LA CONSULTA SEMANAL

OCTUBRE 2000

CONSULTA

Br J Neurosurg 2000 Aug;14(4):317-25
Effect of photodynamic therapy on recurrent pituitary adenomas: clinical phase I/II trial--an early report.
Marks PV, Belchetz PE, Saxena A, Igbaseimokumo U, Thomson S, Nelson M, Stringer MR, Holroyd JA, Brown SB
Department of Neurosurgery, General Infirmary at Leeds, UK.
Pituitary adenomas, although histologically benign, are not always curable by surgery alone, principally because of dural infiltration, as well as their peculiar anatomical location. Radiotherapy has been employed as an adjuvant therapy to address residual disease with favourable results. This approach is, however, not without side effects, and it cannot be repeated. We are therefore investigating the effectiveness of photodynamic therapy (PDT) on recurrent pituitary adenomas in humans. This study details the protocol applied to 12 patients with recurrent pituitary adenomas, which involved systemic administration of photosensitizer (Photofrin) followed, after a period of 24-48 h, by intraoperative illumination of the tumour bed using 630 nm laser light. The primary end points were visual, endocrine and radiological improvement. The incidence of side effects was also monitored. The longest follow-up is 2 years. Most patients suffering from visual acuity or field defects have shown improvement when followed for 12 months or more. Three patients showed complete recovery of their visual fields. All those who presented with functional adenomas have shown reduction in their hormone levels. Tumour volume, relative to the preoperative size, was 122, 87, 66, 60 and 46% at 4 days, and 3, 6, 18 and 24 months, respectively. One patient developed severe skin photosensitization due to early exposure to direct sunlight and three others displayed minor skin reactions. There was no treatment-related mortality or morbidity. One patient (operated transcranially) developed hemiparesis postoperatively, which recovered completely. We think this is unrelated to the treatment. This prospective study demonstrates that PDT may be safely applied to the pituitary fossa by the trans-sphenoidal route and indicates the need for a randomized, controlled trial in order to establish its therapeutic potential.

Journal of Molecular Endocrinology 22 9-18 (February 1999) [Texto completo en formato PDF]
Gene therapy strategies for the treatment of pituitary tumours
M G Castro
Molecular Medicine Unit, Department of Medicine, University of Manchester, Stopford Building, Room: 1.302, Oxford Road, Manchester, M13 9PT, UK
Gene therapy can be defined as the introduction of therapeutic nucleic acids into cells with the aim of ameliorating or curing a disease. Initially, gene therapy paradigms focused on single-gene disorders. Recently, it has become apparent that potential therapeutic nucleic acids can be considered as drugs and as such could also be used for treating a variety of diseases (Verma & Somia 1997, Lowenstein 1997). With recent advances in gene transfer technologies, gene therapy has become a reality, with more than 2100 patients undergoing clinical gene therapy trials (Marcel & Grausz 1997). Given the high expectations from this new therapeutic modality, and in spite of the lack of conclusive evidence for efficacy from the initial trials, very valuable information has been gained from the preclinical and clinical trials.

Journal of Endocrinology 157 177-186 (May 1998) [Texto completo en formato PDF]
Current perspectives on the pathogenesis of clinically non-functioning pituitary tumours
N J L Gittoes
Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH
Pituitary tumours are classified by the characteristic clinical syndromes that accompany tumour hormone production. All of the constituent hormone-secreting cell types of the anterior pituitary are capable of undergoing neoplastic change, although it is evident from histochemical analysis that adenomas derived from pure, functional lactotrophs, corticotrophs, somatotrophs, gonadotrophs and thyrotrophs are the exception rather than the rule. Tumours frequently express more than one hormone (Scheithauer et al. 1986, Kovacs & Horvath 1988), most frequently GH and PRL, although immunohistochemical detection of hormones is not a marker of true secretory function. Pituitary tumours that secrete intact hormones result in clinical syndromes of hormone hypersecretion- PRL causing clinical features of hyperprolactinaemia, GH causing acromegaly or gigantism, ACTH causing Cushing's disease and TSH causing secondary hyperthyroidism. Approximately 25-30% of all anterior pituitary neoplasms, however, do not cause clinical syndromes of hormone hypersecretion and are termed non-functioning tumours (NFTs). The term non-functioning is strictly a clinical term, as it is now clear from the results of immunohistochemistry that the majority of these tumours do indeed synthesise and sometimes secrete hormones (Arafah 1986), predominantly subunits of the GPHs (GPHs; LH, FSH and TSH) or occasionally intact GPHs (Snyder et al. 1979, Snyder et al. 1984, Snyder 1985, Jameson et al. 1987, Klibanski 1987, Black et al. 1987, Warnet et al. 1994). Figure 1 shows typical immunostaining properties of a NFT.

