Anton de Haen (1704-1776) and his extraordinary "portentosum infundibulum" case: the futile skull cauterization of a blind patient with a craniopharyngioma.

Anton de Haen (1704-1776) became one of the most influential physicians in the Habsburg Empire as a reformer of clinical instruction at Vienna Citizen's Hospital (Bürgerspital), where he introduced the bedside teaching method he had learned from Herman Boerhaave in Leyden, Holland. He also promoted the meticulous recording of clinical observations and the use of postmortem studies to identify the cause of death in hospitalized patients. Among the numerous clinicopathological reports compiled in his monumental 18-volume work Rationis Medendi in Nosocomio Practico, published in 1761, was the first documented patient with amenorrhea caused by a pituitary tumor, appearing in the 6th volume. This 20-year-old amaurotic woman, who had suffered from chronic excruciating headache, died after the unsuccessful application of a cauterizing iron to her temporal bone. At the autopsy, a large solid-cystic and calcified tumor with gross characteristics typical of adamantinomatous craniopharyngioma was found encroaching on the infundibulum and third ventricle. This is the first known account of an infundibulo-tuberal lesion associated with the impairment of sexual functions, predating by 140 years the pathological evidence for a sexual brain center sited at the basal hypothalamus. In this paper, the authors analyze the historical importance and impact of de Haen's foundational report on the fields of neuroendocrinology and neurosurgery.

Coexisting lipomatous meningioma and glioblastoma in Cowden syndrome: A unique tumor association.

Cowden syndrome (CS) is a rare hereditary hamartoma-cancer disorder related to germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) gene. Association of CS with intracranial tumors, apart from Lhermitte-Duclos disease (LDD), is not well recognized. We present an exceptional instance of concomitant meningioma and glioblastoma in CS, the first case ever reported. Following a new-onset seizure, a 62-year-old male harboring the PTEN gene germline mutation c.334C > G was diagnosed with multiple brain tumors, which were erroneously thought to correspond to metastases. Because no primary cancer was found, an operation was proposed for histopathological diagnosis. Examination of surgical specimens obtained from the two lesions removed, one extra-axial and the other intracerebral, demonstrated a metaplastic meningioma with a lipomatous appearance and an isocitrate dehydrogenase wild-type glioblastoma, respectively. Loss of the PTEN gene expression was demonstrated immunohistochemically in both lesions, a finding that supports their relation to CS. A thorough literature review revealed only 25 additional CS patients with intracranial tumors other than LDD. All of them corresponded to primary lesions, with meningiomas accounting for 76% of the cases (19 patients), followed by pituitary tumors (three cases) and glioblastomas (two patients from the same family). Our report and literature review highlight the association between CS and primary brain tumors rather than metastasis. For judicious management of a CS patient with multiple intracranial tumors, different primary brain pathological entities should also be suspected first before considering metastasis. Close neurological monitoring and brain magnetic resonance imaging are advocated as part of the cancer screening in CS patients, particularly in cases with a family history of intracranial tumors.

Craniopharyngioma treatment: an updated summary of important clinicopathological concepts.

INTRODUCTION: Craniopharyngiomas (CPs) are benign histological tumors that may develop at different positions along the hypothalamic-pituitary axis. Their close, heterogenous relationship to the hypothalamus makes surgical removal challenging even though this remains the primary treatment strategy. AREAS COVERED: This article presents a critical overview of the pathological and clinical concepts regarding CPs that should be considered when planning treatment. Thus, we have performed a comprehensive review of detailed CP reports published between 1839 and 2020. EXPERT OPINION: CP surgery should pursue maximal tumor resection while minimizing the risk of injuring the hypothalamus. Therefore, surgical strategies should be individualized for each patient. Accurate assessment of presenting symptoms and preoperative MRI has proven useful to predict the type of CP-hypothalamus relationship that will be found during surgery. CPs with dense and extensive adhesions to the hypothalamus should be highly suspected when MRI shows the hypothalamus positioned around the mid-third of the tumor and an amputated upper portion of the pituitary stalk. Symptoms related to functional impairment of the infundibulo-tuberal area of the third ventricle floor, such as obesity/hyperphagia, Fröhlich's syndrome, diabetes insipidus, and/or somnolence, also indicate risky CP-hypothalamic adhesions. In these cases, limited tumor removal is strongly advocated followed by radiation therapy.

