Morphological Researches Concerned Of The Pattern Of The Growth Of Pituitary Adenoma

Part I:Pathologic study on the effect of pituitary adenoma on sella floor's duraBackgroundAccording to biological behaviour, pituitary adenoma is classfied into pituitary adenoma and invasive pituitary adenoma (IPA). Since invasive pituitary adenoma (IPA) was proposed by Jefferson in 1940, there have been controversies in its concept, diagnostic criteria and incidence rate, with different reports from medical institutions. At first it was defined as "the pituitary adenoma grows to break its envelope and to invade the adjacent structures such as the dura, the optic nerve, bone and so on." Then it was defined as the pituitary tumors that grew to break its envelope or invade the adjacent structures by Martins et al. in 1965.While the invasive pituitary adenoma was classified as the interim type between pituitary tumor and pituitary cancer by Scheithauer, and it was also thought that the pituitary adenoma, pituitary tumor and pituitary cancer could not be completely distinguished in histology, the differences of the three lie only in the biological behaviors. Others thought that there were no strict boundaries between the invasive pituitary adenoma and non-invasive pituitary adenomas, the differences were dependent on the strength of invasion. The uniform objective criteria to effectively diagnose the invasive pituitary adenoma were still lacking, although there were many pathologic criteria, imaging criteria and operative standards, they still have considerable controversies. Just because of the diversity of the IPA concept and diagnostic criteria, the reports on IPA were very different, so far, the incidence rate of IPA was reported as 6%-85% The complex and confusing of the IPA concept and diagnostic criteria have affected the treatments and strategies of surgeons, leading to the unsatisfactory resection rate of IPA and the unsatisfactory improvement of post-operation clinical symptoms. To clearly confirm the properties of IPA invasion signs would have very important clinical significances, so the present study was designed.The researches of IPA were focused on the improvement to the ways of clinical surgery, and the summary of clinical effects, as well as the molecular biology of the basic researches, especially the researches on genetics and invasion indicators, the studies on pathomorphology were fewer. Many studies have noted the invasion of tumor to the dura, but only based on the subjective judgments of the rough sense of the dura felt by the surgeon intraoperatively and on the brief observation on the invasion of tumors to the dura.Not only have the relationship between tumor and the pituitary capsule not been mentioned, but also most of the pathology materials were taken from the craniotomy and only limited to the tumor tissue itself. In this present study, "adenoma+membrane" specimen was got by the transsphenoidal approach used commonly and the relations between adenoma, pituitary cupsule and dura were obsevered, which has not been reported, and is of great clinial significance.ObjectiveIn this study, the "tumor +membrane" (the dura mater of sellar floor on one side, the tumor tissues on another side) specimen was obtained by the transsphenoidal approach, the relationship was observed between tumor cells, the pituitary capsule and dura, and the invasion signs of pituitary adenoma was explored. And this study can provide pathologic basis for further study on the pattern of growth of pituitary adenoma.Materials and MethodsThe 30 pituitary adenoma specimens were from the patients who accepted the inpatient treatment in the neurosurgical department of nanfang hospital of Southern Medical University:21 males and 9 females; age from 20 to 76 years old, average age was 48.3 years, the average disease duration was 2.9 years; 20 cases had headache,21 cases had visual disorder,8 cases had menstrual disorders or amenorrhea and lactation,5 cases had diabetes insipidus,4 cases had acromegaly,3 cases had central obesity,3 cases had loss of libido,10 cases had lethargy,1 case had tumors who was accidentally discovered in the physical examination; The pathological types:9 cases of PRL type,4 cases of GH type,2 cases of ACTH,10 cases of the mixed hormone expression type,5 cases of non-functional type, of which 3 cases were the zero hormone expression type.All patients available should be conducted