Pituitary Carcinoma




Introduction


Primary pituitary carcinomas are rare tumors defined as primary adenohypophyseal neoplasms that have undergone cerebrospinal or systemic metastasis. They constitute 0.1% to 0.2% of all pituitary tumors and their definition has been a subject of debate for many years. It is well known that pituitary tumors grow by expansion and displacement of adjacent structures and while dural invasion has been reported in 45% of cases, histological invasion does not confer the diagnosis of pituitary carcinoma. Presence of distant metastases is generally accepted as the diagnostic hallmark of pituitary carcinoma. Histological criteria alone are not sufficient for the determination of malignancy in pituitary tumors. Definitive diagnosis of pituitary carcinoma is based on the following criteria :



  • •

    The primary tumor must be identified as a pituitary tumor by histology


  • •

    An alternative primary tumor has been excluded


  • •

    Metastases are clearly disconnected from the primary tumor


  • •

    Structural features or marker expressions of metastases should correspond or be similar



In a review of the literature on the subject until 2004, we found 170 pituitary carcinomas. The vast majority of reported pituitary carcinomas are endocrinologically active (143/170, 84.2%), with 64 (37.6%) of the reported lesions being ACTH-secreting tumors, 48 (28.2%) PRL-secreting, *


* References , , , , , .

13 (7.6%) GH-secreting, †

† References , , , , , .

7 (4.1%) LH- or FSH-secreting, and only 1 (0.6%) producing TSH. Null-cell pituitary carcinomas represent 27 (15.8%) of the reported cases. ‡

‡ References , , , , , .

No sex predominance has been reported. Before the 1970s, PRL levels were not measured and immunohistochemical staining was not performed. Therefore, a significant number of PRL-producing carcinomas were probably unrecognized, making data from older literature somewhat unreliable.




Pathogenesis of Pituitary Carcinomas


Almost all cases of pituitary carcinomas arose after diagnosis and treatment (surgery and radiation therapy) of a macroadenoma several years earlier. In the review by Lubke et al. only three cases (3 of 70) were encountered that had not had prior surgery or irradiation. Several possible causes have been proposed for the pathogenesis of pituitary carcinomas:



  • 1.

    Consequence of previous irradiation in the treatment of a pituitary tumor


  • 2.

    Microscopic tumor seeding from a previous pituitary surgery


  • 3.

    Malignant progression of a pituitary tumor


  • 4.

    De novo carcinoma



Brada et al analyzed 334 patients with pituitary tumors who were treated with surgery and radiotherapy (median dose 45 Gy) and were followed for a total of 3760 patient years. In five of these patients, a second brain tumor developed (two astrocytomas, two meningiomas, and one meningeal sarcoma). No cases of malignant transformation of the pituitary tumor were observed. Similarly, other clinical and epidemiological studies have not supported a pathogenetic role of either surgery or radiotherapy in the development of pituitary carcinomas.


Tumor seeding from opening of the subarachnoid space during previous pituitary surgery has been suggested, but no definitive correlation has yet been made.


Although de novo development cannot be excluded, the initial presentation of pituitary carcinomas as macroadenomas, the long interval needed for the progression to carcinoma development, and the progressive accumulation of genetic aberrations, support the view that pituitary carcinomas mainly arise from the transformation of initially large but benign adenomas. It has been suggested that under the influence of unknown growth-enhancing stimuli an early proliferative stage of polyclonality is followed by monoclonal or multiclonal mutations, leading to selective growth advantage, and into a state of invasiveness through alterations of the function of oncogenes and/or tumor suppressor genes. *


* References , , , , , , .

Invasive pituitary tumors and carcinomas exhibit a more protracted sequence of events compared with benign pituitary adenomas, where neoplastic cells acquire the capability for invasion of surrounding tissues and eventually metastasis.


Tumor Spread


The interval between the first manifestation of the disease and development of metastases is variable, ranging from a few months to several years (median 5 years). In a series of 15 pituitary carcinomas, the latency period between presentation of a sellar adenoma and manifestations of metastasis was appreciably shorter in PRL-producing tumors (mean 4.7 years) than in ACTH-producing lesions (mean 9.3 to 9.5 years).


