Resistance to dopamine agonists is not uncommonly seen in prolactinomas. However, development of resistance to dopamine agonists after an initial period of robust treatment response is rare, and only 39 cases have been reported in the past four decades. We describe a Chinese man with this rare condition and explored the postulated mechanisms that may explain this phenomenon. We compiled similar cases that were previously reported and compared their etiology, progress, and response to treatment. On the basis of these cases, we derived a list of differential diagnoses to consider in patients with secondary resistance to dopamine agonists.

A 63-year-old Chinese man presented with blurred vision and was subsequently diagnosed with a macroprolactinoma. He had initial response to cabergoline but developed secondary resistance to it after 5 years. The prolactinoma continued to grow, and his serum prolactin remained markedly elevated despite adherence to escalating dosages of cabergoline up to 6 mg/week. The patient finally underwent transsphenoidal surgery and was found to have a sparsely granulated lactotroph tumor with Ki-67 index of 5%. Postoperatively, there was improvement in his serum prolactin level, although he still required treatment with cabergoline at 6 mg/week.

Surgery can facilitate disease control in patients with prolactinomas that develop secondary resistance to dopamine agonists. Malignant prolactinoma is an important differential diagnosis in this group of patients, especially when serum prolactin remains markedly elevated despite resolution or stability of the primary pituitary lesion, suggesting a metastatic source of prolactin secretion.

Aggressive tumors of the pituitary gland are classically defined as pituitary tumors with a massive invasion of the surrounding anatomical structures and rapid growth. They are notoriously difficult to manage and are associated with poor prognosis because the therapeutic options are limited and the tumors are generally unresponsive to therapy.

This review focuses on treatment options for aggressive pituitary tumors, including surgery, radiotherapy and medical treatment, as well as focusing on the promising therapeutic options for aggressive pituitary tumors, evaluating the literature of the last 15 years. With the exception of prolactinomas, surgery is the first-line option, but most aggressive pituitary tumors often require repeated surgery. Pharmacotherapies are useful when surgery is unlikely to improve symptoms, or as an adjunct therapy to surgery. In prolactinomas, dopamine agonists are the first-line treatment and normalize prolactin levels in most patients, even those with macroprolactinomas. Somatostatin analogs are effective agents for primary therapy, pre-operatively or post-operatively to control tumor re-expansion of pituitary adenomas. However, dopamine agonists and somatostatin analogs are not as effective as they are for the treatment of non-aggressive adenomas. When surgery and pharmacotherapy fail, radiotherapy is a useful third-line strategy. Conventional chemotherapy is poorly effective but recent case reports with the temozolomide, an alkylating agent, have provided better results in the short term.

Aggressive pituitary tumors are associated with poor prognosis as therapeutic options are limited. Moreover, they tend to recur quickly after initial treatment, are generally unresponsive to therapy, and are difficult to manage. To improve the overall response rate, the early application of current therapeutic approaches with the incorporation of new therapeutic developments is mandatory.

Olfactory neuroblastoma is extremely rare as a second neoplasm. We report an unusual case of olfactory neuroblastoma in a 59-year-old woman who had undergone two operations and received 54 Gy of irradiation for pituitary adenoma 20 years ago. At the time of admission, the patient presented with nasal obstruction and frequent epistaxis. Imaging studies showed a large mass in the nasal cavities and ethmoid sinus, extending to the intracranial area, with no evidence of any recurrence of the previous pituitary adenoma. The tumor was completely excised via a trans-cranial and trans-nasal approach. A diagnosis of olfactory neuroblastoma was established, and the patient was given postoperative chemotherapy. Although relatively uncommon, second neoplasms are an important consideration in the differential diagnosis of patients with new or recurring symptoms after treatment for pituitary adenoma. Furthermore, it is likely that radiation played a critical role in the development of olfactory neuroblastoma in our patient.

The aim of this study is to review the results of surgery for pituitary adenomas in children less than 18 years old.

A retrospective review was done of pituitary adenoma patients with the age of less than 18 years who were treated in the period 1979-2003 at Dr. Shariati Hospital.

Twenty-one patients (12 girls and 9 boys) were identified. The age range (mean) in girls and boys was 9-18 (15.8) and 9-17 (14.8) years, respectively. The duration of follow-up was 1-23 (13.4) years. Eight patients (38.1%) had adrenocorticotropic hormone-secreting tumors, 33.3% had prolactin-secreting tumors, 19% had growth hormone-secreting tumors, and 9.53% had nonfunctioning adenomas. Multidisciplinary management included surgery and, if necessary, reoperation with/without radiotherapy and pharmacotherapy. Eleven patients, mostly with prolactinomas, acromegaly, and nonfunctioning adenomas, needed reoperation and radiotherapy. There were two deaths, one of which was because of apoplexy. The biological behavior of pediatric pituitary adenomas seems more aggressive than adults' adenomas. The chance of pituitary apoplexy in pediatric invasive pituitary adenoma is high.