the MRI head scans, CT examination, including the scans to the nasal cavity and the axial and coronal positions of paranasal sinuses, to understand the structure of the nasal cavity, the extent of sphenoid gasification and the situation of separation and its symmetry; MRI scan was used to observe the shape, size and the expansion direction of tumors. The invasiveness of adenoma should be judged according to Hardy-Wilson classification and/or Knosp classification, the pituitary adenomas above the Hardy-Wilson standardⅢ-Ⅳlevel and (or) pituitary adenoma of C～E phase and Knosp classification 3-4 level were considered as the IPA. In the pituitary tumors of the selected 30 patients,3 case was consistent with Hardy-Wilson StandardⅢlevel,14 cases were C phase,5 cases were D phase,9 cases were E phase; 7 cases were consistent with Knosp classification 3 level,5 cases were of 4 level. All of them were in line with the IPA standard.The operation methods to all the patients in this group or the operation methods of their first surgery were used transsphenoidal approach by virtu of endoscope. When the dura was seen, the specimen was like-tetragonal body cutted by dagger with dura mater on one side and tumor on another side, and the specimen was put into 10% formalin to be futher deal with.Following the fixing,embedding,dehydrating and slicing,the specimens were stained by H.E.and Massion's triple. Under the Olympus-DP70 inverted microscope (Germany), the relationship between the tumor tissues and pituitary capsule, dura should be carefully observed and recorded. The thicknesses of pituitary capsule were measured as follows:5 points were selected for each case, taking the average value, compared with the normal thickness of pituitary capsule measured in the past by our research group.Statistical method was t-test, and conducted on the software spss13.0.ResultsThe tumors were almost removed in the I phase surgery. Of the all cases,28 cases have improved the clinical symptoms or remained the stability; 1 case (74 years old) have been conducted the hematoma drainage hole surgical due to postoperative chronic subdural hematoma; 1 case has lost information after operation. The compressed and distorted peritumoral structure was oberved being reposited clearly in 15 cases through the post-operation Imaging review. No patients suffered death, postoperative cerebrospinal fluid leakage, meningitis or visual deterioration.The materials of 28 cases were in line with the experimental requirements among the 30 cases. The staining to the specimen was satisfactory. The slices should be observed carefully by the inverted microscope,The pathological results showed the pituitary capsule with different thickness could be identified in 25 specimens, however, the thickness was 0.16±0.07mm, being statistically less than the thickness of the normal pituitary capsule (t=21.998, p=0.000).The pituitary capsules of 2 cases were suspected to be invaded by tumor cell, but the pituitary capsules were integrated, without being broken by suspect tumor cells. The dural maters of all cases were integrated, without being infiltrated by tumor cells. In 19 cases, a distinguished gap between the dura and pituitary capsule (envelope gap) can be obviously identified with variant sizes, the rest envelope gaps were hard to identify. It could also be found that besides pituitary cupsule with different thicknesses, envelop gap with different sizes and dura without tumor cells were been seen.Thicknesses of IPA is thinner than normal (t=21.998, P= 0.000).ConclusionsIn this study, the "tumor +membrane" (the dura mater of sellar floor on one side, the tumor tissues on another side) specimen was obtained by the transsphenoidal approach by virtu of endoscope, the relationship was observed pathologicly between tumor cells, Combined with the relevant literatures, conclusions can be drawn as follows:1. In order to study the relationship between tumor and peritumoral dura, it was not only reasonable but feasible obtaining the specimen of "tumor+membrane" from the sellar floor, which can reflect the real relationship (ie. invasive sign) between pituiary adenoma and peritumoral structures in other directions;2. The membranous structures around the IPA tumors still exist in all cases, which indicates the traditional concept of "invasion" is not accurate with big possibility. The suspect tumor cells found in pituitary capsule may be the main