Judging surface slant for placing objects: a role for motion parallax

People have a variety of sources of information (cues) about surface slant at their disposal. We used a simple placing task to evaluate the relative importance of three such cues (motion parallax, binocular disparity and texture) within the space in which people normally manipulate objects. To do so, we projected a stimulus onto a rotatable screen. This allowed us to manipulate texture cues independently of binocular disparity and motion parallax. We asked people to stand in front of the screen and place a cylinder on the screen. We analysed the cylinder’s orientation just before contact. Participants mainly relied on binocular cues (weight between 50 and 90%), in accordance with binocular cues being known to be reliable when the stimulus surface is nearby and almost frontal. Texture cues contributed between 2 and 18% to the estimated slant. Motion parallax was given a weight between 1 and 9%, despite the fact that it only provided information when the head began to move, which was just before the arm did. Thus motion parallax is used to judge surface slant, even when one is under the impression of standing still.
Introduction
It is often important to accurately judge the slant of surfaces in our nearby environment. Whether placing our foot on the ground when we walk or climb stairs, or our fingers on an object when we grasp it and place it elsewhere, the interaction always involves making contact with surfaces. In order to interact successfully, we need to know the orientation of these surfaces. We have many ways to judge a surface’s orientation, including ones based on texture gradients, binocular disparity and motion parallax.
One important cue that contributes to most people’s slant perception is binocular disparity (see Howard and Rogers 1995 for an extensive review of the literature on binocular vision). The small differences between the images in the two eyes suffice to obtain information about the slant in depth. From the literature on grasping it could be inferred that binocular cues normally dominate our actions. For example, Servos and Goodale (1994) claim that binocular vision is the principal source of information for reaching and grasping movements. However, binocular information does not guarantee correct grasping (Hibbard and Bradshaw 2003), so there is reason to expect other cues to also play a role in guiding our actions.
A second cue that contributes to slant perception is the deformation of any surface texture and of shapes’ outlines as a result of perspective. We will refer to the combined information from all such sources as the texture cue. This is the cue that allows us to have a powerful and striking impression of surface slant from a flat image, as exemplified in Fig. 1. It is well known that surface texture provides valuable information on slant perception (Gibson 1950; Stevens 1981; Buckley et al. 1996; Landy and Graham 2004) and motor control (Knill 1998a; Watt and Bradshaw 2003).
Fig. 1The deformation of the regular texture of a chess board provides a profound impression that the surface is slanted relative to the plane of the 2D picture
Retrieving the slant of a surface from texture cues is based on the assumption that the distribution of texture elements over the surface is more or less even and that shapes are more or less symmetrical, see Rosenholtz and Malik (1997). This assumption holds for a wide variety of natural and artificial objects.
The third cue that we will consider is motion parallax (Rogers and Collett 1989; Rogers and Graham 1979, 1982; Ono and Steinbach 1990; Gillam and Rogers 1991; Ujike and Ono 2001). For a review of the widespread use of motion parallax in the animal kingdom, see Kral (2003). Movement of the head relative to a surface generates changes in the surface’s retinal image over time. These changes depend on the motion of the head relative to the items in the surrounding, and on the items’ relative distances. The latter dependency can be used to obtain information about depth and slant. Watt and Bradshaw (2003) have shown that motion parallax can guide human movements when binocular cues are not available.
When more than one cue is available the cues are combined. It is generally accepted that the estimated slant is a weighted average of the slants indicated by various cues, and that the weight of a cue is related to its accuracy, although some details of the mechanism are still under debate (Landy et al. 1995; Hillis et al. 2002; Hogervorst and Brenner 2004; Rosas et al. 2005; Muller et al. 2007). The relative contribution of binocular cues and texture cues depends on the distance (Hillis et al. 2004) and surface orientation (Knill 1998b; Buckley and Frisby 1993; Ryan and Gillam 1994), because binocular vision is better nearby and texture gradients change least rapidly with the angle of slant for near-frontal surfaces (for purely geometrical reasons). Knill (2005) measured how binocular cues and texture cues to surface orientation are combined to guide motor behaviour. Cue weights were found to be dependent on surface slant and also on the task: more weight was given to binocular cues for controlling hand movements than for making perceptual judgements. Knill used cue-consistent and cue-conflict stimuli in a virtual reality environment.
We wanted to find out whether motion parallax contributes to judgement of slant in the presence of other cues (such as binocular and texture cues) under more or less natural conditions. To do so, we used a setup in which the physical slant of a surface could be manipulated independently of the slant indicated by a pronounced texture. Thus a conflict between the texture cue and all the other cues was created by violating the assumption that the distribution of texture elements is homogeneous. The judged surface slant was determined by asking participants to swiftly place a flat cylindrical probe on the slanted surface (as in Knill 2005). Our main interest was in the extent to which head movements and the resulting motion parallax contribute to the perceived surface slant. So, conditions in which the head could move freely were compared with one in which a head restraint was used. We compared conditions with and without binocular vision in order to be able to evaluate the importance of motion parallax in relation to this cue.