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

Pituitary carcinoma is rare, with fewer than 100 cases having been reported in the English-language literature. The diagnosis of pituitary carcinoma requires the demonstration of cerebrospinal and/or systemic metastases rather than local invasion. The lesion carries a poor prognosis; fewer than 50% of patients survive beyond 1 year after diagnosis. In this report the authors describe the case of a 68-year-old man who had undergone transsphenoidal debulking surgery and pituitary radiotherapy 4 years earlier for a pituitary adenoma. He presented with cervical cord compression due to a single metastasis from pituitary carcinoma. The authors discuss the management of this entity and review the literature for current opinion on the pathogenesis of these tumors, factors resulting in malignant transformation, and the reliability of markers that predict future malignant behavior. Evidence for the various treatment modalities is also appraised.

Pituitary carcinomas, defined as distant metastases of a pituitary neoplasm, are rare; fewer than 140 reports exist in the English literature. The initial presenting pituitary tumor is usually a secreting, invasive macroadenoma, with adrenocorticotropic hormone (ACTH)--and prolactin (PRL)--secreting tumors being the most common. The latency period between the diagnosis of a pituitary tumor and the diagnosis of a pituitary carcinoma is 9.5 years for ACTH-producing lesions and 4.7 years for PRL-secreting tumors. Survival after documentation of metastatic disease is poor; 66% of patients die within 1 year. Treatment options include additional surgery, radiotherapy, and chemotherapy, all of which are associated with poor results. Future studies will focus on identifying those invasive pituitary tumors most likely to metastasize and treating them aggressively before they progress to pituitary carcinomas.

We present a 68-year-old male patient with an exceptionally aggressive tumour which invaded to the skull base, cavernous sinus, nasopharynx, sphenoid sinus, pituitary fossa, bilateral parasellar regions, premedullary cistern, and left infratemporal fossa. Headache was the only symptom. The serum prolactin level was 95,973 ng/ml. The patient was treated by right subfrontal craniotomy with removal of the tumour. Because it did not respond well to surgical treatment and the electron micrograph showed abundant secretory granules in some parts of the specimen, post-operative radiotherapy and bromocriptine therapy were instituted. After combined therapies and a long-term follow-up, only little residual pituitary tumour was seen with serum prolactin progressively dropped to 717 ng/ml with no obvious symptoms. The histological findings, the ideal treatments and the clinical course of multi-invasive giant prolactinoma will be discussed.

A 54 year old man was referred to the department of neurosurgery for frontal headache and vomiting. The patient was known in the department because of previous multiple surgery for a locally invasive pituitary prolactinoma (eight years, three years, and one year previously). The neurological examination revealed a frontal mass, which adhered to the dura, suggesting a meningioma. One year later, a left temporal metastasis was removed. Three months later, the patient died, with spinal metastases, of massive lung embolism. Histology revealed a progression of adenohypophyseal prolactinoma on neuroendocrine carcinoma, with an increase in proliferating indexes and modification of hormone production. This study documents a 10 year history of a rare prolactin producing pituitary carcinoma, which metastasised via liquoral flow.

Telomerase activity responsible for cellular immortality may participate the development of human cancers. Telomerase is a multisubunit ribonucleoprotein composed of at least three components: hTERT, hTERC, and TEP1. This is the first report showing telomerase activity and telomerase component expression in pituitary adenoma with histological malignant transformation.

A 16-year-old male with a prolactin-producing pituitary adenoma with metastasis is presented. The patient underwent three partial resections of an intra- and suprasellar lesion over a 2-year period and received focal irradiation. Eight years after the first admission, a metastatic lesion to the subarachnoid space around the medulla oblongata was detected and the lesion was resected as the fourth operation. Furthermore, the suprasellar lesion showed regrowth and partial resection was performed as the fifth operation. The last two specimens were diagnosed as pituitary carcinoma. Radiotherapy with gamma knife was performed for the residual suprasellar lesion and a new lesion in the left temporal lobe after the fifth operation. Telomerase activity was examined by TRAP/TRAP-HPA methods, qualitatively and quantitatively. Telomere length was examined by Southern blot analysis, and the expression of telomerase components (hTERT, hTERC, and TEP1) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The MIB1 index, telomerase activity, and hTERT expression increased according to histologic malignancy chronologically in this patient. None of the specimens showed immunoreactivity for p53, EGFR, or bc12. No telomerase activity was detected in pituitary adenomas without malignant transformation, other benign brain tumors, or normal brain tissues.