reason to misjudge the invasion.3. It seems that the invasivness of pituitary adenoma has nothing to do with types of hormones, age and gender;4. There are obvious discrepancies between pathological diagnosis and imaging diagnosis.5. Currently, some views about the IPA is worth thinking, discussing and improving; there are great possibilities that the pattern of growth of pituitary adenoma is expansivness,not invasivness.6. The influence factors about the pattern of growth of are deserved to be further explored.PartⅡ:Morphological characteristics of later bone window (LBW) and carotid sulcus (CAS) and their relations with the pattern of growth of pituitary adenomaBackgroundSella turcica lies in the center of the skull base, It is generally believed that the scope of the sella turcica is:the former boundary is the lateral border of clinoid process and the front edge of chiasmatic sulcus; the posterior boundary is posterior clinoid process and dorsum sellae; and carotid sulcus lies in both sides of sella turcica. Owing to its complex and unique anatomical features, sella turcica was ever thought to be blind and restricted region of neurosurgery operation. With the micro-surgery being carried out generally, morphological study of the region has aleadly been put into attention,too.Sellar pituitary adenoma is the most common tumor, according to the different biological behavior of pituitary adenomas, it is divided into invasive pituitary adenomas and non-invasive pituitary adenomas. The researches of IPA were focused on the improvement to the ways of clinical surgery, and the summary of clinical effects, as well as the molecular biology of the basic researches, especially the researches on genetics and invasion indicators. There are many literatures and monograph of microscopic anatomy of the sella turcica,however, after a overall review of the literatures concerned, it was found that morphological characteristics of lateral bone window(LBW) and carotid sulcus(CAS) and their relations with the growth pattern of pituitary adenoma haven't ever been studied.In the present reasearch, on one hand, samples of adult dry skull base of chinese were collected, with the help of associated software, the value of area LBW was measured successfully, which could provide important data for anotomical study of sella turcica. At the same time, morphological characteristics of LBW were first described and classified, and combined with the clinical literature, its relations with the growth pattern of pituitary adenoma was explored, particularly when pituitary adenoma grows into the parasellar area (cavernous sinus). On the other hand, CAS is important sellar bone structure existing in both lateral sides of sella turcica, although there were severa anatomical study, its classification of the clinical application was not still reported. In this article, CAS was diveded into four types, combined with imaging data of sellar CT scan, in the first time, from the view of the its relations with the expandsive "hobby" of pituitary adenoma particularly when pituitary adenoma grows into the parasellar area (cavernous sinus); Futhermore, its relations with the growth pattern of pituitary adenoma was explored. This study will be greatly statistical antomically and clinically.ObjectiveIn this study, detailed observation and description of the morphological characteristics of LBW and CAS are about to provide morphological study of sella trucica with important data and chinese physical investigations with anatomical data and references; Futhermore, relations were explored between LBW, CAS and the pattern of the growth of pituitary adenoma, in order to provides anatomic bases for the "hobby" of parasellar extension of pituitary adenoma.Materials and Methods1.Specimen for measurementAdult dry skulls were collected from department of anatomy of a few home medical schools, delt with conventionally and sawed open from superciliary arch to 1cm above the occipital skull carina, in order to expose the view of the inner surface of the skull base.530 cases were selected with relatively complete bony structures. Besides,50 cases (including 100 side) saddle thin sagittal reconstruction of coronal CT scan images (mainly for observation CAS classification) were observed and measured. Typical samples and pictures were photoed, reserved for archive to get ready for follow-up use.2. Contents of measurementContents of measurement in