Methods
Participants
Five people, four of whom were male, participated in the experiment. All participants gave their informed consent prior to their inclusion in the study. The experiment was part of an ongoing research program that was approved by the local ethics committee. All participants were right-handed, had normal or corrected-to-normal vision and good binocular vision (stereo acuity <40 arcseconds).
Experimental setup
Participants were standing upright in front of a large rotatable screen. A sketch of the setup is given in Fig. 2. The screen was a plexiglass plate covered with projection foil. Images were projected from below by an Hitachi cp-x325 LCD projector with a resolution of 1024 × 768 pixels. The screen and the projector could be rotated as a whole. Participants wore computer-controlled PLATO shutter-glasses, with which we could alternate between monocular and binocular vision, see Milgram (1987). A chessboard pattern was projected onto the screen (see Fig. 3). Slants were defined relative to the gravity-defined horizontal. A grey ring, 104 mm in diameter, indicated the target position for the probe. Two positions of the ring, one near the participant (the target’s centre 100 mm below the stimulus centre) and one further away (100 mm above the stimulus centre) were displayed in random order to make sure that participants did not simply repeat the previous movement. Figure 3 shows the stimuli with 0° and 10° texture slant relative to the surface’s physical slant. The geometry of the stimulus was calculated by projecting the texture-defined slant on the physically rotated surface. The projection is calculated from the point of the observer’s eyes. The 0° stimulus was a 40 cm square, with 40 cm corresponding to a visual angle of about 27°. A dark grey rim was drawn around the stimulus to mask any real edges that could become visible due to reflections within the set-up. To avoid illuminating objects around the set-up, the luminance of the image at the position of the eyes was limited to 0.4 Cd m−2. This was achieved by placing filters in front of the projector.
Fig. 2Participants were standing upright, facing the screen. They moved a probe from a starting position 50 cm to the right of the surface midline to a target position on the surface (indicated by the grey ring). Participants wore PLATO glasses with which we could switch between no, monocular and binocular vision. During the experiment, only the slanted surface was visibleFig. 3Examples of consistent (left) and conflict (right) images. The left panel shows the 0° texture slant on a 0° surface slant as seen from above. The right panel shows the 10° texture slant on the 0° surface slant. The deformation of the stimulus is consistent with the actual viewing geometry but for clarity the image is presented as seen from above. The target (grey ring) indicates the position at which participants have to place the probe. The targets are shown at the ‘near’ position. The dark grey rim’s shape is in accordance with the texture cue
The probe was a flat cylinder (diameter = 104 mm, height = 22 mm, mass = 0.2 kg). Movements of the probe were registered by an optotrak 3020 system (northern digital inc., Waterloo, ON, Canada). This system tracks the position of active infrared markers with an accuracy better than 0.5 mm. The 3D-positions of five markers on the probe were tracked at a rate of 200 Hz. The position, orientation and velocity of the probe were calculated from these data.
Procedure
Experiments were performed in a completely dark room. The dark environment and the low intensity of the stimuli ensured that there was no visible external reference frame. Participants were instructed to place the probe at the indicated target position on the surface. They were to start moving as soon as the target was visible. Stimuli were shown for 2.5 s. All movements were completed well within this interval.
In order to avoid dark adaptation a bright lamp was turned on for 5 s immediately after each trial. During this period participants placed the probe at the starting position, 50 cm to the right of the midline of the screen. Then the light was turned off for about 5 s, during which time the experimenter adjusted the orientation of the screen in preparation for the next trial.
Figure 4 shows the six combinations of surface slant and texture slant that were used in the experiment. The different combinations could be viewed monocularly or binocularly. The four consistent combinations (on the diagonal in Fig. 4) were used as a standard. The physical surface slant (see Fig. 2) was −10°, 0°, 10° or 20°, and the image on the surface was as shown on the left in Fig. 3. The two conflict combinations either involved presenting the image shown on the right in Fig. 3 on a horizontal surface (surface slant 0°; texture slant 10°) or presenting a similarly transformed image (slanted in the opposite direction) on a surface with 10° slant. All six stimuli were presented under various conditions. In total there were four experimental conditions, each consisting of 192 trials, divided into 3 blocks of 64 trials. Within every condition 75% of the trials were without conflict and 25% involved a conflict between texture and the other cues present in that condition.
Fig. 4The six combinations of physical surface slant (continuous lines) and slant suggested by texture (dashed lines) that were used in the experiment. In four cases there was no conflict between the cues (solid disks). In two cases there was a conflict (open disks). The slants have been exaggerated for clarity
We used four conditions in which different combinations of the available cues were presented. The choice of conditions will become clear when we describe the data analysis. We chose three conditions with which we could calculate the five parameters of our model, and one condition to test one of our assumptions.