We report a patient with pituitary adenoma transforming to carcinoma. The tumor cells acquired immortality and revealed malignant transformation during the course of the disease, that was proved by an increase of telomerase activity and hTERT expression.

Malignant prolactinomas are rare events. To date, only 14 patients with metastases in- or outside the central nervous system have been reported.

We present a patient who developed a metastasis to the cauda equina, which is the first case documented with MRI. A giant prolactinoma in this 51-year-old man was partially removed by a transcranial approach. After radiotherapy and treatment with bromocriptine, the patient had a remission for 3 years. Thereafter, a sacral intraspinal tumor was diagnosed. Because of increasing prolactin levels not responding to bromocriptine and a radiologically suspected intrasellar tumor, we operated transsphenoidally first and found only fibrous tissue. We performed a sacral laminectomy and almost totally removed an intradural tumor. Histopathology and immunohistochemistry confirmed the diagnosis of a prolactinoma metastasis. The patient received radiotherapy and bromocriptine and has no evidence of recurrent tumor or metastases after a follow-up of 38 months, thus being the second reported patient with long-term remission of the disease.

We review the literature on this topic and try to establish common features of the course of this rare malignant disease and the efficacy of therapy in the cases reported hitherto.

Pituitary carcinomas are rare adenohypophysial neoplasms, the definition, diagnosis, therapy, and prognosis of which are controversial.

Pituitary carcinomas were defined as primary adenohypophysial neoplasms with documented craniospinal and/or systemic metastases. The authors report a clinicopathologic study of 15 examples examined by light microscopy, immunohistochemistry, and image analysis. Both proliferative activity and p53 tumor suppressor gene expression were studied.

The study group consisted of 15 patients, including 8 males and 7 females ranging in age from 34-71 years (mean, 56 years). Of these patients, seven had adrenocorticotropic hormone (ACTH)-producing tumors (four in the context of Nelson's syndrome), seven had prolactin-producing tumors, and one had a nonfunctioning tumor. No evidence of diabetes insipidus was seen in any case. Fourteen tumors were initially considered macroadenomas. Of the ten cases for whom tumor extent was known, all had invasive tumors. The interval from the initial diagnosis of adenoma to that of carcinoma ranged from 0.3 to 18.0 years (mean, 6.6 years; median, 5.0 years); the longest mean interval (15.3 years) occurred for patients with Nelson's syndrome. The latency was twice as long for ACTH-producing tumors as for prolactin (PRL) cell tumors (9.5 vs. 4.7 years). All carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis; the rate of systemic metastasis was 71% for PRL cell tumors and 57% for ACTH-producing tumors. Thirteen percent of tumors showed both patterns of metastasis. Fully 50% of primary tumors and the majority of metastases showed nuclear pleomorphism and/or hyperchromasia. The mean mitotic, MIB-1, and proliferating cell nuclear antigen indices for primary tumors and metastases were as follows: 2/10 high-power field (hpf), 2.6% and 11%, respectively; 6/10 hpf, 7.8% and 16%, respectively. Staining for p53 protein was noted in 57% of primary tumors and 88% of metastatic tumors; a relative increase in p53 expression in metastases was noted in 83%. All but one of the primary and metastatic tumors were aneuploid. The most common treatments were radiation therapy and, for PRL cell carcinomas, dopamine agonist administration. Both treatments provided only palliation. Eighty percent of the patients died of metastatic disease 7 days to 8 years after the diagnosis of carcinoma; of these, 66% died within 1 year. At last follow-up, 20% of patients were alive with metastases 9-18 months after diagnosis.

Nearly all pituitary carcinomas present as functioning, microscopically atypical or mitotically active, invasive macroadenomas. By definition, after an interval related to their immunotype, all metastasize. The tumors show a greater tendency toward systemic metastasis than craniospinal metastasis and are associated with poor prognosis. Radiation and dopamine agonist therapy generally provide only palliation. Proliferation indices and p53 expression tend to be higher in metastases than in primary tumors. The current definition of pituitary carcinoma requires the demonstration of metastasis; however, high mitotic and MIB-1 labeling indices as well as p53 immunoreactivity suggest the diagnosis and appear to be of prognostic significance. A redefinition of aggressive pituitary tumors is proposed--one that facilitates the recognition of tumors prone to metastasis.