this study are as follows:①The value of LBW area was measured, the correlation between both LBW areas and the correlation between LBW and depth of sella turcica were analyzed;②APD (distance between anterior clinoid process and posterior process), MTD (maximum traverse diameter) and MLD (maximum longitudinal diameter) were observed and measured;③Occurrence characteristics of STB (sella turica bridge) and MCP (middle clinoid process) were observed and measured;④LBW was classified and typed according to relevant data and shapes;⑤LBH (height of latera bone) was measured, ie. between the highest point of LBW bottom to sellar floor;⑥Length of CAS was measured(which can indirectly reflect the length of cavernous segment of internal carotid artery);⑦CAS arc level got quantitativly classified (which can indirectly reflect the CAS package degree of internal carotid artery).3. Methods of measurement Measurement of LBW was accomplished with the main aid of plasticine, caliper, camera and software ImageJ; morphological classification of CAS:along CAS arc, a circle was drawn and divided into 12 equal parts, namely each arc is 30 degree, by which, degree of CAS arc can be determined, reflect ing tdegree of CAS on the CA package (detailed descriptions can be seen in the results).4. Statistical processAll data processing were carried out in SPSS 13.0 statistical software. Mean of measurement data was compared with t-test; data correlations were analyzed using Pearson orrelationwith analysis. The criterion for statistical significance for all tests was P<0.05.Results(I) Morphological characteristics of LBW1. Concept, location and composition of LBWLBW is like a window, located in lateral bony structure of sella turcica, including left LBW and right one. The upper bound is the connection level of anterior clinoid process and posterior clinoid process, the lower bound is the inner edge of carotid sulcus, the front bound is posterior border of the optic nerve column, and the posterior bound is the lateral border of dorsum sellae. Sometimes there are MCP and STB inside LBW, when STB appears, which is the connection between elinoid processes, the upper bound of LBW is the lower of STB; when the MCP and anterior clinoid process form carotico-clinoid foramen henle (CCFH), the front bound of LBW is the front border of CCFH.2. Area and classification o f LBWLeft area value of LBW is 75.99±25.81mm2, and right area value is 76.00±25.53 mm2. STD (depth of sella turica) is 11.00±1.82mm, ie, distance from midpoint of the line from sphenoidal limbus to the highest point of dorsum sellae to the sellar floor; there are no statistical difference between bilateral areas of LBW (paired t-test, t=0.03.p=0.998); there is a good positive correlation between bilateral areas of LBW (pearson correlation analysis, r=0.638) and a weak positive correlation between bilateral area of LBW and STD (pearson correlation analysis, the left r=0.214, the right r=0.180);Based on the measured results as above, LBW size can be graded as follows: Grade A is LBW area of less than 60 mm2 (20% patients in this group); Grade B is LBW area between 60 mm2 to 90 mm2 (60% patients in this group); Grade C is LBW area larger than 90 mm (20% patients in this group).3. Morphology of LBWIn this study, in order to observe morphology of LBW, three factors were mainly considered as follws:APD (distance between anterior clinoid process and posterior process), MCP (middle clinoid process)and formation of STB (sella turica bridge).According to overall observation results, LBW can be typed as follows:TypeⅠ(open type):APD larger than half MTD;TypeⅡ(half-open type):APD larger than one fourth MTD,smaller than half MTD;TypeⅢ(complete type):APD smaller than one fourth MTD, including typeⅢa(relatively intact type) and typeⅢb(absolutly intact type);Ⅲb means that APD equal to zero or that STB appears;TypeⅢ(obexlike type):inside LBW, MCP appears, like a obex of a door. According to shape and size of MCP and combined with classification of CCFH by keyes, this type can be typed again as follows:Ⅳa(equivalent to complete type CCFH);Ⅳb(equivalent to contact type CCFH);Ⅳc(equivalent to incomplete type CCFH) IVd(ie, complete type LBW plus complete type CCFH).4.Measurment of LBHLBH (height of latera bone) with different values lies in the bottom edge of LBW just like a latch of a door. The values:Left LBH is 1.23±0.79mm, right LBH is 1.22±0.82mm; there is no statistical difference beteen bilateral LBH (paired t-test, t=1.388.p= 0.166).