In the ‘binocular’ condition viewing was binocular and head-free in both conflict and consistent trials. In this condition all cues to slant perception were available. In the ‘monocular’ condition the conflict and consistent trials were both presented monocularly and head-free. Stimuli were viewed with the left or right eye in random order. No binocular cues were available, but all other cues were present. In the ‘biteboard’ condition the head was fixed in combination with monocular viewing. The biteboards were made individually with an impression of the participant’s teeth. The biteboard severely limits head movements, removing information from motion parallax.
In the consistent trials of the ‘mixed’ condition the screen was viewed monocularly (75% of all trials), but in the conflict trials (25%) it was viewed binocularly. This condition was included to evaluate whether participants adapt their strategy at the level of a session rather than per trial. In the ‘binocular’ condition binocular information was always reliable, so participants could have learnt to use this cue. In the ‘mixed’ condition, in contrast, binocular cues were absent in the majority of trials, so participants could have learnt to use texture or motion parallax. Note that the 25% binocular, conflict trials in the ‘mixed’ condition are identical to the conflict trials in the ‘binocular condition’, whereas the 75% consistent trials are identical to the consistent trials in the ‘monocular’ condition. Thus the ‘mixed’ condition serves as a control condition to test whether the weight given to the cues stays about the same under changing viewing conditions on other trials.
Analysis
During some moments of some trials the participant’s fingers or hand occluded one or more of the five markers. The position of each marker relative to the centre of the probe is known, so the position and orientation of the probe can be calculated from any set of at least three markers. Frames in which fewer than three marker positions were known were not analysed. Figure 5 shows a schematic side-view of the path followed by the probe. The end of the movement was defined as the first sample at which the centre of the probe was less than 2 mm from the screen. The probe orientation was averaged over all samples at which the centre of the probe was between 100 and 20 mm from its position at the end of the movement (the grey line segments in Fig. 5). The last 20 mm of the path were excluded to avoid considering moments at which the edge of the probe could be in contact with the real surface of the projection screen.
Fig. 5The upper left panel gives a schematic side view of the probe’s path (curved thin line) towards the slanted surface (straight thick line). The position and orientation of the probe were measured by the optotrak system. The upper right panel shows a side view of a few paths towards the ‘far’ target position. The average probe orientation is determined during the last 100 to 20 mm before the end of the movement (indicated schematically by the dark-grey line segments). The lower panels show examples of the probe orientation with time intervals of 25 ms
To understand our method for determining the cue weights, consider the two extreme hypothetical outcomes shown in Fig. 6. At the one extreme, if information from the texture cue is not used at all, probe orientations will always follow the slant of the physical surface (left panel). At the other extreme, if the observer only relies on texture cues the orientation of the probe will follow the texture-defined slant (right panel). In the latter case the line connecting the cue-conflict conditions has approximately the opposite slope of that for consistent conditions. Note that the probe orientations in the consistent trials may differ from the physical surface slant (grey line). Some flattening may arise because the hand may still be rotating towards the surface slant during the last 100 mm of its trajectory. Participants may also rely to some extent on previous slopes that they encountered during the experiment. We will model these effects as a prior for a single surface slant for all conditions.
Fig. 6A schematic depiction of possible results for two extreme cases: probe orientation is not affected by texture at all (left panel) or only depends on the texture slant (right panel)
We assume that the weights that participants give to the different cues are the same in all conditions. This would for instance be so if observers base the weights on the reliability, as in optimal cue combination (Landy et al. 1995). We can therefore model the estimated slant (S) as a weighted average of the slant estimated from each of the available cues (si), which are all assumed to give veridical estimates except for the prior for a fixed slant (as mentioned in the previous paragraph):where wi is the weight (in arbitrary units) given to each available cue, with i ∈ {b, m, t, r, p} indicating binocular vision, motion parallax, texture, a rest category containing any other valid cues, and the prior. Note that we predict that the cue weights (wi) of all available cues will be the same in all conditions, although the relative weight given to a cue (wi/∑wi) will differ between conditions because it depends on the cues that are available in that condition.
The slant of the prior is a constant. Its value is likely to be near the mean of the slants in all previous conditions, but this is not essential for our analysis:
If s denotes the simulated slant, then the slants indicated by all other available cues are: except for the conflict trials, for which the texture differs 10° from all other available cues (see Fig. 4):  Combining these equations gives: and
The sums in Eqs. 5 and 6 are only over cues that were available in each condition. The slopes (β) of the regression lines in Fig. 6 are given by the first derivatives of the estimated slant:  Combining Eqs. 7 and 8 yields: and
Equations 9 and 10 apply to all experimental conditions as modified for cue availability, except for the ‘mixed’ condition. In the ‘binocular’ condition all cues yield information about the surface’s slant:
Similar equations can be written for the other conditions. Binocular information is not available in the ‘monocular’ condition, so wB does not occur in the equation:
Similarly, motion parallax ceases to contribute to the estimated slant in the ‘biteboard’ condition, giving:
Since the weights are in arbitrary units, we are free to define them in such a way that the sum of all weights is one:
First we determine the weight of the prior relative to that of texture (wP/wT) for each condition, using Eq. 10. Then, the weighted average of these ratios is calculated for each participant. We found no clear evidence that the assumption that wP/wT is the same across conditions was not justified. Next, determining the ratios between the slopes in the ‘binocular’, ‘monocular’ and ‘biteboard’ conditions from our data allows us to use Eqs. 11 to 14 to determine the values of the weights (wB, wT, wM and wR).
