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Topographical variations of the incisive canal and nasopalatine duct in human fetuses

The incisive canal for nerves and vessels is generally thought to run along a suture between the incisive bone (IN) and maxilla. In contrast, there was a report saying the canal passes through the IN or primary palate in human fetuses. Examination of sagittal and frontal sections from 69 fetuses (31 of gestational age [GA] 9–15 weeks and 38 of GA 26–34 weeks) showed that the canal often penetrated the IN at the nasal half of its course and that, in other fetuses, the canal penetrated the IN along its entire course, irrespective of involvement of the nasopalatine duct. Canals developing in and corresponding to parts of the suture resulted in partial enlargement of the thin and tight sutures, which contained loose tissue, vessels, nerves and even a duct. Small processes of the IN were identified as upper irregular parts continuous with inferior main masses of bone in frontal sections but as bone fragments in sagittal sections. In some sections, a thin layer of the maxilla along the canal covered the medial or inferior aspect of the IN. Therefore, the incisive canal with or without duct exhibited a spectrum of variations in topographical relation to the IN-maxillary border. Because the primitive oronasal communication passes through the suture, the nasopalatine duct may have originated from the secondary developed elongation of the nasal epithelium at midterm. A large incisive fossa along the midline on the oral surface of the palate might make a macroscopic finding of variants difficult even in adults.


Introduction
In adults, the incisive canal is a narrow bony canal connecting the nasal cavity and incisive fossa, allowing passage of the nasopalatine nerve, a branch of the greater palatine artery and, in some individuals, a remnant of the nasopalatine duct [1]. The incisive canal is generally regarded as passing through the border between the primary and secondary palates, i.e., along the incisive-maxillary or transverse suture of the bony palate [2][3][4]. Gray's Anatomy [1] also described the course along the bony suture. The bony canal in adults consistently opens to an incisive fossa at a cross point of the transverse and longitudinal sutures of the bony palate. Moreover, examination of sagittal sections showed the presence of the duct, nerves and vessels through a canal along the suture [3,[5][6][7]. Therefore, the canal is usually considered to pass through a border between the primary and secondary palates, while the duct is commonly known as a derivative from a primary oronasal communication. However, Vacher et al. [3] demonstrated that, in sagittal sections of a single fetus at 14 weeks, the canal passes through the incisive bone (IN) or premaxilla. Moreover, Radlanski et al. [8] postulated a new concept that the canal develops within the embryonic IN or primary palate according to a relatively small number of spec-imens after palatal closure (six fetuses at approximately 10-27 weeks). Could such a limited observation change one of essential knowledges of embryology? Otherwise, are there individual and/or age-related variations present in topographical relation between the incisive canal and suture?
Using frontal sections of human midterm fetuses, our group recently demonstrated that the bony canal penetrates the IN, not along the IN-maxillary suture, in fetuses "with" a persistent nasopalatine duct [9]. It is unclear, however, whether the intra-IN course of the duct corresponds to a bony variation or anomaly. Is the intra-IN canal likely when the fetuses had no epithelial duct? In contrast to our previous study using frontal sections [9], comprehensive studies of the bony palate (e.g., Wood and Kraus [10]) were almost always based on observations of sagittal sections. However, since a single sectional plane chosen is likely to make an identification of thin bony structures difficult, we need to compare results from multiple sectional planes. Consequently, in spite of the long history of research, we should emphasize that anatomy of the incisive canal and duct is still debatable. This study therefore assessed the topographical anatomy of the incisive canal and the INmaxillary suture using a large number of midterm and latestage fetuses with or without a persistent nasopalatine duct.