Pituitary carcinomas show a tendency toward both craniospinal metastases and systemic metastases. In general, craniospinal metastases are a consequence of subarachnoid spread, whereas systemic spread is felt to be secondary to cavernous sinus invasion with venous spread and systemic diffusion. The most frequent intracranial sites of metastases are the frontal and occipital lobes. The most common localization outside the central nervous system is the liver. Other common systemic sites are lymph nodes, lung, and bone but metastases from pituitary carcinomas have also been observed in the heart, mediastinum, and kidneys. Overall, prolactin-secreting pituitary carcinomas metastasize more frequently through subarachnoid spread to the craniospinal axis (48%), while ACTH-secreting carcinomas (67%) preferentially metastasize to the liver.




Histological Analysis


The histological and cytological characteristics of pituitary carcinomas vary from bland and monotonous to frankly malignant. Fifty percent of primary tumors and the majority of metastases display nuclear pleomorphism and/or hyperchromasia. An increased number of mitotic figures are seen in pituitary carcinomas ; however, the mitotic index for all pituitary tumors (such as pituitary adenomas, invasive adenomas, and pituitary carcinomas) is low, with a mean mitotic index of only 0.016%. Therefore, mitotic figures do not necessarily provide an indication of a tumor’s invasive potential.




Proliferative Markers


Expression of the Ki-67 antigen occurs during the S, M, and G1 phases of the cell cycle and is demonstrated using the MIB-1 antibody. The resulting labeling index (LI) quantifies the proportion of mitotically active cells. Shibuya et al stained 65 pituitary masses, revealing that primary pituitary tumors had a lower amount of Ki-67 (0.8%) when compared with recurrent tumors (3.6%, p < 0.005). In pituitary tumors MIB-1 labeling has produced consistently higher MIB-1 LIs in higher-grade tumors. The MIB-1 LIs for invasive tumors range from 1.7% to 4.66% for invasive adenoma, compared with those for pituitary carcinomas, which range from 7.8% to 11.91%.


The BrdU LI is used to identify only those cells in the DNA synthesis phase (S phase). The BrdU is administered 1 hour before surgery via an intravenous infusion (200 mg/m 2 ). Excised tumor specimens are fixed in 70% ethanol and stained using the indirect peroxidase method in which anti-BrdU monoclonal antibody is used as the first antibody. This provides a more accurate index of DNA synthesis than Ki-67 labeling, and BrdU labeling typically yields lower values, reflecting its greater specificity. One study of 65 tumors showed a significant difference between the BrdU LI of primary and recurrent tumors (0.3% compared with 1.4%, p < 0.005). Nagashima et al performed BrdU labeling on 21 pituitary tumors and found less than a 1% LI for all except two cases of Nelson’s syndrome, which exhibited LIs greater than 1%. No statistically significant association has been found between the BrdU LI and clinical findings of malignancy.




Molecular Analysis and Cytogenetics


Immunohistochemical staining studies of p53 gene expression in pituitary carcinomas, as opposed to invasive and noninvasive pituitary tumors, show a marked increase in staining as the pituitary lesion progresses to a pituitary carcinoma. One quantitative immunohistochemical analysis of p53 expression in pituitary tumors demonstrated labeling in 0% of noninvasive tumors, 15.2% of invasive tumors, and 100% of metastatic lesions. Another study of four ACTH-secreting pituitary carcinomas showed progressively stronger staining of p53 in metastatic lesions, with a mean LI in the metastasis group of 49.9% compared with 37.3% in the primary pituitary tumor group. However, p53 expression can be absent in metastatic pituitary tumors.


Rickert et al studied four metastatic pituitary carcinomas by using comparative genomic hybridization. Chromosomal gains were found in all four metastatic carcinomas. Overall, metastatic pituitary carcinomas were found to have a mean of 8.3 chromosomal imbalances per tumor (7 gains compared with 1.3 losses): 10 in metastatic PRL-producing carcinoma (7.5 gains compared with 2.5 losses) and 6.5 in metastatic ACTH-producing carcinoma (6.5 gains compared with 0 losses). The most common changes were gains of chromosome 5, 7p, and 14q (in three tumors each). High-level gains were found on 13q22 and 14q (two cases each) and on 1q, 3p, 7, 8, 9p, and 21q (one case each).


