Ulrich J. Knappe

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.

Cushing's disease: a surgical view; This Publication is dedicated to our professor emeritus Dr. med. Rudolf Kautzky

The management of adrenocorticotropic hormone (ACTH)-dependent Cushings disease implies difficulties in the differential diagnosis, in the detection of minute pituitary adenomas, as well as in the radical removal of invasive adenomas. Magnetic resonance imaging (MRI) is unspecific and often negative in minute adenomas of three or less millimeters diameter. The trias of detectable ACTH, suppression of cortisol in the high-dose dexamethasone test, and stimulation in the corticotropin-releasing-hormone (CRH)-test has a high accuracy to prove pituitary dependency. In unclear cases, the use of inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS) for the exclusion of ectopic ACTH-syndrome is currently advised especially in cases where cranial MRI is negative. The reliability of these methods to localize the mostly lateralized microadenomas is still discussed. Transsphenoidal microsurgical adenomectomy, the accepted primary therapy of Cushings disease, has been published from experienced pituitary centers with remission rates ranging from 70% to 98% in the last decade. False diagnosis (pseudo-Cushing, ectopic ACTH-syndrome), incorrect adenoma localization by IPSS or CSS, and the rate of minute or non-resectable invasive tumors influence the results. The handling of minute specimen implies problems for surgeon and pathologist. Intraoperative tumor localization was improved by ACTH measurement from the cavernous sinus and the adenoma itself, by cytology, and frozen sections. The histology of the anterior lobe (rate of Crookes cells) bears information of clinical relevance. Invasive macroadenomas may deserve repeat microsurgery, medical treatment, and radiosurgery.

Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue.

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushings disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.

Pituitary Surgery in Elderly Patients with Acromegaly

Because of the common belief that there is an increase in surgical risk and morbidity involved in the surgical therapy of elderly patients with acromegaly, physicians tend to either neglect therapy altogether or choose radiation therapy combined with medical treatment. In consideration of the expected increasing number of elderly patients resulting from social structure change in the coming years, we decided to investigate the outcome in 15 patients with acromegaly (13 women and 2 men) older than 64 years (mean, 68.3 yr) at the time of surgery in the form of a retrospective study. Medical treatment using either dopamine agonists (9 patients) and/or octreotide (4 patients) were attempted in 11 patients. For various reasons, however, medical therapy could not be permanently continued in any of these patients. The mean preoperative growth hormone (GH)-plasma level without medical treatment was 47.4 +/- 64.2 (mean +/- standard deviation) micrograms/L. At the time of operation, 13 of 15 patients had additional diseases, which led to an increased anesthesiological risk. Transnasal tumor removal was performed without anesthesiological or surgical complications in all patients. The radicality of tumor removal was controlled intraoperatively by GH measurements in eight patients. There was no postoperative mortality or serious morbidity. Postoperative basal GH-plasma levels were normal (< 4.5 micrograms/L) in all patients. None of the 13 patients who participated in long-term follow-up examinations (mean, 4.2 yr) revealed signs of definite tumor recurrence. The mean GH-plasma level at follow-up was 1.6 +/- 0.9 (mean +/- standard deviation) micrograms/L. One patient died 2 years after the operation of causes unrelated to pituitary surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct intraoperative micromethod for hormone measurements of pituitary tissue in Cushing's disease.

BACKGROUND During transsphenoidal surgery (TSS) for Cushings disease, the surgeon depends on experience to find minute adenomas. Cytological slide preparations or frozen sections, even when successful, are not specific concerning the hormone activity. In an attempt to improve accurate localization of minute ACTH adenomas, we evaluated a new intraoperative method of ACTH measurements in adenoma and anterior lobe microsamples. As most ACTH adenomas are monohormonal, the possible benefit of a GH measurement was investigated. METHODS We included pituitary tissue of 32 patients, 22 with Cushings disease and 10 endocrine inactive pituitary adenomas as control. All patients underwent TSS by one surgeon. Preoperative data, intraoperative and perioperative hormone measurements of homogenized, weighed pituitary tissue samples, and histological findings are presented. RESULTS In ACTH adenomas, the median ACTH content was found to be 1,688 ng/mg, minimum 345 ng/mg. The median GH was measured at 36 ng/mg. Anterior lobe tissue contained median 80 ng ACTH/mg, maximum 279 ng/mg. Median GH was 2,200 ng/mg. In hormonally inactive adenomas ACTH was less than 0.1 ng/mg, median GH was 5.5 ng/mg. There was no overlap of ACTH content in the tissues investigated. Therefore, by adopting 300 ng ACTH/mg as a cutoff level, a clear discrimination is given. Additional GH measurements are not necessary. CONCLUSION This new intraoperative method permits a clear differentiation between adenoma and pituitary tissue. In addition to intraoperative cytology and histology, this method can serve as a specific proof that the ACTH adenoma has been identified during surgery. This may be valuable in difficult cases with unclear intraoperative findings, especially after previously negative exploration.