Pituitary carcinomas are defined by their metastatic growth. Most of them also invade into surrounding tissues. They should be classified by the site of their metastases (cerebrospinal, systemic, or combined) and by the presumable cell type of origin, respectively with the hormone being demonstrable by immunohistochemistry (adrenocorticotrophic hormone [ACTH], prolactin [PRL], growth hormone [GH], hormone-negative). Pituitary carcinomas develop from invasive adenomas. Nearly all tumors had been treated by surgery or X-ray before they metastasized. Since 1976, 37 cases demonstrated with modern methods were reported: 23 had metastasized into the brain or meninges, 10 showed extracerebral metastases, and 4 showed both types of metastases. In our collection of pituitary tumors, three carcinomas (0.13%) were identified: two with systemic metastases (one ACTH secreting and one PRL secreting) and one with meningeal dissemination and ACTH production. The diagnosis of pituitary carcinomas should be based on four criteria: a demonstrable metastasis, identification of the primary tumor as a pituitary tumor, similarity between the structure and immunohistological marker expression of metastasis and primary tumor, and exclusion of an alternative primary tumor.

Prolactin-secreting pituitary carcinomas are uncommon, locally destructive neoplasms that rarely metastasize outside the central nervous system. The authors report a case of a prolactin-secreting tumor that initially presented as the empty sella syndrome. Two recurrences along transsphenoidal surgery tracts in cheek pouches were followed by distant metastases later in the abdomen and pelvis. Only 10 previous cases of either extracranial or intracranial metastases from prolactin-secreting pituitary carcinomas have been reported. No metastases below the diaphragm have been reported previously.

The patient's cheek pouch implants, lymph node metastases, ovarian metastases, and uterine metastases were studied with prolactin-specific immunohistochemistry.

Long term treatment with bromocriptine, several debulking surgeries, extensive local radiation therapy (external beam and proton beam), and cytotoxic chemotherapy had little impact. Tamoxifen, however, may have slowed tumor growth.

Tamoxifen may have efficacy in the treatment of prolactin-secreting pituitary carcinomas.

A 37-year-old man developed multiple intracranial, intraspinal, and general metastases from an invasive nonfunctioning pituitary adenoma after surgery and radiation therapy. This is the first gonadotropic pituitary carcinoma reported in literature.

It is not always possible to differentiate invasive pituitary adenoma from the other parasellar tumours. A case of an invasive pituitary adenoma mimicking a meningioma is reported. The importance of a correct pre-operative diagnosis is emphasized.

Only 12 cases of pituitary tumors that metastasized within the central nervous system have been reported. A further case is presented in which the histology of the multiple dural metastases remained identical to that of the original tumor, a pituitary adenoma. The authors discuss management of these rare lesions that appear histologically benign.

Only seven cases of metastatic prolactin-secreting pituitary tumour have been reported in world literature. The metastases were intra-cranial in five cases and extra-cranial in two cases. We report a further case with multiple intra-cranial metastases in the supra-tentorial compartment. Histologically, both primary and metastatic tumours were benign with strongly positive immuno-histochemical staining for prolactin. Our case exemplifies the inconsistent correlation between the histopathological appearance and biological behaviour of malignant pituitary tumours.

Leptomeningeal dissemination of pituitary adenoma is a very rare occurrence. The present report describes the case of a 28 year old man with a nonfunctioning pituitary adenoma which was operated on and irradiated. Eight years later, the patient developed Cushing's syndrome and multiple leptomeningeal masses were revealed by brain CT and MNR. The diagnosis was ACTH-cell adenoma, without malignant histological signs. The growth fraction of the tumor, detected by means of the immunohistochemical demonstration of proliferating cell nuclear antigen (PCNA), was 5.45% of cells; this figure is higher than that reported for non-recurrent pituitary adenomas. From a review of the reported cases, the possibility of predicting late malignant behaviour is discussed. The microscopic aspect has no prognostic value, since metastasizing cases are not overtly malignant in a histological or cytological sense. The application of methods aimed at detecting the growth fraction of the tumor may prove useful in the early identification of aggressive pituitary tumors.

The authors report a case of a pituitary carcinoma which was locally invasive and which metastasized to cervical lymph nodes more than 9 years after the initial presentation. Cells from the tumour and metastasis immunostained with antibodies to prolactin and growth hormone, even though there was no clinical or biochemical evidence that the tumour was secreting prolactin or growth hormone. In addition, ultrastructural studies showed a monomorphic tumour with secretory granules much smaller than those normally associated with prolactin and growth hormone secretion. The clinical and pathological features suggest that the tumour is probably an acidophil stem cell adenoma, which although known to be aggressive in its clinical behaviour has not been previously reported to metastasize.