Bates et al genetically analyzed a metastatic ACTH-producing pituitary carcinoma and compared it with a previous sellar recurrence from the same patient, finding a loss of heterozygosity at loci on autosomes 1p, 3p, 10q26, 11q13, and 22q12. Genetic analysis of invasive masses and pituitary carcinomas may enable better prediction of those tumors associated with a poor prognosis.


Clinical Presentation


The clinical features of pituitary carcinomas, similar to invasive and noninvasive pituitary adenomas, are due to the mass effects of surrounding tissues and/or to the effects of excessive hormonal secretion. Most ACTH-producing tumors occur with Cushing’s syndrome; only a few cases of silent corticotroph carcinomas have been reported. Of the seven ACTH-producing adenomas reported in one series, four occurred in the setting of Nelson’s syndrome and the serum ACTH levels ranged from 145 to 280,000 pg/mL (normal level 0 to 60 pg/mL). Roncaroli et al reported patients with clinically silent corticotroph carcinomas, noting that these pituitary carcinomas presented as invasive macroadenomas with symptoms of mass effect. The outcome for the patients harboring these five tumors was similar to that of patients having Cushing’s disease.


As expected, PRL-producing carcinomas occur with amenorrhea, galactorrhea, or impotence. Initially, serum PRL levels can range from 6 to 22,000 ng/mL, with increasing serum levels noted in the presence of tumor recurrence and metastasis. Gonadotroph carcinomas are rare, with only a few published examples. Elevated serum levels of the glycoproteins LH and FSH, and of the α-subunit are seen on routine laboratory analysis. The α-subunit of glycoprotein hormones, a 92-amino-acid chain, is a component of glycoproteins produced by the adenohypophysis (LH, FSH, and TSH). The GH-secreting pituitary carcinomas present as invasive macroadenomas with acromegaly. Elevated serum levels for GH and insulin-like growth factor I are usually present.


Imaging Findings


Pituitary carcinomas almost always present as invasive macroadenomas that metastasize both to the CNS and systemically. Magnetic resonance imaging is the best diagnostic method to define the extent of CNS spread. Pituitary carcinomas usually occur in the setting of a known invasive macroadenoma. The intrasellar component is typically displayed as an aggressive pituitary tumor with suprasellar extension and possible invasion of the cavernous sinus. Within the CNS, pituitary carcinomas metastasize to the cerebral lobes, cerebellum, spinal cord, leptomeninges, and subarachnoid space. Interestingly, dural metastases can mimic meningiomas on imaging studies appearing as homogeneously enhancing dural-based lesions. Matsuki et al compared the MRI characteristics of both primary intrasellar pituitary tumors and metastatic lesions on T1- and T2-weighted images, noting similar signal intensities. These MRI findings reflect the similar vascularity and stroma of the primary pituitary tumors and the metastatic lesions.


Muhr et al used positron emission tomography and dopamine D 2 -receptor binding to assess tumor amino acid metabolism (11C-labeled l-methionine) in vivo in a patient with multiple intracranial metastases of a PRL-producing pituitary carcinoma. They demonstrated a high level of dopamine D 2 -receptor binding and a high amino acid metabolism within the tumor. After institution of bromocriptine injections, repeated PET imaging was performed demonstrating decreases in tumor D 2 -receptor binding and amino acid metabolism. These findings correlated with a decrease in circulating serum PRL. Radionuclide scintigraphy performed using indium 111-octreotide can detect active neuroendocrine neoplasias with somatostatin receptors, such as pituitary tumors, islet cell tumors, medullary thyroid carcinomas, pheochromocytomas, carcinoids, and paragangliomas. Octreotide is an eight-chain amino acid analog of somatostatin that, when combined with a radioactive isotope, is used for radionuclide scintigraphy. This imaging examination allows for the identification of distant pituitary metastasis.


Treatment


Treatment options for pituitary carcinoma include resection, dopamine agonists (for PRL-producing tumors), somatostatin analogs (for GH-producing tumors), radiotherapy, and chemotherapy. These treatments are palliative only and the mean survival time for these patients ranges from 1.9 to 2.4 years although several reports of long-term survivors have been published.


