Pituitary adenomas are usually benign but there are some isolated cases of pituitary carcinomas described in the literature. More than 50% of pituitary carcinomas are non-functioning but PRL, ACTH, GH and TSH secreting carcinomas have also been described. Regarding somatotroph carcinomas, 11 patients have been reported since the beginning of the century 1-9. Metastasis in central nervous system occurred in all the cases except in the fourth. In other four cases, metastasis were localised in lymph nodes of neck1,7-9. We describe here a patient with refractory acromegaly after four craniotomies, two radiotherapy sessions and apparently biochemical cure of GH excess without any medical treatment.
CASE REPORT
The patient is a 42 years old man first seen in 1994 after two surgical procedures and one irradiation. He was studied in another medical center in 1990 to investigate the cause of a confusional state and the diagnosis of acromegaly due to a GH secreting pituitary macroadenoma was made (fig. 1). He was operated in 1990 by subfrontal way. The postoperative magnetic resonance imaging (MRI) showed tumoral persistence because of the patient was irradiated with 50 Gy. In 1993, the patient complaint of loss of vision in the left eye and the MRI showed a very large tumour with suprasellar invasion and hydrocephalus. Another adenomectomy by subfrontal way was then necessary to partially remove the tumour.
In 1994, at the moment of the first visit to the hospital, the hormonal values of the patient were GH 3.7 µ g/l and IGF-I 420 ng/ml (normal range < 400 ng/ml) with abnormal suppression of GH (GH > 2 µ g/l) following an oral glucose load. In August 1994, the patient developed neurological alterations as loss of vision in the left eye, disturbance of intellectual function and somnolence. It was necessary another surgery because the MRI showed an important tumoral regrowth. Three months after the craniotomy, MRI showed an important cyst involving tumoral nodes in the left hemisphere and the patient underwent stereotaxic radiosurgery with a total dose of 1,000 cGy (fig. 2). Endocrine investigations revealed GH levels of 6 µ g/l and IGF-I 708 ng/ml. The patient did not present GH paradoxical responses after infusion of TRH (250 µ g i.v.) or GnRH (100 µ g i.v.). Treatment with somatostatin analogues was then initiated (lanreotide 0.03 g i.m./28 days) and after 3 months of therapy, GH and IGF-I levels decreased to 2 µ g/l and to 325 ng/ml respectively, and normal suppression of GH after an oral glucose load was observed. The patient continued with the same treatment but in the sixth month of therapy an unexpected recurrence was observed. In fact, GH levels raised to 14 µ g/l with IGF-I to 925 ng/ml and the patient developed neurological alterations as progressive weakness in the lower limbs and abnormal gait. MRI demonstrated a large tumoral mass in the anterolateral part of the frontal lobe and an enlargement of the posterior cyst (fig. 3) and in October 1996, the patient underwent his forth surgical procedure by subfrontal way. The excision was nearly complete except for tumoral tissue around cavernous sinus. Following surgery, MRI scan of the brain revealed 4 tumoral deposits. Three of them localised in the frontal lobe and the other one, in the cavernous sinus. Then, the patient received near 1,000 cGy in each deposit by stereotaxic radiosurgery. Nowadays, the patient follows periodic controls in order to detect another recurrence. Endocrine investigations have shown normal levels of GH and IGF-I (0.5 µ g/l and 314 ng/ml, respectively) so the patient does not receive any medical treatment. Last MRI, performed after 1 year of the last adenomectomy, shows tumoral nodes of approximately 1 cm of diameter around the cyst in the left frontal lobe. He has also undergone a 99Tc octreotide scintiscanning that has not shown evidence of somatostatin receptors. Gastrointestinal tract examination, chest X-ray film, gallium scintigram and abdominal ultrasonography have not revealed any metastatic lesion.