The data of the ‘mixed’ condition was analysed by comparing the slopes (βconflict and βconsistent) with the matching slopes in the ‘binocular’ and the ‘monocular’ conditions. Data for ‘near’ and ‘far’ target positions were pooled before calculating the slopes. The weights of the cues were calculated for individual participants. In addition, we also pooled the data of all participants before calculating the slopes, which yields the weights for ‘All’ participants.
Results
We determined average probe orientations for each participant and condition. The slopes of probe orientation as a function of surface orientation for conflict and consistent conditions enable us to calculate the cue weights, as explained in the ‘methods’ section.
Conditions
The upper panel of Fig. 7 shows the probe orientations in the binocular condition. Conflict (open symbols) and consistent (closed symbols) probe orientations are almost the same. The difference between the slopes is small but significant (P < 0.05). The second panel of Fig. 7 shows the probe orientations in the monocular condition. The slopes clearly differ between the conflict and the consistent trials (P < 0.01). In the ‘biteboard’ condition (third panel of Fig. 7) the conflict trials have almost the opposite slope than the consistent trials. The difference between the slopes is significant (P < 0.01). The cue weights were calculated using Eqs. 10 to 14 and the values of the regression slopes.
Fig. 7Pooled data for all participants. Each panel is for one of the four experimental conditions. Average probe orientations are shown for surfaces with (open symbols) and without (closed symbols) conflicts between real slant and texture slant. The error bars show the overall standard deviation. Correct probe orientations for the consistent trials (grey lines), linear regression (black lines) and regression slopes, β (numbers in lower right corner) are also shown. Asterisks indicate whether the difference between the regression slopes is significant (*P < 0.05; **P < 0.01)
The ‘mixed’ condition was included as a control to ascertain that the cue weights do not depend on the viewing conditions on other trials. We compared the monocular consistent trials with the identical trials in the ‘monocular’ condition, and the binocular conflict trials with the identical trials in the ‘binocular’ condition. The regression slope for monocular, consistent trials (βconsistent = 0.72) is not significantly different (P > 0.05) from the same trials in the ‘monocular’ condition (βconsistent = 0.76). The slope of the (binocular) conflict trials in the ‘mixed’ condition (βconflict = 0.61) is slightly but significantly lower (P = 0.04) than for conflict trials in the ‘binocular’ condition (βconflict = 0.72). Thus the weights may not be completely independent of the conditions. The difference was small enough to accept the calculation of the weights on the basis of the assumption that the condition is irrelevant. Our analysis may however underestimate the weight given to the texture cue.
Cue weights
The weight of the binocular cue lies between 50 and 90%, for individual participants (see Fig. 8). The average standard error is 11%. The errors in the cue weights are calculated by the method of propagation of errors based on the errors in the regression slopes. If we determine the slopes across all participants, the binocular weight is 71 ± 6%. The weight of the texture cue lies between 2 and 18% with an average standard error of 3% for individual participants. The weight given to the texture cue is 8 ± 1% across all participants. The weight given to motion parallax lies between 1 and 9% for individual participants with an average standard error of 6%. The weight given to motion parallax is 8 ± 3% across all participants. The weight attributed to the rest category of cues was only 3 ± 2% across all participants. The prior contributed between 6 and 23% for individual participants with an average standard error of 3%. The weight of the prior varies between 7 and 13% across conditions. Across all participants the weight of the prior is 10 ± 2%.
Fig. 8The weights given to the binocular, texture, motion parallax, other cues and to the prior, for each participant (horizontal axis). The weights are obtained by substituting the slopes of conflict data and consistent data in Eqs. 10 to 14. For ‘All’, first all participant’s data in each condition was pooled and then the weights were determined, which are all significantly different from zero. For individual participants the texture cue was not significantly different from zero in one case, the motion cue in four cases and the rest category in three cases
Head movements
Head movements were measured in the monocular viewing condition for three of the participants. Participants move their head considerably when placing the cylinder: EB moved on average 103 mm, JG 53 mm and DdG 37 mm in the lateral direction. Interestingly, the head movement only started just before the arm movement. Shortly before (100 ms) the onset of arm movement (when the probe was 10 mm from the starting position), the head had only moved 10 mm (EB), 4 mm (JG) or 6 mm (DdG). Thus the information from motion parallax is mainly picked up during the arm movement. None of the participants were aware of having made head movements.
Discussion
We used a physically rotatable screen as a surface. The projected stimulus was viewed in a completely dark environment within a space in which objects are normally manipulated. In our analysis systematic deformations that affect a single cue (like depth compression resulting from an erroneous depth estimate) were not considered. Moreover, we assume that the cue weights are the same in all conditions, so that their contributions to the percept only depend on which cues are available. We determined the contributions of binocular disparity, texture cues, motion parallax, a rest category and a prior. Under these conditions and based on these assumptions we conclude that participants mainly relied on binocular information (between 50 and 90%). Texture cues contributed between 2 and 18% to the estimated slant. Motion parallax contributed up to 9%. The prior contributed between 6 and 23%. Residual cues may account for up to 9%.