Four giant prolactin-secreting tumours invading the skull base are described. All of them occurred in men. The presenting features were sufficiently diverse to be clinically misleading. We advocate the estimation of prolactin levels before embarking on complicated skull base surgery in men where doubt remains regarding the diagnosis after clinical and radiological study.

Invasive prolactinoma is a relatively infrequent variety of macroprolactinoma characterized by a fast and aggressive growth, with infiltration to adjacent structures, and whose management is frequently difficult. We present the case of a fatal invasive macroprolactinoma in whom resistance to different dopaminergic drugs developed.

Prolactin-secreting tumours of the pituitary almost never metastasize extracranially. However, we have recently seen three such patients, whose presentation, clinical course and response to treatment are reviewed in order to determine whether they possess unique clinical features, and to assess optimum therapy.

Three patients with extracranial metastases from prolactinomas have been retrospectively reviewed.

Clinical courses, biochemical parameters and imaging modalities (CT, MR and radiolabelled somatostatin analogue scanning) and histopathology were assessed before and during different therapeutic regimens.

All three patients' presentations were initially unremarkable, but later each had persistent and relentlessly increasing serum prolactin concentrations and evidence of distant spread of their tumours. The first patient presented aged 32 and was treated with repeated transsphenoidal resections of the tumour, pituitary radiotherapy, high dose bromocriptine therapy, the somatostatin analogue octreotide and chemotherapy. Nine years after the original diagnosis a liver biopsy revealed carcinoma cells positively immunostaining for prolactin. At autopsy further microscopically similar metastases were seen in both lungs and the left hilar lymph nodes. The second patient presented aged 48 and was treated with external beam pituitary radiotherapy, bromocriptine, transsphenoidal hypophysectomy and chemotherapy. Fifteen years after the original diagnosis bone biopsy revealed carcinoma cells positively immunostaining for prolactin; the patient developed interstitial nephritis and died in renal failure. The third patient presented aged 48 with hypogonadism and bitemporal hemianopia due to a macroadenoma. This was removed transfrontally and followed by external beam radiotherapy. After recurrence, further surgery and radiotherapy were undertaken, but the tumour continued to grow and the patient died suddenly of a pulmonary embolus. At autopsy, tumour was found in thoracic lymph nodes and lung capillaries.

These three patients may be added to the previous two reported cases of malignant prolactinoma with extracranial spread. Several different therapies were tried but were of limited value in controlling the progression of the disease, although chemotherapy is an important modality to be considered. No particular factor or combination of factors at presentation differentiated these patients from more typical patients whose disease is much less aggressive.

A man with a prolactin secreting pituitary carcinoma was treated by surgery and radiotherapy. Persistent hyperprolactinaemia partially responded to oral bromocriptine for four years. Serum prolactin then rose considerably with rapid, invasive tumour recurrence. Cytotoxic chemotherapy halted tumour progression for twelve months before fatal spread throughout the brain. Failure to normalise serum prolactin with bromocriptine may precede an aggressive course in patients with prolactinoma.

A 44-year-old male suffered epistaxis and headache of sudden onset and was diagnosed as having suppurative meningitis due to streptococci. Four days after the onset of symptoms, he died despite treatment with antibiotics. Destruction and ballooning of the sella turcica was revealed by a plain head X-ray examination during the clinical course. At autopsy, a massive tumorous lesion extended from the ballooned sella turcica to the paranasal cavities, nasopharynx and facial bone, and this had resulted in suppurative meningitis. The tumor was also disseminated to the basal skull. The tumor cells possessed prominent nuclear atypia and were immunohistochemically positive for prolactin. This was diagnosed as a case of pituitary adenoma with markedly invasive pathological findings and a rapid and fatal clinical course.

A 52-year-old woman developed recurrent hypercortisolism 3 yr after successful surgical treatment of Cushing's disease. At postmortem, eosinophilic pituitary tissue showing positive ACTH immunohistochemical staining was present in the frontal lobe and cerebellum but there was no tumor in the sella. In the absence of a pituitary tumor, extrasellar ACTH producing tissue could arise from seeding of the cerebrospinal fluid with tumor cells at the time of operation or from an atypical pituitary carcinoma. In this report we review the mechanisms of intracranial dissemination of pituitary tissue and ACTH-secreting pituitary carcinomas, including parasellar invasion, meningeal seeding, and cerebrospinal and hematogenous spread.

