Dieter K. Lüdecke

Transsphenoidal Microsurgery for Newly Diagnosed Acromegaly: A Personal View after More than 1,000 Operations

The aim of this short review is to inform about the possibilities and limits of transnasal microsurgery in acromegaly. The current reports on surgical remissions, according to the strict criteria with international consensus using age- and sex-related normal levels for insulin-like growth factor-I and suppression of growth hormone (GH) with oral glucose tolerance below 1 µg/l, are more or less agreeable with values between 34 and 74%. In microadenomas (<10 mm in diameter), 59–95% remissions are published. Some improvement might be achieved in macroadenomas which presently have a chance of 26–68% to be satisfactorily operated on. Special instruments introduced by us to visualize and remove partially invasive adenoma parts are described. Intraoperative magnetic resonance imaging is discussed. With intraoperative measurement of GH, small adenoma rests <3 mm can be diagnosed. When GH did not sufficiently decline, an additional tumor search resulted in a significant improvement in results in resectable macroadenomas. With these techniques, we achieved remission rates which can hardly be further increased (micros 95%, macros 68%). In grossly invasive grade 4 adenomas, which are frequent in our unit, only an 80–95% reduction in tumor mass is feasible. Preoperative treatment with somatostatin analogues as used in most of our patients reduces the comorbidity and facilitates adenoma removal which is still controversially discussed in the literature. The complication rate of microsurgery in experienced hands is low.

Hypophysitis in surgical and autoptical specimens

We present the clinical and histological findings of 11 cases of inflammatory anterior pituitary lesions, 8 of which were obtained during surgery and 3 of which were obtained from autopsies. Additionally, we extended the conventional classification of pituitary inflammatory disease by the new entity “secondary hypophysitis”. Of the surgically obtained specimens 5 consisted of inflammatory extension into the pituitary gland out of the surrounding tissue. In all of these patients the inflammation originated from an additional tumor in the sellar region (4 craniopharyngiomas, 1 prolactinoma). These will be referred to as “secondary hypophysitis”, an entity which has not yet been mentioned in the literature. Of the remaining 6 cases, 2 were granulomatous hypophysitis, 2 pituitary abscesses, 1 lymphocytic hypophysitis, and 1 showed extensive scarring of the anterior pituitary lobe due to preceeding lymphocytic hypophysitis. At histological examination the basic structure of the anterior pituitary was maintained in all cases. Relative counts of hormone-producing cells were normal. In secondary hypophysitis, the affected area was composed of fibrous tissue and granulation tissue. B and T lymphocytes were present in equal amounts. Granulomas were not found. Inflammatory infiltrates, granulation tissue and fibroses were seen in different proportions. Based on our results and three other cases reported in the literature so far, we think that the presently used classification of pituitary inflammatory diseases lacks an entity which describes a non-abscess-forming inflammation of the pituitary gland originating from an associated pathological process. Therefore, we introduced the term secondary hypophysitis to describe this fourth entity of pituitary inflammatory disease.

Persistent and recurrent hypercortisolism after transsphenoidal surgery for Cushing's disease.

After transnasal operations in Cushings syndrome persisting hypercortisolism either due to negative pituitary exploration or due to subtotal tumor removal, and recurrence of the disease after successful surgery still are challenging. We report on the therapeutic failures among 310 consecutive patients who underwent primary transsphenoidal microsurgery for Cushings disease. In 287 patients an ACTH-producing pituitary adenoma could be detected (finding rate: 92.6%). In 264 cases remission of hypercortisolism could be attained (remission rate with adenoma 92.0%, for the whole series of primary operations 85.2%). In 23 patients no adenoma could be found despite extensive pituitary exploration (7.4%). Here, we will focus on the management of the 23/287 patients with persistent hypercortisolism after transnasal tumor operation (8.0%) and those 29 cases of the 264 patients with a remission who developed a recurrence of hypercortisolism (11.0%). In recurrent hypercortisolism we recommend transsphenoidal reoperation even when no tumor is visible in MRI. Seventeen of 24 reoperations in recurrent Cushings disease were successful (70.8%). In persistent hypercortisolism we perform a reoperation during the same hospital stay. Nine of 16 early reoperations led to remission of hypercortisolism (56.3%). If transsphenoidal reoperation fails we indicate radiation therapy of different modalities depending on the extension and location of the tumor remnants. Bilateral adrenalectomy is proposed by us only if all other therapeutic measures failed.

Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery.

OBJECTIVE Pituitary tumors causing gigantism are rare in childhood and adolescence. In a review of 2367 patients with pituitary adenomas who were treated between 1970 and 1997, we found 15 cases (0.63%, 9 male and 6 female patients) of growth hormone-secreting pituitary adenomas in patients who were less than 20 years of age at the time of surgery, and we compared their characteristics with those of adenomas in an adult group. METHODS Patients were grouped according to their ages at the first operation, with five patients (33.3%) in the prepubescent group (0-11 yr), eight (53.3%) in the pubescent group (12-17 yr), and two (13.3%) in the postpubescent group (18-19 yr). All 15 patients exhibited the typical symptoms of growth hormone oversecretion. The incidence of hyperprolactinemia among patients with prepubescent onset was 66.7%. Radiological examinations demonstrated microadenomas in 4 patients (26.7%) and macroadenomas in 11 patients (73.3%). The mean follow-up period was 73.5 months. RESULTS Direct transnasal explorations were performed for all patients. Tumor invasion into the cavernous sinus was observed in six patients (40%). Radical tumor resection was performed for four patients (80%) in the prepubescent group, for five patients (62.5%) in the pubescent group, and for neither patient in the postpubescent group. Surgical morbidity was caused by permanent diabetes insipidus in three patients (20%). Rapid growth was postoperatively improved in 80% of the prepubescent age group. The recurrence rate was 13.3% (2 of 15 patients). CONCLUSION Transnasal pituitary surgery was found to be as safe in pediatric patients with gigantism as in adults. Growth hormone-secreting pituitary adenomas in childhood and adolescence were more likely to be invasive or aggressive than were those in adulthood. The clinical biological characteristics for children were different from those for adults.

Transnasal microsurgery in children and adolescents with Cushing's disease.

OBJECTIVE Transnasal adenomectomy is the treatment of choice for Cushings disease. We review the diagnostic peculiarities, specific surgical problems, and outcome of children and adolescents with Cushings disease. METHODS We report on our series of 55 consecutive children and adolescents (range, 4.2-18.9 yr [mean age, 14.4 yr]; female:male = 1.1:1.0; mean follow-up, 54.5 +/- 38.6 mo [standard deviation]) with Cushings disease on whom we performed surgery since 1980. The indication for transsphenoidal surgery is based on endocrinological parameters and not on neuroradiological findings. RESULTS Detection rate of the tumor site was 22% using computed tomography and 33% using magnetic resonance imaging. Only 7 of 13 interpetrosal adrenocorticotropic hormone gradients obtained during inferior petrosal sinus sampling correctly lateralized the tumor site preoperatively (53.8%). In cases of incomplete sphenoid pneumatization, adequate exposure is achieved by drilling. The tumor finding rate is 98%. The remission rate is 100% when two early subsequent operations are included. The recurrence rate for 45 primary operations with follow-up of at least 1 year is 15.5%. Seven of nine subsequent operations for recurrent hypercortisolism were successful. One patient needed three more operations until hypercortisolism subsided; one patient achieved remission after additional pituitary irradiation. The surgical morbidity was low in this series, which consisted of two cerebrospinal fluid fistulas. The incidence of hypopituitarism after primary operations (10.3%) is significantly lower than after subsequent operations (45.5%). CONCLUSION Direct transnasal submucosal surgery for Cushings disease is successful, and pituitary function can be preserved in most of these young patients.

Transnasal surgery for infradiaphragmatic craniopharyngiomas in pediatric patients.