Histological studies of the resected specimen from the last three craniotomies were similar, showing high pleomorphism in cytoplasms and in nucleus. The tumour was poorly vascularizated with diffuse arrangement of well-defined polygonal cells. Cellular cytoplasms were large with a high number of acidophilic granules. Mitotic activity was increased in some areas of the tumoral pieces. There were not signs of vascular invasion. No cells were obtained from the liquid in the cyst.
In all the tumoral pieces, immunocytochemistry staining demonstrated presence of positive cells for GH and absence for the rest of pituitary hormones. As it has been proposed that indices of cellular proliferation be increased in invasive adenomas an often high in carcinomas10, the expression of Ki67 antigen was evaluated. This antigen is a proliferation marker selectively expressed during G1, S1, G2 and M phases of the cell cycle. The presence of p53 tumour suppressor gene was also studied because is thought to play a role in the development or evolution of adenohypophysial neoplasms. In 1993, there were not positive cells for these markers but surgical pieces of 1995 and 1996 showed positivity for both of them. In 1995, the proliferating cell nuclear Ki67 antigen was present in 2.0% of cells and p53 in 1.6% of cells. In 1996, Ki67 was present in 1.5% of cells and p53 in 1.0% of cells.
DISCUSSION
Earlier literature considered locally aggressive tumours to be malignant; however, current classification describes these lesions as "invasive adenomas". Pituitary carcinomas are distinctly uncommon and diagnosis is normally made when metastasis appear in a patient with a pituitary adenoma but the period between the onset of the primary lesion and distant metastasis tends to be long (4 to 19 years)3,10. Therefore, defining the difference between invasive pituitary adenoma and pituitary carcinoma only when metastasis appears could be a matter of time. In fact, the clinical course of most reported cases of pituitary adenocarcinoma has been one of progressive intracranial expansion of a pituitary neoplasm with metastatic lesions discovered post-mortem5. As in the case described before, in all pituitary carcinomas producing GH, the patients had previously diagnosed pituitary tumours with features of acromegaly. All primary tumours were large, with suprasellar extension, requiring a transcranial surgical approach. Primary resection was incomplete in all cases, with residual tissue remaining in the cavernous sinus and/or adherent to the frontal lobes. As a result, all patients also received treatment with radiotherapy. In spite of the diagnosis of malignancy in pituitary lesions being usually made when metastasis appear, the aggressive behaviour of the pituitary lesion in this patient allows to suspect and adenoma to carcinoma transformation. In fact, 3 tumoral recurrences despite surgery, radiotherapy and medical treatment are unusual in other GH pituitary adenomas. With regard to hormonal activity, GH levels seemed to be under-control after three months of therapy with somatostatin analogues but an unexpected recurrence induced an important raise of the hormonal levels. This agrees with previous observations that tumour suppression may not ocurr with somatostatin analogues. Moreover, this patient presented a negative 99Tc octreotide scintiscanning after the last craniotomy.
Histopathological criteria are also unhelpful in determining the malignant potential of pituitary tumours because pleomorphism, abundant nuclei and increased mitotic activity are commonly seen in benign pituitary adenomas and some tumours with metastasis have very regular histology. However, it has been hypothesed that the presence of proliferation indices as well as p53 immunoreactivity suggests the diagnosis of pituitary carcinoma and appears to be of prognostic significance11. In fact, an alternative definition of pituitary carcinoma based on increased mitotic activity, high proliferation indices and the presence of p53 staining has been proposed10. In the case described before, neither Ki67 nor p53 were expressed in 1993 but became present in subsequent surgical pieces. A clear correlation between positivity of these indices and tumoral malignancy has not been demonstrated but the presence of these indices can indicate a more aggressive behaviour of the tumour.
The definition of pituitary carcinoma requires the demostration of metastasis; however the presence of an aggressive behaviour as in the case described before suggests the diagnosis and appear to be of prognostic significance. In order to confirm this hypothesis it would be necessary to survey closely the clinical evolution of this patient and other cases with similar behaviour.
