Pituitary carcinomas are defined as malignant primary neoplasms of the adenohypophysis with either systemic or craniospinal metastases. Although pituitary adenomas are common, pituitary carcinomas only make up 0.1% to 0.2% of all pituitary tumors. Prognosis is very poor with approximately 66% mortality in the first year of diagnosis. Although effective medical and surgical treatments are available for pituitary adenomas, pituitary carcinomas require a multimodality treatment including surgery, hormonal therapy, cytotoxic chemotherapy, and radiation with limited success. Here we review the clinical behavior and pathologic characteristics of pituitary carcinomas and the recent advances in potential therapies for this malignant disease.
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Pituitary carcinomas are rare, with one study reporting only 165 cases reported in the English literature as of 2011.
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Pituitary carcinomas make up only 0.1% to 0.2% of all pituitary adenomas.
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Diagnosis of pituitary carcinoma requires presence of metastases distant from the primary tumor in the sella, as local invasion is common (approximately 35%–40% of pituitary adenomas) and cannot be used to diagnose pituitary carcinomas.
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Most patients with pituitary carcinomas present initially with an invasive pituitary adenoma, although rarely, patients can present with primary pituitary carcinomas without a previous history of pituitary tumor.
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Studies implementing histology, immunohistochemistry, genetic analysis, and ultrastructural imaging with electron microscopy cannot consistently distinguish pituitary carcinomas from adenomas and should be used only to supplement the diagnosis.
Introduction
Pituitary tumors represent 10% to 15% of primary intracranial neoplasms and the overwhelming majority are benign adenomas. Pituitary carcinomas are very rare and consist of 0.1% to 0.2% of all pituitary tumors. According to the 2004 World Health Organization (WHO) classification of endocrine tumors, tumors of the adenohypophysis are classified into benign pituitary adenomas, atypical pituitary adenomas, and pituitary carcinomas. It is not clear whether pituitary carcinomas arise de novo as distinct malignant tumors or are malignant transformation of typical or atypical pituitary adenomas.
Whether there are clinically useful molecular, genetic or pathologic, differences among the 3 WHO classes of pituitary tumors are not known at this time. The histologic, immunohistochemical, radiographical, and ultrastructural analyses are limited in distinguishing typical and atypical adenomas, and malignant carcinomas.
Pituitary carcinomas portend a poor prognosis. They are mostly endocrine active tumors with very aggressive clinical features and rapid progression, often unresponsive to conventional therapies that are often effective against hormonally active adenomas. Clinical progression includes severe medical morbidities related to hormone overproduction (ie, Cushing’s disease) and mass effects from sellar and distant tumor expansion. Current treatment paradigms include multiple surgical resections, although complete resection may be unrealistic given the extent of invasion or with multiple metastatic lesions. Other alternatives, such as radiation therapy, systemic chemotherapy, and medical therapies to treat hormone overproduction are also of limited help (ie, dopamine agonist therapy). Despite aggressive treatments, all of these treatments have proven to be palliative at best. Cytotoxic chemotherapies have yielded disappointing results, despite high proliferative index of pituitary carcinomas. Recurrence with rapid tumor growth is often evident following radiation therapy. Recently, however, some strides have been made with the use of temozolomide, a methylating alkylator agent commonly used to treat malignant gliomas. Here, we review the histopathologic features of pituitary carcinomas relative to benign and atypical pituitary adenomas, how pituitary carcinomas are best managed in the modern era, and the future directions that will hopefully lead to better treatment for this aggressive malignant disease.
Histopathologic definitions and features
Definition of atypical pituitary adenomas is currently made on histologic grounds, while the definition of pituitary carcinoma requires the presence of metastases distant from the primary tumor in the sella. Atypical pituitary adenomas are defined as pituitary adenomas with elevated mitotic index, Ki-67 labeling index greater than 3%, and excessive p53 immunoreactivity. However, cytologic features of pituitary carcinoma can be quite similar to and often indistinguishable from adenomas ( Fig. 1 ).