OBJECTIVE Transnasal surgery has been performed in only a small number of cases of pediatric craniopharyngiomas, and its efficacy is still a matter of debate. METHODS We analyzed the results of transnasal surgery performed in 11 pediatric patients (6 male and 5 female patients) with infradiaphragmatic craniopharyngiomas who were younger than 15 years at the time of surgery (age range, 7.7-14.9 yr) and who were treated between 1985 and 1996, when more refined diagnostic and surgical techniques were available. Two of the patients had undergone primary surgery elsewhere. The transnasal approach was chosen because of sellar enlargement and the presence of an infradiaphragmatic tumor. The duration of the clinical follow-up period was at least 1 year. RESULTS Five patients required drilling of incompletely pneumatized sphenoid sinuses to reach the sella, but in no cases were the anatomic differences related to patient age or size thought to be a limiting factor in the transnasal procedure. The normal pituitary gland was incised to expose a dorsally located tumor in each of eight patients (72.7%). This surgical procedure has never provoked any major functional damage to the anterior pituitary gland. Complete tumor resection was achieved in three patients (27.3%) and subtotal removal in eight (72.7%). Twenty-two (95.7%) of 23 normal functions were preserved after subtotal tumor removal. In contrast, only one of four normal functions was maintained after complete tumor resection. Persistent diabetes insipidus occurred after total tumor resection in one patient. Tumor regrowth occurred in two patients. No tumor recurrence was observed during the follow-up period. CONCLUSION Based on the present findings, transnasal surgery seems to be indicated for most infradiaphragmatic craniopharyngiomas occurring in pediatric patients. Transnasal surgery is as safe to perform in pediatric patients as it is in adult patients. The concept of subtotal tumor removal with preservation of pituitary function, avoiding damage to hypothalamic structures and excessive cerebrospinal fluid leakage, seems to be justified in pediatric patients.

Proliferation Markers in Different Types of Clinically Non-Secreting Pituitary Adenomas

Abstract160 clinically non-secreting pituitary adenomas were examined in regard to their expression of the markers PCNA, bcl2, Ki 67 in the mib-1 modification and p53 which are still under investigation for their relevance to cell proliferation. The series contained 60 null cell adenomas, 60 oncocytomas and 40 gonadotroph adenomas. The groups that showed a definitely negative and definitely positive staining were evaluated in regard to their further characteristics such as size, invasiveness and recurrence. PCNA showed a highly represented immunostaining index throughout the groups, but not correlation between the PCNA index and an increased recurrence rate could be found. The staining for bcl2 was only rarely positive and only in a small number of cells. No correlation with the clinical data could be seen. We found a significant higher rate of staining in the invasive adenomas in the group of null cell adenomas and oncocytomas for Ki 67, especially in those adenomas expressing p53. p53 positivity was restricted to the invasive adenomas but was found only in 20% of all invasive adenomas. These data confirm in a sufficiently large series of clinically endocrine inactive pituitary adenomas, that p53 and Ki 67 immunohistology is usefull in evaluating the aggressive behavior of clinically silent pituitary adenomas. Nevertheless, negative results do not exclude clinically relevant invasive behavior.

Surgical Treatment of Clinically Nonsecreting Pituitary Adenomas in Elderly Patients