(Ⅱ) Morphological characteristics of CAS1. Location, shapes and adjacent structures of CASCarotid sulcus (CAS) lies in the lateral wall, one on each side and carotid cavernous segment (C4) of ICA lies inside it; Most shapes of CAS is straight, and few shapes is like "S"; The front edge of CAS is the migration department between cavernous segment and knee segent of ICA, and the later edge is the front edge of foramen lacerum; the inner edge is the lateral border of the pituitary fossa, ie. the lower edge of LBW, and its lateral margin is adjacent to middle cranial fossa; both ends of CAS is the deepest, and the middle segent of CAS is the most shallow, even sometimes it is flat,sulcus's shape is not obvious.2. Measurment of CASCASL (length of CAS):left CASL is 19.83±1.87mm, right CASL is 20.45±1.84mm; there is statistical difference beteen bilateral CASL(paired t-test, t=-8.032. p=0.000),and right CASL is longer than left CASL.3. Typing of CASSpecific measurement was accomplished in the thin sagittal reconstruction of coronal CT scan images of normal adults. In the mid-coronal CT scan, circle was drawn according to the degree arc of CAS (for the convenience of drawing, CT picture can be enlarged to be easy see clear CAS, and to be measured). Then the circle was divided into 12 equal portions, Line between point A (inner highest point of CAS), point B(outer highest point of CAS) and point O (center point of the circle) was linked respectively, and then angle AOB formed; the degree of angle AOB was obsevered, which not only reflect the depth of CAS, but also the width of CAS.Based on measurement,CAS was typed as follows:TypeⅠ:arc degree of CAS is less than 30°(42 side,42%);TypeⅡ:arc degree of CAS is between 30°and 60°(33 side,33%);TypeⅢ:arc degree of CAS is at between 60°and 90°(19 sides,19%);TypeⅣ:arc degree of CAS is greater than 90°(6 sides,6%).ConclusionsIn this study, detailed observation and description of the morphological characteristics of LBW and CAS were carried in dry skull base of normal adults and the thin sagittal reconstruction of coronal CT scan images of normal adults; their relations with the growth pattern of pituitary adenomas(especially pituitary adenoma growing parasellarly into cavernous sinus) were explored and analyzed. Combined with literature review, the following conclusions can be drawn:1. This study provided morphological study of sella trucica with important data and chinese physical investigations with anatomical data and reference;2. Anatomic factors of LBW,CAS and etc. of sella turcica can affect to different degrees the growth pattern of pituitary adenoma, especially, especially pituitary adenoma growing parasellarly into cavernous sinus. With regard to LBW,,as a "throat" of between pituitary adenoma and parasellar structures (cavernous sinus),its areas and shapes have close relationship with tumors expanding through LBW, big area can benefit tumors expanding parasellarly more "smoothly " than small area; and cancer by level of difficulty should be closely related area is greater than the small area were "; Resistance from typeⅠ,Ⅱ,Ⅲa,Ⅲb,Ⅳa,Ⅳb,Ⅳc,Ⅳd of LBW should become biger and biger to pituitary adenoma growing parasellarly into cavernous sinus; With regard to CAS, from type A to type D, resistance should become gradully to baffle tumor to encase ICA; APD's "Skylight" function, STB's "fence" effect, MCP's "latch" role, LBH's "threshold" effect and CCFH'"hoop" effect on ICA's is worth considering when cavernous sinus invasion of pituitary adenomas is defined, because the studies show that the incidence can not be ignored;3. None of definition standards of IPA used commonly, particularly for the diagnosis criteria of cavernous sinus invasion of pituitary adenomas, takes into account anatomical impact factors of sella turcica such as LBW, CAS and etc., which preliminarily indicates these diagnostic criteria are in short of conscientiousness.4.Combined with literatures, it seems that sella anatomic factors appear to be used to explain the features of growth patterns of pituitary adenoma;5. Disputes among the diagnostic criteria of IPA and discrepancies of IPA incidence from various reports exist,which suggests that diagnostic criteria be uniformed and improved as soon as possible;6. it is worth futher study on the factors that can affect growth pattern of pituitary adenomas.