Clin Endocrinol (Oxf) 1998 Apr;48(4):527
Retinoid X receptor gamma mRNA expression is reduced in recurrent non-functioning pituitary adenomas.
Gittoes NJ, McCabe CJ, Sheppard MC, Franklyn JA
Publication Types:
  Letter

J Neurosurg 1998 Jun;88(6):1002-8
Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy.
Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G
Neurosurgery Department, Institute of Neuroradiology, Klinik Im Park, Zurich, Switzerland. 1000123.1666@compuserve.com
OBJECT: The authors tested the assumption that gamma knife radiosurgery is more effective than fractionated radiotherapy for the treatment of patients with acromegaly who have undergone unsuccessful resective surgery. Untreated and uncured acromegaly causes illness and death. Acromegalic patients in whom growth hormone and, particularly, insulin-like growth factor I are not normalized must undergo further treatment. METHODS: After unsuccessful operations, 16 patients suffering from recurrent and uncured acromegaly underwent stereotactic radiosurgery (25 Gy to the tumor margin, 50 Gy maximum), the outcome of which was compared with the result obtained in 50 patients who received fractionated radiotherapy (40 Gy). The cumulative distribution functions of the two groups (Kaplan-Meier estimate) differed significantly (p < 0.0001 in the log-rank test of Mantel). The mean time to simultaneous normalization of both parameters was 1.4 years in the group treated with the gamma knife and 7.1 years in the group treated with fractionated radiotherapy. CONCLUSIONS: The authors suggest the use
of stereotactic radiosurgery as the preferred treatment for recurrent acromegaly resulting from unsuccessfully resected tumors.

Arch Intern Med 1997 Nov 10;157(20):2377-80
Late complications in remission from Cushing disease. Recurrence of tumor with reinfarction or transformation into a silent adenoma.
Dickstein G, Arad E, Shechner C
Division of Endocrinology, Bnai Zion Hospital, Haifa, Israel.
Two of 4 patients who underwent spontaneous remission from Cushing disease (CD) demonstrated regrowth of the pituitary adenoma 2 and 5 years later. In the first patient, the recurrent tumor also secreted corticotropin, with subsequent relapse of fulminant cushingoid features. However, after 14 more months, it again became infarcted, and the patient underwent complete clinical remission, which has persisted for about 3 years. In the second patient, the regrowth of the tumor occurred silently, as no clinical cushingoid features or rise in cortisol levels were noticed. Because of its size, the tumor was resected and found to have immunoreactivity for corticotropin (silent corticotroph adenoma). About 4 years after the first operation, a second surgical procedure was performed because of massive regrowth of the tumor. Again, there was no concomitant elevation of cortisol levels or endocrinologic symptoms. This time, the tumor did not even stain for corticotropin. While spontaneous remission in CD is rare, recurrence is even rarer. Reremission of CD and the change from a corticotropin-secreting adenoma to a silent one are described herein for the first time (to our knowledge). These cases demonstrate that patients with CD have to receive careful follow-up, even if they undergo remission, and that the long-term outcome of such remission is unpredictable.