Comparing conditions with and without head movement revealed that motion parallax plays a role in slant perception. This is evident from the weights (Fig. 8) but also from a comparison of performance in the ‘monocular’ and ‘biteboard’ conditions (Fig. 7). It is not unusual to move the whole body, including the head, when making large arm movements. Beside mechanical reasons for doing so we here show that it may also have perceptual advantages.
We included in our analysis a rest category of cues that might contain information about slant that was not manipulated. The results suggest that this category indeed includes cues that yield some information about slant. Accommodation, or the rate at which the image becomes blurred with distance from fixation, might provide such information (Mather 1997; Watt et al. 2005). However, artefacts of our setup such as the possible visible micro texture (fibres in the projection foil or pixels on the screen) and the angular distribution of the light scattered from the surface could play a role too. Taken together in a rest category such cues contribute only a few percent to the estimated slant.
The probe orientations in the consistent trials in Fig. 7 are not equal to the physical surface slant. We incorporated a prior in our model to take into account behaviour that is not related to the instantaneous information, like visual or haptic information from previous trials. The slant indicated by the prior cue is a constant; i.e. it does not depend on the stimulus. Flatter slopes indicate that the prior plays a relatively large role. The weight of the prior is about as large as the weight of the texture cue. One component of the prior could be that the hand orientation is still changing towards its final value at the moment that we sample, which is slightly before contact (Cuijpers et al. 2004). Any biases towards a certain orientation of the hand or towards a certain perceived slant will also contribute to the weight of the prior.
The purpose of having the ‘mixed’ viewing condition was to check whether the weights change under different conditions. Ernst et al. (2000) have shown that haptic feedback can make more weight be given to a visual slant cue that is consistent with the feedback. In our study the haptic feedback was always consistent with the physical slant of the surface, so only the texture cue was sometimes unreliable. So, with a conflict between surface slant and texture the haptic feedback may yield a bias towards other cues than texture. Our results show a small difference between the ‘mixed’ condition and the comparable trials in the ‘monocular’ and ‘binocular’ condition. Thus here too the extent to which cues are used does probably depend to some extent on experience in previous trials. This indicates that the estimated slant does not only depend on the accuracy of the presented cues, as is often assumed in theories of optimal cue combination (Landy et al. 1995; Hillis et al. 2002; Muller et al. 2007 ). It is however possible that the difference arises from less use of motion parallax when binocular information was always available, perhaps because participants move less when there is enough information from other sources than motion parallax. We do not know whether this is the case because we did not measure head movements in all conditions. However, these differences are all too small to be taken seriously without further research.
In our study binocular disparity is given most weight, which is in accordance with binocular cues being known to be reliable when the stimulus surface is nearby and almost frontal. Because experimental conditions were all in favour of binocular disparity, the role of motion parallax and texture cues is probably smaller here than in natural viewing conditions. Motion parallax and texture cues both contribute to a small but significant extent to slant perception, although marked differences between participants were observed. Motion parallax was available only shortly and began relatively late, as the head began to move only just before onset of the arm movement. From animal studies it is known that a range of animals gain depth information by moving from side to side just before the performance of an action, see Kral (2003). We have shown that humans are able to use motion parallax during an action. It was known that monocular depth information can be used to guide our actions (Marotta et al. 1998; Dijkerman et al. 1999; Watt and Bradshaw 2003). It was not known, however, that motion parallax plays a role under conditions where other cues are dominantly available and without actively moving one’s head before starting the action. We conclude that motion parallax is used as a cue to manipulate objects in our nearby environment, even when one is under the impression of holding one’s head still. Motion parallax should therefore not be ignored in a ‘static’ task unless the head is really fixated.

motion parallax
binocular
texture
cue integration
cue conflict


Manifestation of palmoplantar pustulosis during or after infliximab therapy for plaque-type psoriasis: report on five cases

Infliximab is a monoclonal antibody directed against TNF-α. It has been approved for use in rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis and plaque-type psoriasis. In case reports, positive effects on pustular variants of psoriasis have also been reported. However, paradoxically, manifestation of pustular psoriasis and plaque-type psoriasis has been reported in patients treated with TNF antagonists including infliximab for other indications. Here, we report on 5 patients with chronic plaque-type psoriasis who developed palmoplantar pustulosis during or after discontinuation of infliximab therapy. In two of the five cases, manifestation of palmoplantar pustulosis was not accompanied by worsening of plaque-type psoriasis. Possibly, site-specific factors or a differential contribution of immunological processes modulated by TNF inhibitors to palmoplantar pustulosis and plaque-type psoriasis may have played a role.