These WHO definitions focus on histologic evidence of mutations and proliferation (atypical adenomas) or distant metastases (pituitary carcinomas), but they ignore other aspects of pituitary tumor behavior–like invasion. This is because gross evidence of local invasion during surgery is demonstrated in approximately 35% to 40% of pituitary adenomas, meaning that the presence of invasion alone is not sufficiently restrictive to be included in the definition of atypical adenoma or carcinoma. Recent studies suggested that atypical pituitary adenomas show higher rates of local invasion by imaging compared with “typical” pituitary adenomas. Thus, local invasion is a feature common to both typical and atypical pituitary adenomas, especially in large macroadenomas, but not enough to render it diagnostic criteria for atypical adenomas. On the other hand, distant metastases are quite rare and thus represent an extremely restrictive criteria, making pituitary carcinoma a rare diagnostic entity. Some argue that there must be mutation(s) predisposing to metastatic ability, the presence of which might allow widening the diagnostic criteria to include pituitary tumors that look highly aggressive under a microscope without systemic metastases, but no such mutation(s) have been identified to date. Thus, although there is a clear need for well-validated genetic or histologic markers to better distinguish pituitary tumors by clinical aggressiveness, clinicians for the moment must recognize the 3 WHO classes of pituitary tumors defined as described previously.
Histopathologic definitions and features
Definition of atypical pituitary adenomas is currently made on histologic grounds, while the definition of pituitary carcinoma requires the presence of metastases distant from the primary tumor in the sella. Atypical pituitary adenomas are defined as pituitary adenomas with elevated mitotic index, Ki-67 labeling index greater than 3%, and excessive p53 immunoreactivity. However, cytologic features of pituitary carcinoma can be quite similar to and often indistinguishable from adenomas ( Fig. 1 ).
These WHO definitions focus on histologic evidence of mutations and proliferation (atypical adenomas) or distant metastases (pituitary carcinomas), but they ignore other aspects of pituitary tumor behavior–like invasion. This is because gross evidence of local invasion during surgery is demonstrated in approximately 35% to 40% of pituitary adenomas, meaning that the presence of invasion alone is not sufficiently restrictive to be included in the definition of atypical adenoma or carcinoma. Recent studies suggested that atypical pituitary adenomas show higher rates of local invasion by imaging compared with “typical” pituitary adenomas. Thus, local invasion is a feature common to both typical and atypical pituitary adenomas, especially in large macroadenomas, but not enough to render it diagnostic criteria for atypical adenomas. On the other hand, distant metastases are quite rare and thus represent an extremely restrictive criteria, making pituitary carcinoma a rare diagnostic entity. Some argue that there must be mutation(s) predisposing to metastatic ability, the presence of which might allow widening the diagnostic criteria to include pituitary tumors that look highly aggressive under a microscope without systemic metastases, but no such mutation(s) have been identified to date. Thus, although there is a clear need for well-validated genetic or histologic markers to better distinguish pituitary tumors by clinical aggressiveness, clinicians for the moment must recognize the 3 WHO classes of pituitary tumors defined as described previously.
Epidemiology of pituitary carcinoma
Pituitary carcinomas are very rare, with one study reporting only 165 cases reported in the English literature as of 2011. Although the evidence of local invasion is found intraoperative in 35% to 40% of cases, pituitary carcinomas make up only 0.1% to 0.2% of all pituitary adenomas. By comparison, atypical pituitary adenomas represent approximately 15% of all pituitary adenomas. Thus, the transformation that allows a pituitary carcinoma to form (ie, metastases) from either a pituitary adenoma, directly from normal pituitary gland tissue, or from an as yet unidentified precursor state is a rare event.
Both genders are equally affected by pituitary carcinomas with a mean age at presentation in the fifth decade. By contrast, pituitary adenomas, especially of prolactinomas, are more common in women, possibly because of the ease of detecting endocrine symptoms in women compared with men.
Pituitary carcinoma seems to affect only the adult population, although one case report of pituitary carcinoma in a 9-year-old girl with widespread metastases to the craniospinal axis has been reported. In one study of 15 patients (8 males and 7 females) with pituitary carcinoma, the mean age was 56 with a range of 34 to 71.
Most (88%) pituitary carcinomas are hormonally active tumors. The incidence of nonfunctioning pituitary carcinomas has been very low in recent years. According to a study, hormonally active pituitary carcinomas predominantly consist of adrenocorticotropic hormone (ACTH) (42%) and prolactin-secreting (33%) carcinomas, followed by growth hormone (6%), gonadotropic hormones (5%), and thyroid-stimulating hormones (1%). Null-cell pituitary carcinomas represent approximately 12%.
Pathophysiology of pituitary carcinomas
Etiology of Pituitary Carcinomas: De Novo Versus Malignant Transformation of Invasive Pituitary Adenomas
Whether pituitary carcinomas occur de novo or progress from invasive, typical, or atypical pituitary adenomas is unknown. Pituitary carcinomas without evidence of a prior benign lesion have been reported, suggesting the possibility of de novo occurrences. As an entirely speculative possibility, pituitary carcinomas may start out as atypical adenomas that undergo malignant transformation. Typically, histologic features of aggressive pituitary adenomas as well as pituitary carcinomas remain more or less similar throughout the disease course (see Fig. 1 ). Recurrence of pituitary carcinoma is common, and may require repeated surgical resections, more aggressive medical therapy, and radiation therapy. Despite these aggressive measures, most tumors progress and result in the demise of the patient.