Joseph Engel (1816-1899), author of a meaningful dissertation on tumors of the pituitary infundibulum: his report on the oldest preserved whole craniopharyngioma specimen.

Joseph Engel (1816-1899) was a Viennese anatomist and pathologist trained under the mentorship of Carl von Rokitansky (1804-1878), the man who laid the foundations of gross anatomical pathology. In 1839, Engel completed his first scientific project: the dissertation entitled "Über den Hirnanhang und den Trichter" (About the pituitary gland and the infundibulum). This work analyzed the pathological and clinical characteristics of the pituitary and infundibulum tumor specimens collected at the Vienna Pathologic-Anatomical Museum. This little-known work represents one of the earliest attempts to determine the function of the pituitary gland-infundibulum complex. Among the 12 pituitary/infundibulum tumors examined in Engel's dissertation, one of the cases (no. 10) was instrumental for the definition of hypophyseal duct tumors, or craniopharyngiomas (CPs). This huge cyst, approximately the size of a goose egg (6 × 6 × 4.5 cm), was found in 1828 during the autopsy of a 33-year-old patient who suffered from severe headache, blindness, apathy, and finally somnolence. The cyst had replaced the hypophysis and extended upwards into the hypothalamic region and downwards into the sphenoid sinus, its inferior pole protruding through the soft palate. In 1904, the Viennese pathologist Jakob Erdheim (1874-1937) re-examined this lesion and conclusively categorized it as a hypophyseal duct tumor after a detailed histological study. The original tumor specimen corresponding to this CP case is still preserved at the Narrenturm, the circular building within the old Allgemeines Krankenhaus (Vienna General Hospital) that today holds the pathological collections of Vienna's Federal Pathologic-Anatomical Museum. To the best of our knowledge, this tumor is very probably the oldest preserved whole CP specimen in the world. This paper presents a comprehensive review of Engel's dissertation, the pioneering pathological work on pituitary and infundibulum tumors which laid the groundwork for the proper clinical, topographic, and pathological categorization of craniopharyngiomas.

Craniopharyngioma adherence: a reappraisal of the evidence.

Craniopharyngioma (CP) adherence represents a most baffling problem for the neurosurgeon. The highest priority of current surgical treatment is to maximize tumor removal without compromising the patients' long-term functional outcome. Surgical damage to the hypothalamus may be avoided or at least ameliorated with a precise knowledge regarding the type of adherence for each case. This article presents a comprehensive review of the pathological, surgical, and radiological sources of evidence supporting that CP adherence, despite being heterogenous, is characterized by repeating patterns. The key underlying factors of CP adherence are also discussed. Three components define the type of adherence for each case: (i) the intracranial structures attached to the tumor, (ii) the adherence morphology, and (iii) the adhesion strength. Combination of these three components gives rise to five hierarchical levels of increased risk of hypothalamic injury during tumor removal. Tumor topography has been identified as the major predictor of the type of CP adherence. The most extensive and strongest adhesions to the hypothalamus occur in CPs originated in the suprasellar cistern that secondarily invade the third ventricle (secondary intraventricular CPs) and in those originated within the third ventricle floor itself (not-strictly intraventricular CPs). Three findings observed on preoperative conventional MRI scans have proven to be reliable predictors of adherence severity. A position of the hypothalamus around the middle portion of the tumor, an amputated pituitary stalk, and an elliptical tumor shape points to the severe and critical risk levels, and in those cases, a safer limited removal is strongly recommended.