Journal of Endocrinology 155 553-555 (1997) [Texto completo en formato PDF]
Evidence supporting surgery as treatment of choice for acromegaly
R Fahlbusch, J Honegger and M Buchfelder
Neurochirurgische Klinik mit Poliklinik der Universität Erlangen-Nürnberg, Schwabachanlage 6, D-91054 Erlangen, Germany
Within a period of fourteen years 531 operations for growth hormone (GH)-secreting adenomas were carried out. In this consecutive series 73% of the 396 patients who underwent primary transsphenoidal surgery achieved basal GH levels below 5 µg/l, and 58% also had an adequate suppression following an oral glucose tolerance test (OGTT). Slightly less favourable results were found in patients requiring surgery following an initial therapy. However, 41% of the 121 such patients, who had either been operated upon previously or who had received external or internal irradiation, nevertheless achieved basal GH levels below 5 µg/l after the surgical reintervention. Normal suppression of serum GH during an OGTT was observed in 23% of these patients. The overall complication rate was low and tumour recurrences were very rare. To facilitate easier tumour removal, octreotide was preoperatively administered in 53 patients undergoing primary surgery of large adenomas. Recurrences were documented in a few exceptional cases. These data support our previous experience that once a normal suppression of growth hormone has been documented following surgery of pituitary adenomas, the long-term outcome is favourable.

Neurosurgery 1994 Jul;35(1):39-44
Changes in the immunophenotype of recurrent pituitary adenomas.
Mindermann T, Kovacs K, Wilson CB
Department of Neurological Surgery, School of Medicine, University of California, San Francisco.
Only two cases have been reported of a pituitary adenoma that changed phenotype between its initial resection and recurrence. To determine the frequency of such cases among our patients, we examined the clinical course of these tumors and characterized any patterns. We reviewed the charts of 1023 patients with pituitary adenomas who underwent surgery between 1984 and 1992 at the University of California at San Francisco. Of the 65 patients (6.4%) who had operations for or clinical evidence of tumor recurrence, five (7.7%) had tumors that changed phenotype. The female-to-male ratio was 4:1, and age at the onset of symptoms was 33.2 +/- 15.3 years (mean +/- standard deviation). Changes occurred in hormone production and hormone release after 6.4 +/- 3.4 years. At some point, all five tumors were invasive and four were macroadenomas. Two patients had more than one operation for tumor recurrence; three had silent or symptomatic pituitary apoplexy; and three had undergone sellar irradiation before the changes in phenotype occurred. The behavior of these tumors therefore seems to be aggressive. We do not yet know whether phenotypic changes in pituitary adenomas have any treatment implications. Therefore, we advocate the complete immunostaining of primary and recurrent pituitary adenomas so that additional data about their clinical course can be collected.

BMJ 1994;308:1087-91 (23 April) [Texto completo]

Fortnightly Review: Diagnosis and management of pituitary tumours

A Levy, S L Lightman 

University of Bristol, Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW Correspondence to: Dr Levy.

J Neurosurg 1993 May;78(5):753-61
Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence.
Hsu DW, Hakim F, Biller BM, de la Monte S, Zervas NT, Klibanski A, Hedley-Whyte ET
Division of Neuropathology, Massachusetts General Hospital, Boston.
The recurrence rate of pituitary adenomas has been reported to be as high as 10% to 35% despite their generally benign nature. A monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) was used to investigate whether the proliferative index might help to predict adenoma recurrence. This antigen is a nuclear protein identified as the auxiliary protein of deoxyribonucleic acid polymerase delta, and its gene expression correlates with cell proliferation. The authors studied 30 patients with recurrent pituitary adenomas, 32 with nonrecurrent adenomas, and seven normal pituitary tissue samples. The mean interval to recurrence ( +/- standard error of the mean) was 5.3 +/- 0.7 years. The age- and sex-matched nonrecurrent group had a mean follow-up period of 6.6 +/- 0.3 years without clinical recurrence. Mean percentages of PCNA-positive tumor nuclei in both the initial and the second surgical specimens of the recurrent adenomas (13.45% +/- 3.02% and 19.56% +/- 3.66%, respectively) were significantly higher than that of the nonrecurrent group (2.49% +/- 1.21%). In addition, recurrent tumors had a higher PCNA index than the initial tumors in the same patients. Normal anterior pituitary gland tissue had a significantly lower mean PCNA index (0.12% +/- 0.11%) than either patient group. Stepwise multivariate regression analysis indicated that factors which collectively correlated significantly with recurrence were: high PCNA
index, large tumor size, extrasellar extension, and incomplete surgical excision. The PCNA nuclear count was not associated with age, sex, or hormone hypersecretion, but was higher in macro- than in microadenomas, in tumors with extrasellar extension, and in those incompletely excised. A higher PCNA index also correlated with a shorter disease-free interval. The authors conclude that evaluation of the PCNA index assists in predicting the likelihood of pituitary adenoma recurrence.