Materials and Methods
This study was performed in accordance with the principles of the Declaration of Helsinki 1995 (as revised in 2013). Serial or semiserial sections were obtained from 69 fetuses, including 31 specimens at gestational age (GA) 9-15 weeks and crown rump length (CRL) 36-110 mm and 38 of GA 26-34 weeks and CRL 210-290 mm. The sectional planes were sagittal in 32 specimens (nine midterm and 23 late-stage) and frontal in 37 specimens (22 midterm and 15 late-stage). In the world, to our knowledge, there is no collection of histological sections from abundant fetuses at 20-25 weeks or CRL 140-200 mm.
The 31 specimens of midterm fetuses were part of the large collection kept at the Embryology Institute of the Universidad Complutense, Madrid, and originated from miscarriages and ectopic pregnancies at the Department of Obstetrics of the University. All specimens were sectioned serially (frontal or sagittal) ( Table 1). Most sections were stained with hematoxylin and eosin, with others stained with Masson trichrome, azan, orange G, or silver stain. The study protocol was approved by the ethics committee of the Universidad Com-plutense (B08/374). All midterm specimens were of Spanish white origin.
The 38 specimens of late-stage fetuses were parts of the collection of the Department of Anatomy, Akita University, Akita, Japan. These specimens had been donated by their families to the Department from 1975-1985 and preserved in 10% (w/w) neutral formalin solution for more than 30 years. The available data were limited to the date of donation and GA, but there was no information on family name, the name of the obstetrician or hospital and the reason for abortion. All late-stage specimens were of Far-East yellow origin, most likely of Japanese. The use of these specimens for research was approved by the ethics committee of Akita University (No. 1428). After removal of the palate in combination with its surrounding tissues including lower parts of the nose and the pterygoid of the sphenoid, the specimens were decalcified by incubating them at room temperature in Plank-Rychlo solution (AlCl 2 /6H 2 O, 7.0 w/v%; HCl, 3.6; HCOOH, 4.6) for 1-2 weeks. After routine procedure for paraffin embedded histology, frontal or sagittal semiserial sections (numbers of specimen) ( Table 1), 5-μm-thick at 50-μm intervals, were prepared from each block and stained with hematoxylin and eosin. All observations and photographs were made with a Nikon Eclipse 80 camera (Nikon, Tokyo, Japan).  a same bony structure was seen in different anteroposterior levels (e.g., Fig. 5D vs. Fig. 5F). Below, we will describe three types of the incisive canal or possible individual variations: a correspondence between a figure and the type is summarized in Table 2.

Superomedial processes of the IN
In frontal sections, the bony processes were consistently paired and attached to each other across a narrow midline suture below the vomer. Thus, midline sutures of bilateral INs were observed not only in the lower large mass near the oral cavity but also between the upper processes: both were likely to be included in a single frontal section (Figs. 2C, 3E, 5I). These processes were adjacent to anterior (alar) nasal cartilages at anterior sites (Figs. 1B, 2C, 3D) as well as to the vomers at posterior sites (Figs. 3A, B, 5C, F, I). At anterior sites, the INs had generated plate-like processes similar to the paired processes of the vomer sandwiching the nasal septum    (Figs. 2E, 4G, 5C), a morphology defined as being a real nasopalatine duct [9,11]. This morphology was observed in 22 fetuses of CRL >70 mm or GA 11 weeks.

Intra-incisive canal and the canal along the suture
The development of the incisive canal, corresponding to the IN-maxillary suture, resulted in partial enlargement of the thin and tight sutures, which contained vessel-rich loose tissue in 23 of the 69 fetuses (33.3%) (Figs. 1B, 4C, F, 5B, 7B). Along the canal, a thin layer of the maxilla sometimes covered the medial aspect of the IN (Fig. 5B, C). However, other than the maxilla, the incisive canal in 46 fetuses (66.7%) was sandwiched partly or entirely by the upper process and the lower  (Figs. 2D, 4C, E, 6C, D, 7A, B). These nerves differed from the branches of the major palatine nerve coming from the posterior site (Fig. 6A, B).