Introduction
Increased expression of TNF-α has been identified as an important pathophysiological mechanism in different types of chronic inflammation including psoriasis and psoriatic arthritis. The knowledge about the central role of TNF-α in certain diseases has successfully been converted to the therapeutic level; over the last years TNF antagonizing agents such as the anti-TNF directed antibodies infliximab and adalimumab and the fusion protein etanercept have substantially improved the treatment of some of the most common chronic inflammatory conditions such as rheumatoid arthritis (RA). With 80% of the patients reaching at least a 75% reduction of their baseline skin symptoms after 10 weeks of therapy [14], infliximab is regarded as one of the most potent agents available at present for the treatment of psoriasis vulgaris. Other variants of psoriasis, such as pustular psoriasis have not been formally tested in larger clinical trials. However, in individual reports, positive effects of infliximab on generalized pustular psoriasis (GPP) with dramatic improvements in some cases have been reported [3, 13, 15]. Because this type of pustular psoriasis is believed to correspond to an extreme activation of psoriatic disease mechanisms, the high bioavailability of infliximab and its rapid onset of action following intravenous infusion have been used to explain the surprisingly fast decrease of pustule formation in patients treated with the agent. Paradoxically, on the other hand, manifestation of pustular psoriasis has been reported in patients treated with TNF antagonists including infliximab for other indications.
Palmoplantar pustulosis (PPP) has long been regarded as a localized variant of pustular psoriasis, although more recent epidemiological and genetic findings argue against this concept [2, 12]. Here, we report on five patients with chronic plaque-type psoriasis who developed PPP during or after discontinuation of infliximab therapy.
Cases and discussion
Relevant aspects of the five patients with chronic plaque-type psoriasis who developed PPP during or after discontinuation of infliximab therapy are presented in the Table 1 and Fig. 1.
Table 1Description of casesCase12345SexMaleMaleFemaleFemaleMaleAge3742673041Disease duration (years)17 2830Unknown15Psoriasis typePlaquePlaquePlaquePlaquePlaquePrior pustular psoriasisNoNoNoNoNoPsoriatic arthritisYesNoNoNoYesFamiliy history of psoriasisNegativePositiveNegativeUnknownNegativePrior UV-therapyYesYesYesYesYesPrior systemic therapiesMethotrexateLeflunomideEtanerceptPrednisoloneFumaric acid estersCyclosporineFumaric acid estersFumaric acid estersCyclosporineRetinoidsMethotrexateFumaric acid estersCyclosporineMethotrexateInitial response to infliximabExcellentcPASI 75fPASI 75PASI 75PASI 75Time of manifestation of PPPWeek 38d8 weeks after end of infliximab treatmentWeek 3dWeek 22dWeek 40dConcomitant worsening of plaque psoriasisaYesYesNoNoYesDevelopment of GPP in addition to PPPYesNoNoNoNoPotential trigger factors of PPP Infection prior to PPPYesNoYesNoNo Present smokingNoNoYes (36 packyears)UnknownUnknownDiscontinuation of infliximabYesYesYesNoYesSystemic therapy with sufficient control of PV and PPPbAdalimumab 40 mg e.o.wEtanercept 25 mg BIW plus methotrexate 7.5 mg/week orallyPUVA-therapy of palms and soles(Additional topical therapy)Etanercept 50 mg BIWSystemic therapy that failed to control PV or PPPEtanercept 50 mg BIWe plus methotrexate 15 mg/week orallyEtanercept 25 mg BIWPPP Pustulosis palmoplantaris, GPP Generalized pustular psoriasis, PV Psoriasis vulgaris, e.o.w Every other weeka Loss of >50% of maximum PASI response or increase of physician’s global assessment (PGA) by ≥ 2b All patients received additional topical therapy with glucocorticosteroids and Vitamin D analoguesc Improvement rated by PGA with “almost clear” (PGA = 1)d Week of infliximab treatmente BIW = twice weeklyf PASI 75 = Reduction in the psoriasis area and severity index (PASI) by ≥75%Fig. 1Clinical picture of pustulosis palmoplantaris in patient 3 with pustules in different stages of evolution on a sharply delineated erythematous lesion on the left sole (a) and yellowish pustules on the left palm (b). Histological examination showing intraepidermal vesiculopustular dermatitis (c, H.E. stain of a biopsy from the left plantar arch) with intraepidermal accumulation of neutrophils and subcorneal pustule formation (d)
To the best of our knowledge, the development of PPP during the treatment of plaque-type psoriasis with infliximab has not yet been reported. The occurrence of pustular skin lesions usually resembling GPP or palmoplantar pustular psoriasis has occasionally been observed in patients treated with infliximab for other indications [1, 6, 11, 16–19]. Induction of pustular skin lesions seems not to be limited to infliximab therapy, but has also been described in association with the use of the TNF-antagonists etanercept and adalimumab, including the use in one patient with plaque-psoriasis treated with etanercept [4, 8–10, 16]. One patient with seropositive RA developed GPP as well as PPP during treatment with infliximab [11]. This patient later experienced a relapse of PPP when treatment with etanercept was initiated, which also suggests that a class effect of TNF-antagonists may play a role.