Some investigators believe that pituitary carcinomas progress from invasive pituitary adenomas, possibly with the atypical pituitary adenomas being the most likely culprit. Others have speculated dissemination of aggressive adenomas following surgical resection, but this hypothesis has not been adequately supported in the literature. Similarly, malignant transformation caused by radiation therapy has not received a wide support, although there are reports of sarcomatous changes in pituitary adenomas following radiation therapy. A review of 36 cases of pituitary carcinoma in 1989 found that fewer than half (18 of 38) of patients with pituitary carcinomas were previously treated with radiation therapy. The risk of developing secondary brain tumors following external beam radiotherapy for pituitary adenoma is also relatively low at 1.3% at 10 years and 1.9% at 20 years following treatment with a relative risk of 9.38 compared with the normal population. Although these rates seem higher than the progression rates of pituitary adenomas to carcinomas (0.1%–0.2%), in the same study, there were no malignant transformations of pituitary adenomas in 3760 observed patient years. Thus, it appears that radiation treatment does not significantly increase the risk of carcinomatous transformation of pituitary adenomas.
Local Invasion: A Step Toward Metastatic Transformation?
Pituitary adenomas commonly invade through local structures, such as dura, bone, cavernous sinus, and even blood vessels and nerve sheaths (see Fig. 1 D). Although evidence of local invasion by gross observation during surgery ranges from 35% to 40%, microscopic demonstration of dural invasion can be demonstrated in up to 85% of patients with pituitary adenomas. Atypical adenomas have significantly higher rates of local invasion (83%) by imaging compared with “typical” adenomas (45%).
The natural expansion of an adenohypophysial tumor involves the dura mater. Therefore, it is not surprising to find dural invasion increasing in frequency with increasing tumor size. In one study, microadenomas, macroadenomas, and tumors with suprasellar extension had 69%, 88%, and 94% incidence of dural invasion by microscopic evaluation, respectively. In a larger cohort study consisting of 354 patients treated with trans-sphenoidal surgery, percentage of tumors with dural invasion correlated with increasing tumor size: 24% for 10 mm or smaller, 35% for 10 to 20 mm, 55% for 20 to 40 mm, and 70% dural invasion for larger than 40 mm tumor size. Whether dural invasion should be considered similar to invasion of surrounding soft tissues is debatable. There is still much work needed to correlate the extent of dural invasion with evidence of biologic aggressiveness not related to simple tumor growth rate. Currently, there is no evidence to suggest that dural invasion is independent of tumor size or growth rate as a prognostic indicator.
Evidence against this suggestion is the observation that local invasion, including dural invasion, does not confer malignancy or predict future transformation to pituitary carcinomas, as most invasive pituitary adenomas do not metastasize. For example, a recent study found that although dural invasion was significantly more common in the repeated trans-sphenoidal surgery group (69%) compared with the primary surgery group (41%), it is not a predictive factor for recurrence. This study also found that mortality rates were higher in the group with dural invasion (9%) compared with the group with no invasion (0%) at the end of a 6-year follow-up. However, this mortality rate is very small compared with the typical mortality rate in pituitary carcinomas, where 66% of patients with pituitary carcinoma die within the first year of diagnosis. Furthermore, determination of dural invasion does not appear to be independent of tumor size or growth rate. It is still possible that invasive features may predict a more aggressive clinical course and may portend a higher risk, especially in hormonally active tumors. Most importantly, however, invasive features do not consistently predict malignant transformation.
Further evidence suggesting that local invasion does not consistently confer malignancy comes from studies looking at hormonal profiles of pituitary adenomas. For example, dural invasion is most frequently found in the nonfunctioning pituitary adenomas at 54.2%, whereas most pituitary carcinomas are endocrine active. By comparison, only 30% to 35% of endocrine-active tumors have dural invasion. Most of the invasive nonfunctioning pituitary adenomas will never progress to pituitary carcinomas. In another study, 50% of atypical pituitary adenomas were nonfunctioning lesions, suggesting the possibility that only a small percentage of endocrine-active, atypical pituitary adenomas could transform into pituitary carcinomas. The factors that determine which tumors progress to pituitary carcinomas remain elusive at this time, although invasive, atypical macroadenomas that are endocrine active are the most likely candidates.