Pituitary adenomas rarely are metastatic. Extracranial visceral metastases of prolactinomas were not previously reported. The authors report a case of a 34-year-old man with a prolactin-producing pituitary carcinoma and histologically proven lung metastases. Pathologic examination of the pulmonary spread included electron microscopy and immunohistochemistry; these confirmed prolactin production by the tumor. The patient's presentation at initial diagnosis, disease recurrence, clinical course, management, and response to therapy (with its theoretic basis) are detailed. Despite the use of dopamine analogues (to tolerance and in combination), there was documented intracranial and extracranial disease progression. Possible future therapeutic maneuvers are discussed.

We report the case of a 25 year old man with pituitary carcinoma with Cushing's syndrome. Though the diagnosis was initially proposed, it was only confirmed by the appearance of meningeal and lymphatic metastases. These were secretory, as confirmed by immunocytochemistry and electron microscopy. These tumours are rare, whether they secrete or not, and can be confirmed only by the existence of metastases, most often in the brain or the liver.

There are 36 reported cases of metastatic pituitary carcinoma and almost half (44%) of these were associated with syndromes of hormonal hypersecretion. The case of a 56-year-old acromegalic man with cervical lymphatic and spinal metastases from a primary pituitary carcinoma is described. Elevated basal levels of plasma growth hormone (GH) and insulin growth factor-1/Somatomedin C (IGF-1/SmC) were found. GH levels did not increase after TRH or LHRH administration but decreased after L-Dopa and glucose. Immunostaining of the metastatic tumor for GH and electron microscopy findings confirmed the diagnosis of pituitary GH-secreting carcinoma. Striking clinical improvement and a 46% decrease in plasma GH levels were observed with bromocriptine treatment, although IGF-1/SmC levels increased during therapy. The clinical course of most reported cases of pituitary adenocarcinoma has been one of progressive intracranial expansion of a pituitary neoplasm. In only 25% were metastatic lesions discovered antemortem, and disabling symptomatology caused by metastases was rare. Only four previously reported patients of 36 with pituitary carcinoma had acromegaly.

Two of the largest prolactinomas ever documented that have been followed for nine and 10 years, respectively, demonstrate how aggressive prolactinomas may become and how difficult invasive prolactinomas are to treat. One of these prolactinomas invaded both internal auditory canals and simultaneously grew inferiorly, reducing the bony support of the skull and necessitating the patient to utilize both hands to hold his head up. The second patient's prolactinoma invaded the sphenoidal, ethmoidal, and cavernous sinuses. Both of these patients had neurosurgical debulking of their tumors followed by radiation therapy. Neither patient's prolactin levels decreased significantly during their first five years post-surgically, at which time bromocriptine was added. Since then, there has been a gradual lowering of serum prolactin levels and a decrease in the size of these tumors. These cases demonstrate that prolonged treatment and very large doses of bromocriptine may be necessary for tumor reduction in patients with invasive prolactinomas.

Of the 510 patients with pituitary adenoma treated surgically at our hospital in the period 1956-1984 319 were treated by the microsurgical technique, in the period 1973-1984, 235 by transsphenoidal approach and 84 by subfrontal-pterional approach. The transsphenoidal route was used almost exclusively in microadenomas, in intrasellar adenomas, in suprasellar adenomas with midline development, in adenomas invading the sphenoidal sinus and in haemorrhagic adenomas with considerable suprasellar development. In some giant adenomas the transsphenoidal route was used in a first stage operation for debulking the tumour, later removed by transcranial route. The latter route was preferred in large adenomas and especially in adenomas with laterosellar development. In some patients with PRL secreting adenomas post-operative treatment with bromocriptine proved useful when the hormone levels failed to normalize. Post-operative radiotherapy was of value in invasive adenomas and in cases in which tumour removal was not radical.

A 64-year-old woman experienced an episode of disorientation in relation to time, place, and people, as well as of visual defect and impaired balance. Physical examination showed a bitemporal hemianopsia and truncal ataxia. Computerized tomography of the skull revealed a sellar mass consistent with the diagnosis of pituitary adenoma. The patient progressively lost consciousness and died. At postmortem examination, a pituitary neoplasm with arachnoid metastases was present. Metastatic cervical lymph nodes were also detected. Histologic aspects of the primary tumor and of lymph node metastases were quite similar. Immunohistochemical investigation revealed the epithelial origin of the neoplasm and failed to disclose endocrine activity. At ultrastructural examination, the cells of the primary tumor and of the metastases lacked specific granules. These findings support the evidence of a primary metastasizing pituitary carcinoma.