In two of the three cases in whom an exacerbation of plaque-psoriasis occurred parallel to the manifestation of PPP, typical trigger factors for active psoriasis could be identified such as an infection (case 3) and the abrupt termination of anti-psoriatic treatment (case 2). These two cases are compatible with the existence of common trigger factors for plaque psoriasis and PPP. What are other factors that might contribute to the development of PPP during treatment of psoriasis vulgaris? While the exact etiology of PPP remains to be established, a history of smoking is the most important known risk factor for PPP. However, only one out of the three patients in whom a smoking history had been obtained was a smoker at the time of onset of pustular psoriasis (case 3). Streptococcal infection, a known risk factor for psoriasis vulgaris, has not been established as a risk factor for PPP and probably plays a minor role there. However, in the cases presented here, one patient (case 3) suffered an upper respiratory tract infection a few days before manifestation of PPP, while another patient (case 1) had suffered from a persistent cold 6 weeks before manifestation of pustules. In the former patient, the close temporal relationship between infectious symptoms and manifestation of PPP may point to a possible contribution of the infection to triggering PPP, and a modulation of the immune response to infliximab appears possible.
It is likely that beyond the contribution of known risk factors, other, immunological mechanisms may be involved in the manifestation of PPP under infliximab therapy. Interferon (IFN)-α has been suggested as a cytokine mediating the manifestation of psoriasiform lesions in patients treated with TNF-inhibitors as a consequence of crosstalk of TNF-α and IFN-α: TNF-α is known to suppress the generation of plasmacytoid dendritic cells that are very potent producers of IFN-α. Appearance of plasmacytoid dendritic cells (and IFN-α) in ths skin is considered to be an early and crucial step in the pathogenesis of psoriasis (reviewed in [7]). Thus, in patients treated with TNF-antagonists, the inhibition of TNF-α might induce an increase of IFN-α in the skin favoring the manifestation of psoriasiform dermatitis. In fact, an increase of IFN-α signaling has been shown in biopsy specimens from psoriatic plaques induced by TNF-inhibitors compared with traditional psoriatic plaques [6]. The relevance of IFN-α for PPP and TNF-inhibitor induced PPP, however, still needs to be determined. The observation of an improvement of pre-existing psoriasis plaques parallel to the first manifestation of PPP in two of the cases described here supports the concept that immunological mechanisms and/or local factors are not identical in the pathogenesis of plaque-type psoriasis and PPP. Differences in pathogenesis between plaque psoriasis and PPP are also supported by their different genetic background, with plaque psoriasis, but not PPP being linked to PSORS1, the major susceptibility locus for plaque-type psoriasis located on 6p21 [2]. The localized nature of the pustules on palms and soles occurring in association with infliximab therapy in some patients suggests a contribution of site-specific factors. Possibly, eccrine sweat glands that are numerous in the palmoplantar location are involved in these processes. Changes secondary to binding of infliximab to TNF-α, that has been shown to be expressed in eccrine sweat glands, have been suggested as a possible mechanism [11].
Withdrawal or dose reduction of systemic cyclosporine and systemic or topical glucocorticosteroids given for treatment of psoriasis vulgaris have been associated with manifestation of GPP, but not with PPP. To the best of our knowledge, no reports on manifestation of GPP or PPP associated with treatment with methotrexate, another drug frequently used in the therapy of psoriasis, exist. However, in the clinical trials with the CD11a-antagonist efalizumab in the indication plaque psoriasis, development of PPP has also been observed in 0.2% of 1,620 patients during the first 12 weeks of treatment with efalizumab, compared to none of the 715 patients in the placebo groups [5].
Whether therapy with TNF-antagonists may induce a more severe form of plaque psoriasis or psoriatic arthritis in some patients treated for these indications is difficult to determine, as the natural course of both plaque psoriasis and psoriatic arthritis is variable and a loss of effect is not easily differentiated from an induction of a more severe form of the respective disease. However, as a manifestation of plaque psoriasis has been noted in a number of patients treated with TNF-antagonists for other indications without a personal or family history of psoriasis [6, 16], it is likely that TNF-antagonists may in some individuals and probably in conjunction with environmental factors favor manifestation or worsening of psoriatic skin and/or bone disease.
The treatment of patients with plaque-psoriasis developing PPP should be decided on an individual basis. In case plaque-psoriasis remains controlled under infliximab therapy, addition of topical therapy may be sufficient for treatment of PPP in some instances (case 4). However, in some cases, additional topical therapy may not be sufficient and UV-therapy or another systemic therapy may be necessary in addition to or as replacement of infliximab therapy (case 3). When manifestation of PPP is accompanied by worsening of plaque-psoriasis, discontinuation of infliximab therapy is advisable and initiation of other systemic antipsoriatic agents, such as cyclosporine or a different TNF-antagonist, may be necessary (cases 1 and 5).
