as endocrinologists, neuropathologists, and neuroradiologists, a dedicated neurosurgeon with expertise in pituitary tumor surgery, an oncologist, and possibly a nuclear physician. Therapeutic procedures should be reviewed in an attempt to establish a consensus on the best evidence-based management. Due to the relative rarity of such tumors, optimum management should be undertaken in centers with relevant experience and expertise. Conclusion Pituitary carcinomas usually arise from invasive pituitary adenomas and are generally associated with high proliferative rates and/or specific gene defects, which can be used to predict the biological behavior of the tumor. Current therapeutic modalities are mainly palliative, and once metastases develop, the prognosis of these tumors is relatively poor, although a number of patients experience long-term survival. To improve the overall response rate, early application of current therapeutic approaches with the incorporation of new therapeutic developments is mandatory. Specifically, we would anticipate that knowledge of the precise molecular derangements in pituitary carcinomas would allow for precise molecular targeting using, for example, drugs based on growth factor and kinase inhibitors. 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