Pituitary adenomas may remain intrasellar or infiltrate dura and bone. Invasive adenomas are not considered to be malignant; in biological behavior they are between non-infiltrative adenomas and pituitary carcinomas. The latter are defined as tumors with subarachnoid, brain, or systemic metastasis. Invasion may be defined radiologically, operatively, or histologically. On the basis of operatively assessed tumor size and gross invasion of dura and bone as well as immunocytochemical and ultrastructural analysis of 365 pituitary adenomas, the following data were obtained. There were 23 growth hormone (GH)-cell adenomas: 14% microadenomas and 86% macroadenomas; their overall frequency of invasion was 50%. There were 24 prolactin (PRL)-cell adenomas: 33% microadenomas and 67% macroadenomas, with an overall frequency of invasion of 52%. Mixed GH-cell and PRL-cell adenomas were found in 35 cases; 26% were microadenomas and 74% were macroadenomas, and the overall frequency of invasion was 31%. Sixty patients had adrenocorticotropic hormone (ACTH)-cell adenomas (Cushing's disease): 87% microadenomas and 13% macroadenomas; the overall frequency of invasion was 25% (in 8% of microadenomas and 62% of macroadenomas). Twenty patients had ACTH-cell adenomas (Nelson's syndrome): 30% microadenomas and 70% macroadenomas; the overall frequency of invasion in these cases was 50% (in 17% of microadenomas and 64% of macroadenomas). Silent ACTH-cell adenomas, 100% macroadenomas, were found in 11 patients, with an 82% frequency of invasion. There were 32 follicle-stimulating and luteinizing hormone adenomas, all macroadenomas, with a frequency of invasion of 21%. Four patients had thyroid-stimulating hormone adenomas, all macroadenomas, with a 75% frequency of invasion. Null-cell adenomas were found in 93 cases: 2% microadenomas and 98% macroadenomas, with a frequency of invasion of 42%. There were 63 plurihormonal adenomas (GH, PRL, glycoprotein): 25% microadenomas and 75% macroadenomas, with a 50% overall frequency of invasion. Based on this study, and on their usual frequency of occurrence, the estimated rate of gross invasion by pituitary adenomas of all types is approximately 35%. It is concluded that immunocytochemical and ultrastructural characteristics of pituitary adenomas reflect the tendency of these tumors to infiltrate and hence may be of prognostic significance.

A 48-year-old woman developed multiple intracranial and intraspinal metastases from an invasive growth hormone-secreting pituitary adenoma after surgery and radiation therapy. This is the first reported case to show that the cells in the metastatic tumors and in the cerebrospinal fluid contained growth hormone.

Our experience with prolactinomas started in 1972 and is based on about 370 patients. Of these 247 were treated surgically, about 110 underwent medical therapy and a small number of patients were observed only. In microprolactinomas prolactin-levels could be normalized in up to 80% of the patients after selective adenomectomy. However, true recurrences were observed in 16% of the patients during long-term follow-up. The operative risk is rather low. There was no mortality in this series. The rate of complications is about 1%. Medical treatment with dopamine-agonists is successful especially in women who desire pregnancy, but should only be used in small microadenomas, in order to avoid complications. In larger macroprolactinomas h extra-sellar extension in whom primary surgical removal leads to a normalization of prolactin-levels in a minority of cases only primary therapy with dopamine-agonists leads to shrinkage of the tumour mass in about two-thirds of the patients. Since the tumour mass does not disappear completely after short-term medical treatment, we favour additional surgical tumour removal instead of long-lasting administration of dopamine-agonistic drugs in higher dosages.

Shrinkage of a massive, highly invasive, longstanding (probably 40 years) prolactin-secreting pituitary tumour is described in which tumour volume was reduced by 40% 8 d after beginning bromocriptine treatment. After 4 months of treatment the tumour was only 11% of the pretreatment volume and by 8 months it was further reduced in size being confined to the pituitary fossa, which was partially empty. Reduction in tumour volume was accompanied by a gradual reduction in serum prolactin concentrations to normal values at 4 months. Between 4 and 18 months serum prolactin has remained normal on 5 mg of bromocriptine daily. Visual function improved within 48 h of starting bromocriptine and was almost normal by 6 d. CSF rhinorrhoea developed as the tumour shrank and was successfully managed with the relatively minor procedure of a diversionary lumbo-peritoneal shunt. Bromocriptine should be considered as the initial treatment of choice for massive invasive prolactinomas because of the significant risk of morbidity from neurosurgical treatment.