The evidence for malignant transformation of pituitary adenomas rather than de novo pituitary carcinoma formation include the following:
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Most pituitary carcinomas initially present as aggressive pituitary tumors with multiple recurrences that “escape” medical, surgical, and radiation treatments ;
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The latency of transformation from pituitary adenomas to carcinomas usually takes months to years. In the setting of Nelson syndrome, in which ACTH-secreting carcinoma develops following bilateral adrenalectomy for Cushing syndrome, the mean interval between the diagnosis of adenoma and carcinoma is 15.3 years ;
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There is no histologic distinction between pituitary carcinomas and invasive macroadenomas. The decision of a pituitary carcinoma is made only after a metastatic focus is discovered.
Genetic, Molecular, and Ultrastructural Make-Up of Pituitary Carcinomas
Numerous studies have attempted to distinguish the genetic, molecular, and ultrastructural make-up of pituitary carcinomas from adenomas. Although some trends are important to note, generally the case-to-case variability has been so large that all of these features have failed to consistently distinguish among benign, invasive, and malignant pituitary tumors. Histologic features that define malignancy in other brain tumors, such as necrosis, invasion of surrounding structures, hypercellularity, increased mitotic activity, and pleomorphism, are found in benign and atypical pituitary adenomas, as well as pituitary carcinomas.
Studies indicate that proliferative and mitotic activities are generally higher in carcinomas compared with invasive adenomas. In one study, Ki-67 cell cycle–specific nuclear antigen detected by MIB-1 antibody was increased in the order of invasiveness: mean Ki-67 fractions were 1.37%, 4.66%, and 11.91% for noninvasive adenomas, invasive adenomas, and pituitary carcinomas, respectively. Setting the Ki-67 labeling index threshold at 3% allows one to distinguish noninvasive from invasive tumors with 97% specificity and 73% sensitivity. However, other studies have not found such clear correlation of Ki-67 labeling with the invasive potential of tumors. Evaluation of mitotic figures and proliferating cell nuclear antigen have shown increased proliferation index in more invasive, higher grade tumors as well.
Molecular oncogenes that are often altered in other malignancies, such as p53, p27, Ras, retinoblastoma gene, MEN-1, gsp, nm23, and HER-2/neu, are also found to be affected in pituitary carcinomas, but not consistently enough to allow differentiation from benign adenomas. In one study, p53 was expressed in a larger fraction in higher-grade pituitary tumors with 0%, 15.2%, and 100% expression in noninvasive adenomas, invasive adenomas, and pituitary carcinomas, respectively. Interestingly, a higher fraction of metastatic lesions (83%) expressed p53 compared with primary sellar lesions (57%), suggesting that metastatic lesions may have accumulated more genetic abnormalities that make them able to metastasize.
An ultrastructural study using transmission electron microscopy also confirmed significant cellular atypia and mitotic activity in most pituitary carcinomas, but concluded that pituitary adenomas and carcinomas cannot be distinguished on ultrastructural features alone. A detailed summary of histologic, immunohistochemical, and genetic alternations; proliferation indices; and ultrastructural studies of pituitary carcinomas have been thoroughly reviewed elsewhere.
Clinical presentation and progression of pituitary carcinoma
Clinical Presentation
Most patients with pituitary carcinomas present initially with an invasive pituitary adenoma, although rarely, patients can present with primary pituitary carcinomas without a previous history of pituitary tumor ( Fig. 2 ). Transformation of pituitary adenomas to pituitary carcinomas usually takes 6 to 8 years. Clinical progression includes symptoms related to hormone overproduction (ie, Cushing disease), symptoms of local mass effect from tumor expansion of the sellar and suprasellar space, or symptoms of systemic metastases. Mass effects near the sellar region consist of symptoms similar to those found in macroadenomas, including visual field deficits and decreased visual acuity owing to compression of optic chiasm; headaches from stretching of the nearby dura or diaphragm sella; cranial neuropathies from compression of cranial nerves in the cavernous sinus; and hypopituitarism owing to compression of portal vessels, pituitary stalk, and/or pituitary gland. The most common presentation of pituitary carcinoma occurs in the setting of a patient with a history of invasive pituitary neoplasm, often with multiple surgical resections or previous radiation therapy, who undergoes rapid recurrence with resistance to medical therapy, as evidenced by rising serum hormone levels. Metastases away from the primary pituitary tumor must be confirmed on imaging.
Related posts:
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Management of Incidentally Found Nonfunctional Pituitary Tumors
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Visual Outcomes After Treatment of Pituitary Adenomas
Medical Management of Persistent and Recurrent Cushing Disease
Medical Versus Surgical Management of Prolactinomas
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