Arch Intern Med 1992 May;152(5):977-81
Recurrent Cushing's disease after transsphenoidal surgery.
Tahir AH, Sheeler LR
Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, OH 44195.
Thirty-four patients with proven Cushing's disease underwent transsphenoidal surgery between January 1976 and August 1988. Postoperatively, all the patients had biochemically proven remission. Seven patients who had recurrence of their disease (incidence, 20.6%) were evaluated clinically and biochemically and the results are presented. All of seven patients had surgically and pathologically proven pituitary adenomas. All of seven patients had postoperative adrenal insufficiency necessitating steroid replacement for a mean of 8 months. The time of recurrence varied widely and ranged from 29 to 62 months, with a mean of 40 months. We conclude that (1) the longer the period of follow-up, the higher the incidence of recurrence; (2) although the recurrence rate is low (20.6%), it is certainly appreciable; and (3) the time of recurrence can be delayed (62 months) and thus we recommend yearly follow-up with urinary free cortisol determinations.

Br J Neurosurg 1992;6(1):33-40
Pituitary adenoma proliferative indices and risk of recurrence.
Carboni P Jr, Detta A, Hitchcock ER, Postans R
Department of Neurosurgery, Midland Centre for Neurosurgery and Neurology.
Twenty unselected pituitary adenomas have been examined for proliferative indices (PIs), and anterior pituitary hormone expression. All but two of the tumours were non-functional with proliferative indices from less than 0.1 to 0.5%. Two tumours were null cell adenomas with PIs less than 0.1 and 0.2%. The PIs of the three recurrent tumours was less than 1.0%. Gonadotrophin and TSH immunoreactivity was heterogenous and was found in 12/20 (60%) of the tumours. There was no significant relationship between PI, hormone expression or any other measured parameter. The biological behaviour of pituitary adenomas with a PI of less than 0.1% is uncertain, but those with a PI of greater than 0.1% are more likely to recur although longer follow-up is needed to confirm this.

Radiology 1990 Oct;177(1):273-5
Recurrent pituitary adenomas after surgical resection: the role of radiation therapy.
Kovalic JJ, Grigsby PW, Fineberg BB
Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110.
Postoperative radiation therapy for pituitary adenomas is usually reserved for extensive lesions or those that are incompletely resected. Nineteen patients who received external beam radiation as a salvage procedure after recurrence following surgery alone for pituitary adenomas were studied. At recurrence, nine patients underwent reexcision. All 19 patients underwent external beam irradiation for salvage. Within a median follow-up time of 11.8 years from the time of surgical failure, two patients have died of progressive adenoma, two are alive with disease progression, eight are alive without disease progression, and seven have died of intercurrent disease. The 5-, 10-, 15-, and 20-year overall actuarial (and progression-free) survival rates were 79% (90%), 62% (90%), 44% (80%), and 44% (53%), respectively. Dose of radiation, suprasellar extension at the time of surgical failure, and histologic findings had no bearing on prognosis. One patient developed a radiation-induced brain necrosis that was successfully resected. Radiation therapy can be an effective salvage modality for recurrent pituitary adenomas after surgical failure.