Bias suggested by the sectional plane and other factors
Although sagittal sections were advantageous for understanding the anteroposterior arrangement of the IN, maxilla, palatal bone and upper teeth, the vomer and nasal septum cartilage of late-stage specimens tended to be injured during histological preparation of sagittal sections (Fig. 7). Because of difficulties identifying irregularly shaped upper processes of the IN and because of the course of the incisive canal along the left-right axis near the nose, the intra-IN canal tended to be more frequently observed in frontal than in sagittal sections (Table 1). Sagittal sections sometimes provided a complicated morphology, in that the IN-maxillary suture appeared to be a "branch" of the incisive canal (Figs. 4F, 7B, C). Our observations of late-stage specimens were not based on serial sections but on semiserial sagittal sections at 50 micron Hematoxylin and eosin staining. Panels A-D display a specimen of crown rump length (CRL) 82 mm, and panels E-G exhibit a specimen of CRL 100 mm. All panels were prepared at the same magnification. Panels A and E show the most lateral sites in each of the specimens. Panels D and G exhibit the presence of an epithelial pearl in the incisive fossa of both specimens. The smaller specimen showed a simple morphology, in which the suture (stars) was partly dilated to contain a duct (C). The larger specimen showed a complicated morphology, in which the suture (stars) appears to merge with an intra-incisive canal (triangles) in panel F. In panel G, however, the intra-incisive canal (anterior; triangles) and the suture (posterior; stars) are separated by a process of the incisive bone (IN). This morphology looks like a branching of the suture. Scale bar=1 mm. B in circles indicates a tooth bud of the lateral incisor. MX, maxilla; pearl, palatal epithelial pearl; VM, vomer.
www.acbjournal.org https://doi.org/10.5115/acb. 19.111 intervals. We were concerned that this method may be associated with a failure to identify the small upper processes of the IN. However, possibly due to easy identification of thick loose tissue continuous with the submucosa of the nose, the intra-IN canal tended to be found more frequently in semiserial sections of late-stage fetuses than in serial sections of midterm fetuses (Table 1). There was no evidence of rearrangement or reconstruction of the upper parts of the IN during intra-uterine growth after 15 weeks.
Consequently, in both of midterm and late-stage fetuses, we found not only the intra-IN canal but also the "classical" canal along the IN-maxillary suture (Figs. 1, 4, 6). There were variations between both of the typical morphologies ("mixed" in Table 2). Nevertheless, we should pay much attention to avoid bias from sectional planes. Sagittal sections were better for the demonstration of the classical canal because, converse- Hematoxylin and eosin staining. Panels A-C displays a specimen of crown rump length (CRL) 230 mm with a duct; panels D-F exhibits a specimen of CRL 250 mm without a duct, and panels G-I show a specimen of CRL 270 mm with a duct. All panels were prepared at the same magnification. Panels A, D and G exhibit the most posterior site in each specimen. In all three specimens, an epithelial elongation of the nose extended into loose tissue of the incisive canal. Stars indicate the incisive-maxillary suture. Panels B and C display an incisive canal passing along the suture between the incisive bone (IN) and the maxilla (MX). Panels E and F show an intra-incisive canal on the left-hand side, rather than a canal between the incisive bone and maxilla on the right-hand side. Panel H and I show bilateral intra-incisive canals. Nerves are seen in the canal as well as in the incisive bone (panel F). Scale bar=1 mm. B or C in circles indicate a tooth bud of the lateral incisor, or canine, respectively. pearl, palatal epithelial pearl; VM, vomer.
ly, frontal sections emphasized upper details of the IC as well as a plate-like anterior part of the maxilla.