DOPAMINE AGONISTS


The dopamine agonists bromocriptine, pergolide, quinagolide, and cabergoline offer only palliation in the treatment of metastatic PRL-producing tumors. Initially, these agonists induce decreases in serum PRL levels and retard tumor growth. Unfortunately, these pituitary carcinomas will typically “escape” dopamine suppression and PRL levels may rise as high as 20,000 ng/mL (normal PRL levels 4 to 30 ng/mL in female patients and 4 to 23 ng/mL in male patients).


SOMATOSTATIN ANALOGS


The medical approach to patients with GH-secreting or clinically nonfunctioning pituitary tumor has made considerable progress thanks to the use of new somatostatin analogs such as octreotide. These agents were first used to treat acromegaly in the mid-1980s and numerous studies have shown a reduction in GH concentration in more than 90% of patients with this disorder. Good results were also obtained using slow-release analog treatment for TSH-secreting tumors, whereas the therapeutic efficacy of these peptides for clinically nonfunctioning tumors remains controversial. Treatment with somatostatin analogs improves the patient’s symptoms, normalizes hormone secretion, and in some cases may induce a reduction in the volume of the pituitary tumors. Scintigraphy with octreotide may be useful in selecting patients who respond to this form of treatment.


RADIATION THERAPY


Radiation treatment directed to the sella and to distant metastases is a common adjuvant therapy used after pituitary resection in patients with pituitary carcinomas. Unfortunately, it does not appear to change disease outcome. The sella and the parasellar region are initially treated by fractionated, limited-field irradiation, with total radiation doses between 45 and 55 Gy. Whole-brain radiation therapy is reserved for intracranial metastasis. Recently, stereotactic radiosurgery (gamma knife surgery) was used in the treatment of a PRL-secreting carcinoma, although no mention of benefit was made in that report. In a patient with an ACTH-secreting pituitary carcinoma a regimen of initial radiotherapy to the sella (56 Gy), followed by whole-brain 60Co radiotherapy (24 Gy) after the discovery of craniospinal metastasis, resulted in long-term survival.


CHEMOTHERAPY


To date, a number of different chemotherapy protocols have been used in patients with pituitary carcinomas with disappointing results. The agents used in these protocols have included carmustine, hydroxyurea, 5-fluorouracil, and dexamethasone (to suppress ACTH-producing tumors); bromocriptine and cabergoline (to suppress PRL-producing tumors); and the St. Bart protocol, consisting of 5-fluorouracil with folinic acid and α-interferon (for neuroendocrine tumors).




Prognosis and Predictors of Outcome


Despite limited information due to the rarity of pituitary carcinomas, it appears that, in relation to clinical course and prognosis, there are two distinct groups of patients with pituitary carcinomas. The majority of patients exhibit a variable clinical course as their behavior is indistinguishable from invasive pituitary adenomas except that these tumors develop multiple recurrences and eventually metastases. 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 the biological behavior may overlap, at least initially, with those of benign adenomas. Less commonly pituitary carcinomas can exhibit an early malignant behavior, being highly invasive with multiple recurrences and the early development of metastases. Such tumors exhibit the highest proliferative indices and a considerable number of genetic alterations and are associated with a worse outcome. Once metastases develop, the mean survival in patients with pituitary carcinomas is poor. However, there is wide variation between different tumor subtypes with corticotroph carcinomas exhibiting the worst survival. *


* References , , , , , .

Patients with systemic metastases (mean survival 1 year) have a worse prognosis than patients with craniospinal spread (mean survival 2.6 years).


The current definition of pituitary carcinoma rests on documenting the presence of a discontinuous spread of a tumor within the neuraxis or to systemic sites. Although this approach is pragmatic, it is unsatisfactory because it detracts from the effort to understand the nature of the primary sellar lesions and retards aggressive treatment until late in the course of the disease. Efforts have been made to identify pathological parameters predictive of which neoplasms will behave in a malignant (metastasizing) fashion. These are reflected in the 2000 WHO classification of pituitary tumors, which defines as “atypical” those adenohypophyseal tumors exhibiting all or various combinations of increased mitotic activity, elevation in the MIB-1 LI (>3%), and p53 immunoreactivity. These findings are said to warrant the atypical designation and should prompt careful reassessment of a case and long-term follow-up.


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Jun 10, 2019 | Posted by in NEUROLOGY | Comments Off on Pituitary Carcinoma

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