Treatment and Long-Term Outcome of Pineal Nongerminomatous Germ Cell Tumors

In 1994 we reported on a small series of 3 children with malignant, marker-positive pineal nongerminomatous germ cell tumors treated with a ‘sandwich’ protocol. Here, we report on the long-term survival of these children. Preoperative chemotherapy consisted of two courses of bleomycin, etoposide, and cisplatin. En bloc resection of the tumors via the supracerebellar, infratentorial route was performed immediately after decline of tumor marker levels. Postoperatively, two courses of vinblastine, ifosfamide, and cisplatin were applied, followed by craniospinal irradiation. The patients showed no major neurological deficits and no evidence (neuroradiologically or with regard to tumor marker levels) of recurrence of disease after 66, 71, and 78 months, respectively. We propose this regimen for children with tumors of the pineal region in whom the tumor markers are positive. It should be started without histological classification of the tumor to avoid possible spillage of malignant tumor cells to the cerebrospinal fluid.

Autoradiographic demonstration of in vivo 125I-growth hormone-releasing hormone (GHRH) binding by human GH-secreting pituitary adenomas transplanted on athymic nude mice

This study was designed for the purpose of investigating a method for in vivo tumor labelling of human GH (hGH) secreting pituitary adenomas. Pituitary adenoma tissue removed from four acromegalic patients was transplanted into 62 athymic nude mice. After positive GHRH stimulation tests 125I-GHRH(1-44) NH2 was injected intravenously (i.v.) in ten nude mice. 10 min after 125I-GHRH injection, the nude mice were sacrificed, the transplants excised and prepared for light microscopical autoradiography. The mouse pituitary and skeletal muscle specimens served as controls. After the i.v. injection of 125I-GHRH we observed a marked accumulation of silver grains within the adenoma tissue indicating tumor labelling. This study is a first step in investigating a new method for labelling small residues of hGH secreting pituitary adenomas intraoperatively.

A personal series of 100 children operated for Cushing's disease (CD): optimizing minimally invasive diagnosis and transnasal surgery to achieve nearly 100% remission including reoperations.

Abstract Background Transnasal surgery (TNS) is the first choice in the treatment of pediatric Cushing’s disease. The question is how can high remission rates be achieved with minimally invasive investigations and TNS whilst avoiding radiotherapy or bilateral adrenalectomy in children. Methods Data from a published series 1 (n=55) of surgeon DKL will be compared with his recent series 2 (n=45) until 2009. All patients were operated by direct transnasal microsurgery. Over time, inferior petrosal sinus sampling (IPSS) was replaced by cavernous sinus sampling (CSS), restricted to unclear cases without increase of salivary cortisol in corticotropin-releasing hormone-test, difficult sellar anatomy or negative magnetic resonance imaging (MRI). Multiple direct intra-operative micro-cytology, micro-doppler and adequate visualization techniques are described. Results In series 1, IPSS was performed in 13 (24%) of whom 46% had false adenoma lateralization. All adenomas could be removed with extensive pituitary exploration. Three patients had early successful re-surgery. In series 2, with more refined MRI and endocrinology, CSS was used in only seven patients (15%) and all micro-adenomas were correctly localized. In three of four patients with persistent cortisol excess, repeat-TNS was necessary and successful. Side effects of TNS were minimal. Recurrence rates were 16% and 11% in series 1 and 2, respectively. Only four of 100 children with invasive adenomas were irradiated, significantly less than in other experienced pediatric centers. Conclusions Thus, 98% remission rate could be achieved with fewer invasive pre-surgical investigations, such as central catheter studies, refined TNS and early repeat-TNS. Repeat-TNS in recurrences minimized the need for irradiation.