Discussion
A study history of the incisive canal is very long and, still now, the structure is generally considered as a product according to one of basic rules of embryology, i.e., a gap of the border between the primary and secondary palates (see the Introduction). However, the present observation demonstrated that the incisive canal with or without nasopalatine duct exhibited a spectrum of variations in topographical relation to the IN-maxillary suture. In contrast to the recent new concept [8], some fetuses carried the intra-IN canal opening to the incisive fossa, while the others had the incisive canal along the IN-maxillary suture.
We identified an intra-IN canal, with or without a nasopalatine duct, as a normal morphology. The upper half of each incisive canal was characterized by both the inferomedial elongation of the nasal epithelium and a continuation of the thick nasal submucosal tissue. The canal seemed to be formed during nasal epithelial development at midterm. Conversely, the development of the intra-IN canal did not require a persistent nasopalatine duct reaching the incisive fossa or connecting with the epithelial pearl. Thus, this study did not emphasize our previous definition of the nasopalatine duct as a duct connecting the nasal epithelium and the paramedian epithelial pearl [9]. This duct apparently did not originate from the primitive oronasal communication prior to the midline palatal fusion. Although we previously reported the presence of this duct in specimens of GA 14 weeks [9], in the present study we identified this duct in specimens of GA 11 weeks. This lower limitation of age or stage was difficult to explain if the duct originated from the primitive oronasal communication during early phases of palatal fusion.
Some cells packed in the midline epithelial seam after fusion may later form a duct that connects to the differentiated nasal epithelium. Actually, the midline seam connects to the epithelial pearls in the incisive fossa [11][12][13]. However, the nasopalatine duct in the incisive canal often penetrated the IN, not the IN-maxillary suture. The primitive oronasal communication passes through the suture, as the latter was apparently the most anterior site in the loose midline. Therefore, conversely, most or all nasopalatine ducts likely originate from the "secondary" elongation of the nasal epithelium after midterm. The irregularly shaped upper parts of the IN with several processes seemed also to be a product of invasion of the nasal epithelium and submucosal tissue.
Previous studies showed "sagittal sections" that included the incisive canal along the IN-maxillary suture [2,[5][6][7]14], but these studies did not mention the possibility of an intra-IN canal, which for a long time had not been a focus of study. Thus, at the beginning of this study, we considered that a midterm fetus with an intra-IN canal would likely die before   [4,[15][16][17][18]. Second, the upper processes of the IN were difficult to identify on sagittal sections. In most samples, the intra-IN ca-nal was observed in the nasal half of the course, lying between the upper process and the lower large mass of the bone. Third, an inferomedial elongation of the nasal epithelium, a simple marker for identifying the incisive canal, was found to run along the left-right axis rather than the supero-inferior axis. Therefore, the nasal epithelium entering the canal or suture was often not seen on sagittal sections. In contrast, frontal sections clearly demonstrated that the vomer was sandwiched between the nasal septum cartilage and the upper process of the IN.
Because the present specimens included large fetuses near term, newborns and children are also likely to carry the intra-IN canal. Advances in computed tomography have revealed various abnormalities of the incisive canal and nasopalatine duct in adults [19][20][21][22][23][24]. These abnormalities were apparently caused by a remnant of a nasopalatine duct or its fragment, with or without upper migration, as these variants were connected to the nasal epithelium. However, a large incisive fossa along the midline on the oral surface of the palate might make a macroscopic finding of the intra-IN canal difficult. Detailed examinations of adult morphology may confirm the high incidence of intra-IN ducts. However, the topographical relationship between the IN and maxilla (i.e., the anatomy of the suture) may change during postnatal growth. In this context, we should remind a plate-like anterior part of the maxilla that lined the inferior or medial aspect of IN and that disturbed our clear identification of the IN-maxillary suture (Figs. 2E, F, 5B, F, I). We did not deny a possibility that, depending on eruption and growth of the face, these thin bony plates could be absorbed because they were located closely to anterior teeth and nose.

Study limitations
The present specimens were of two different origins: Spanish for the midterm and Far-East origin for the late-stage. Although this racial difference was likely to influence incidence of variations (Table 1), we were able to demonstrate Fig. 7. Sagittal sections of a late-stage fetus of crown rump length (CRL) 290 mm with an intra-incisive canal and duct. Hematoxylin and eosin staining. Panel A displays the most lateral site in the specimens. The course of the intra-incisive canal with a duct is intra-incisive laterally (A) and along a suture between the incisive bone (IN) and maxilla (MX) medially (B, C). The suture (stars) turns posteriorly in upper sites (B), but the posterior part appears to be a branch of suture. On the lateral side of the canal and duct between the IN and MX, the suture is narrow and closed (stars in panel A). An inset in panel B shows a higher magnification view of the duct. Panels A-C were prepared at the same magnification. Scale bar=1 mm. B in circles indicates a tooth bud of the lateral incisor. AC, alar cartilages of the anterior nose; PA, palatine bone; VM, vomer.  a real presence of variations in one of the basic and famous structures in the human head. Due to the large size, we used semiserial sections (50-μm interval) for observations of the late-stage specimens. We believe that, because of more than 100-μm thicknesses of the canal and duct, even semiserial sections provided a precise information as to whether these structures were present or absent.