OBJECTIVEThe goal of this study was to evaluate the efficacy and safety of transsphenoidal pituitary surgery for elderly patients, using improved techniques of the past decade. METHODSWe retrospectively analyzed 32 surgically treated cases of clinically nonsecreting pituitary adenomas in patients more than 70 years of age (mean, 73.9 ± 3.4 yr). These patients were identified in a review of 982 patients with pituitary adenomas who were treated at University Hospital Eppendorf, Hamburg, between January 1991 and November 1999. RESULTSThe mean preoperative duration of symptoms was 1.9 years (2 wk to 11 yr). The chiasmatic syndrome was present for 27 patients (84.4%). All patients underwent transsphenoidal surgery. Seven patients underwent reoperations. Preoperative assessments of anterior pituitary function revealed growth hormone deficiencies for 21 of 27 patients (77.8%), thyroid insufficiencies for 10 of 30 patients (33.3%), and adrenal insufficiencies for 13 of 29 patients (44.8%). Hypogonadism and hyperprolactinemia were observed for 76.7% and 46.9% of the patients, respectively. All tumors were macroadenomas, ranging from 18 to 50 mm (average, 33.6 mm) in size, including 7 enclosed and 25 invasive adenomas. Complete microscopic tumor resection was achieved in 24 cases, and subtotal removal was performed in 8 cases. There were no severe perioperative complications. In the cases involving hyperprolactinemia, serum prolactin levels were normalized for 8 of 11 patients (72.7%). Normal thyroid function was recovered for 1 of 10 patients (10.0%) with preoperative hypothyroidism. However, growth hormone or adrenal insufficiencies persisted for all patients with preoperative insufficiencies. Visual disturbances were improved for 19 of 23 patients (82.6%). All patients recovered well after surgery, with an average hospital stay of 16.3 days. Histological and immunohistochemical studies demonstrated gonadotroph adenomas in 56.7% of cases, null-cell adenomas in 26.7%, and oncocytomas in 13.3%. CONCLUSIONSurgical treatment of nonsecreting pituitary adenomas causing visual disturbances is standard, even for elderly patients. In this series, transsphenoidal surgery was a safe procedure, with minimal morbidity and excellent tolerance. Age alone is not a contraindication for active treatment, particularly with transsphenoidal surgery.

Clinically nonsecreting pituitary adenomas in childhood and adolescence.

OBJECTIVE AND PATIENTS Clinically nonsecreting pituitary adenomas are rare in childhood and adolescence. We analyzed five cases of clinically nonsecreting pituitary adenomas in patients (4 male and 1 female patient) under 20 years of age at surgery (0.22%), identified by a review of 2288 patients with pituitary adenomas treated from 1970 to 1996 at the Hamburg University. CLINICAL PRESENTATION AND RESULTS Patient age at the onset of symptoms ranged from 8 to 13 years (mean, 10.8 yr), and age at surgery ranged from 12.5 to 19.5 years (mean, 15.5 yr). Two patients presented with endocrine symptoms, two with headache only, and one with a visual field defect. Endocrinological examinations showed pituitary insufficiency in two patients with endocrine symptoms. The serum prolactin level was normal in all patients. Radiological investigations demonstrated resectable macroadenomas with ring enhancement in four patients and a nonresectable macroadenoma with parasellar extension in one. Transnasal explorations achieved radical tumor resection except in one patient. The latter underwent a transcranial resection and radiotherapy because of parasellar tumor rest. Surgical morbidity consisted of left oculomotor nerve palsy after transcranial exploration. In two patients, normal pituitary function was preserved by transnasal surgery. Follow-up duration was 2 to 23 years (mean, 10.9 yr). There was no recurrence except for one parasellar adenoma. Immunohistological diagnosis was null cell adenoma in two patients, silent prolactinoma in two, and silent gonadotroph adenoma in one. The proliferative activity measured by Ki-67 (as the antibody MIB-1) and p53 expression revealed a positive reaction in one adenoma with parasellar extension. CONCLUSION Clinically nonsecreting pituitary adenomas in childhood and adolescence cause different endocrine symptoms from those in adults. They caused pubertal and growth delay and/or primary amenorrhea in the patients investigated in this study. Transnasal surgery in childhood and adolescence is as safe as in adults. The characteristics of nonsecreting pituitary adenomas in this age group, including 20 patients cited from the literature, do not differ from those in adults.

Recent primary transnasal surgical outcomes associated with intraoperative growth hormone measurement in acromegaly

Since 1983, we have measured GH intraoperatively to improve the surgical outcome for acromegalic patients with GH secreting pituitary adenomas. Here, we present the recent results of primary surgery in patients with acromegaly to examine the effect of improved surgical techniques and experience.