A 44-year-old woman developed acute severe visual field defects and was operated on a macroprolactinoma. Since complete resection of the tumor was not possible, radiotherapy was performed and in addition to hormone replacement therapy, bromocriptine (up to 60 mg daily) was started without however complete normalization of PRL levels. Four years later PRL levels increased to 10(5) microU/ml despite continuation of dopamin agonist (mesulergin) treatment. As shown by ophthalmological examination and computer tomography there were no signs of regrowth of the pituitary tumor. At that time the patient complained of severe lumbar pain and myelography revealed a tumor mass in the spinal cord (L1-L2). Since the spinal tumor was not removable, laminectomy was performed. Histology and immunohistochemistry demonstrated a metastasis of the prolactinoma. Radiotherapy and bromocriptine in extreme doses (140 mg daily) together with an antiestrogen were not able to improve the neurological deficits (paraparesis) and to lower the PRL levels. This case of a metastasis of a prolactinoma after operation, radiotherapy, and dopamin agonist treatment stresses the importance of close surveillance of patients with prolactinomas without PRL normalization during dopamin agonist therapy and shows for the first time the possibility of ectopic PRL production due to an intradural spinal metastasis.

A patient with a primary adenohypophyseal neoplasm who had a long course marked by multiple surgical resections, radiation therapy, and high-dose dopamine agonist therapy developed local invasion as well as cranial and extracranial osseous metastatic lesions. The serum prolactin levels were greatly elevated, and immunohistochemical studies demonstrated prolactin in the cytoplasm of primary and metastatic tumor cells. Ultrastructural features of lactotrophic differentiation, including misplaced granule exocytosis, were observed. This is the third reported case of prolactin cell carcinoma that metastasized despite high-dose dopamine agonist therapy. Analysis of the patient's serum prolactin showed no abnormality in the chromatographic profile of biologic activity.

This case report describes a 45-year-old man with a massive extrasellar prolactinoma, treated initially with surgery and radiotherapy, who experienced a dramatic reduction of the bulk of his tumor but persistence and subsequent progression of an extrasellar portion while receiving long-term bromocriptine therapy, despite stable, suppressed prolactin levels. Although the residual tumor was thought to be adenomatous tissue unresponsive to bromocriptine, a meningioma was ultimately diagnosed. Because the meningioma may have been radiation-induced, clinicians are reminded to consider a second neoplasm in cases of apparent bromocriptine treatment failures, especially when prolactin levels are stable.

A 28 year old man presented with partial hypopituitarism and signs of a pituitary tumour. A chromophobe adenoma was partially removed by right frontal craniotomy. Seven years later complete hypopituitarism and hyperprolactinaemia were documented, at which time there was no evidence of tumour recurrence of CT scan. The patient was treated with bromocriptine but the pituitary tumour redeveloped a year later. Nine years after the original operation the first metastasis was demonstrated together with very high prolactin levels. The intracranial metastasis, and the pituitary tumour were removed at a second craniotomy following which the prolactin concentration fell. Further metastases developed subsequently and the patient died 12 years after the initial diagnosis. At autopsy multiple metastases were found in the brain, tumour cells were present in the subarachnoid space and in cerebral veins. The pituitary tumour and secondaries were shown by immunocytochemistry to contain prolactin but not ACTH or growth hormone. This appears to be the third well documented case of a metastasizing, prolactin secreting pituitary tumour.

From a series of 207 patients with pituitary adenoma operated on by microsurgical technique from 1973 to February, 1982, the cases of nine young people whose symptoms had appeared between the ages of 11 and 15 years are presented. The most important data are that all the children were pubertal and that in seven the tumor was, or later became, invasive. By contrast, the tumor was enclosed in eight of nine other patients whose symptoms manifested between the ages of 16 and 20 years, and in 152 of the remaining 189 patients whose symptoms appeared after the age of 20 years. Considering the gravity of the disease treated, the results in this series may be termed encouraging. The treatment was multidisciplinary: starting with surgery, followed by radiotherapy, endocrine replacement therapy, and, in adenomas secreting prolactin and/or growth hormone, medical therapy with bromocriptine. The divergence between authors on the subject of childhood adenomas, especially as to whether they are more often invasive or enclosed, could be overcome, at least in part, if the term "pediatric age" were unequivocally defined and if there were an agreed distinction between puberty and childhood on the one hand and puberty and adolescence on the other.

A 70-year-old man developed panhypopituitarism and was found to have hyperprolactinaemia and a locally invasive pituitary tumour. The visual fields were unaffected and therefore the patient was treated with hormone replacement only. After 3.5 years during which time the pituitary tumour had not enlarged further, the patient developed a mass in the left cerebello-pontine angle. This mass was subsequently shown to be entirely separate from, but histologically identical to, the pituitary tumour and the cells of both contained PRL. Evidence was obtained to show that the tumour had spread by a vascular route. This is the second reported case of a malignant prolactinoma.