Cystic tumors of the pituitary infundibulum: seminal autopsy specimens (1899 to 1904) that allowed clinical-pathological craniopharyngioma characterization.

A heterogeneous group of epithelial cystic tumors developed at the infundibulum and the third ventricle disconcerted pathologists at the dawn of the twentieth century. Very little was known at that time about the physiological role played by the pituitary gland, and there was almost complete ignorance regarding the function of the hypothalamus. Acromegaly, or enlargement of acral body parts, described in 1886 by Pierre Marie, was the only disease linked to primary hypertrophies of the pituitary gland, known as "pituitary strumas". A growing number of young patients manifesting an unexplained combination of physical and mental symptoms, including absent or delayed sexual maturation, progressive obesity, abnormal somnolence, and dementia-like changes in behavior were reported to present large solid-cystic tumors which characteristically expanded within the infundibulum and third ventricle, above an anatomically intact pituitary gland. Between 1899 and 1904, five seminal autopsy studies from different countries thoroughly described the anatomical relationships and histological features of this newly recognized type of infundibular tumors. These cases were instrumental in fostering the systematic investigation of similar lesions by the Austrian pathologist Jakob Erdheim (1874-1937), who in 1904 was able to classify these infundibulo-tuberal cysts under the common category of hypophyseal duct tumors. The pioneering American neurosurgeon Harvey Cushing (1869-1939) unsuccessfully attempted to surgically remove one of these cysts, for the first time in history, in 1902. The term "craniopharyngioma", chosen by Cushing in 1929 to designate these lesions, would eventually prevail over Erdheim's more accurate denomination, which linked their origin to squamous cell remnants derived from the embryological structures that give rise to the pituitary gland. This paper presents a comprehensive, renewed account of the five clinical-pathological reports which laid the groundwork for the proper clinical diagnosis, topographic conceptualization and pathological categorization of craniopharyngiomas.

Current status of artemisinin-resistant falciparum malaria in South Asia: a randomized controlled artesunate monotherapy trial in Bangladesh.

OBJECTIVE: Recent reports indicate that first cases of genuine artemisinin resistance have already emerged along the Thai-Cambodian border. The main objective of this trial was to track the potential emergence of artemisinin resistance in Bangladesh, which in terms of drug resistance forms a gateway to the Indian subcontinent. METHODS: We conducted an open-label, randomized, controlled 42-day clinical trial in Southeastern Bangladesh to investigate the potential spread of clinical artemisinin resistance from Southeast Asia. A total of 126 uncomplicated falciparum malaria patients were randomized to one of 3 treatment arms (artesunate monotherapy with 2 or 4 mg/kg/day once daily or quinine plus doxycycline TID for 7 days). Only cases fulfilling a stringent set of criteria were considered as being artemisinin-resistant. FINDINGS: The 28-day and 42-day cure rates in the artesunate monotherapy (2 and 4 mg/kg) and quinine/doxycyline arms were 97.8% (95% confidence interval, CI: 87.8-99.8%), 100% (95% CI: 91.1-100%), and 100% (95% CI: 83.4-100%), respectively. One case of re-infection was seen in the artesunate high dose arm, and a single case of recrudescence was observed in the low dose group on day 26. No differences in median parasite and fever clearance times were found between the 2 artesunate arms (29.8 h and 17.9 h vs. 29.5 h and 19.1 h). Not a single case fulfilled our criteria of artemisinin resistance. Parasite clearance times were considerably shorter and ex vivo results indicate significantly higher susceptibility (50% inhibitory concentration for dihydroartemisinin was 1.10 nM; 95% CI: 0.95-1.28 nM) to artemisinins as compared to SE-Asia. CONCLUSION: There is currently no indication that artemisinin resistance has reached Bangladesh. However, the fact that resistance has recently been reported from nearby Myanmar indicates an urgent need for close monitoring of artemisinin resistance in the region. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639873.