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
N J L Gittoes
Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham,
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
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,
Neurosurgery Department, Institute of Neuroradiology, Klinik Im Park,
Zurich, Switzerland. email@example.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
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
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
1994;308:1087-91 (23 April) [Texto
Review: Diagnosis and management of pituitary tumours
S L Lightman
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,
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,
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
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.