In summary, pustular psoriasis may show a good response to treatment with TNF-antagonists such as infliximab. However, pustular psoriasis may also manifest during treatment of rheumatological diseases, and, as described here, also in patients with plaque-type psoriasis under treatment with infliximab. Manifestation of PPP under infliximab is not necessarily accompanied by worsening of pre-existing plaque psoriasis. Management of the pustular skin lesions has to be decided on an individual basis. In a subgroup of patients, therapy with the TNF-antagonist has to be discontinued and another systemic therapy (including a different TNF-antagonist) will probably be necessary to sufficiently control plaque-psoriasis and PPP.

pustulosis infliximab psoriasis tnf antagonist


Hereditary diffuse gastric cancer: association with lobular breast cancer

Hereditary diffuse gastric cancer (HDGC) has been shown to be caused by germline mutations in the gene CDH1 located at 16q22.1, which encodes the cell–cell adhesion molecule, E-cadherin. Not only does loss of expression of E-cadherin account for the morphologic differences between intestinal and diffuse gastric cancer (DGC) variants, but it also appears to lead to distinct cellular features which appear to be common amongst related cancers that have been seen in the syndrome. As in most hereditary cancer syndromes, multiple organ sites may be commonly affected by cancer, in HDGC, lobular carcinoma of the breast (LBC) and possibly other organ sites have been shown to be associated with the familial cancer syndrome. Given the complexity of HDGC, not only with regard to the management of the DGC risk, but also with regard to the risk for other related cancers, such as LBC, a multi-disciplinary approach is needed for the management of individuals with known CDH1 mutations.
Introduction
Despite an overall decrease in the global incidence of gastric cancer (GC) [1], the incidence of the subtype, diffuse gastric cancer (DGC) has remained stable and may even be increasing [2]. Within the past ten years, germline mutations in CDH1, which encodes E-cadherin, have been found [3] in over 50% of hereditary diffuse gastric cancer (HDGC) families with at least two cases of GC, with one diagnosed as DGC before the age of 50 years [4]. Within these HDGC families, we and others have noted an overrepresentation of lobular breast cancer (LBC) [4–8]. This observation has led to efforts to determine whether or not CDH1 is a breast cancer susceptibility gene, distinct from its gastric cancer risk. Recently our group has reported a novel germline CDH1 truncating mutation (517insA) in an LBC family with no known history of GC [9]. Within this review we report a germline CDH1 mutation in a second family in which breast cancer is the predominant cancer diagnosis. The management of HDGC in all patients with a particular focus on the management of the breast cancer risk associated with germline CDH1 mutations will be discussed.
Methods
The described family was referred to the ongoing HDGC study at the British Columbia Cancer Agency from a cancer genetics clinic in Seattle, WA, USA. Informed consent was obtained from the proband by the referring genetic counselor following ascertainment of a detailed cancer family history and appropriate genetic counseling prior to germline mutation testing. Our laboratory carried out the molecular genetic testing for the CDH1 mutation on a research basis. Approval for the HDGC study is by the clinical research ethics board of the University of British Columbia.
The proband (IV-4) was diagnosed with widely metastatic lobular breast cancer at age 53 years (Fig. 1a). Her family, of European ancestry, had a history of breast cancer diagnoses occurring in an autosomal dominant fashion on the maternal side of the family where her mother, aunt, and first cousin developed breast cancer in their 50’s. Due to her high-risk pedigree BRCA1, BRCA2, and PTEN genetic testing was undertaken and all were negative. CDH1 testing was also pursued.
Fig. 1(a) Pedigree of family reported showing a predominance of breast cancer. (b) Sequence from family carrying 1565 + 1G→A mutation
Results
All 16 exons were amplified for DHPLC analysis [6]. For exon 10 of CDH1, the initial amplicon failed and was therefore analyzed by direct sequencing and thus revealed a donor splice site mutation, 1565 + 1G > A (Fig. 1b). Due to its position at a donor splice site, this mutation is regarded as pathogenic [10].
The proband’s sisters (IV-2 and IV-6) participated in all aspects of the proband’s genetic consultation. They were appropriately concerned about their risk of breast cancer, but had not thought much about the possibility of getting gastric cancer until the CDH1 mutation was found. IV-2 and IV-6 had predictive genetic testing for the CDH1 mutation testing and both were found to be negative. Other family members are being informed about the availability of predictive genetic testing.
Discussion
E-cadherin
CDH1 (OMIM *192090), located on chromosome 16q22.1 encodes, E-cadherin, an epithelial transmembrane cell–cell adhesion molecule and member of the cadherin superfamily of glycoproteins. In a zipper-like fashion, its extracellular domain forms calcium-dependent homodimers between the E-cadherin molecules of adjacent epithelial cells, to act as the primary mediator of epithelial cell adhesion at the adherens junction complex [11]. Through interactions of its cytoplasmic tail with multiple signalling and structural molecules, such as the catenins, E-cadherin, maintains cellular adhesion and epithelial architecture with this link to the cytoskeleton. The cytoplasmic tail of E-cadherin directly associates with β-catenin and γ-catenin which in turn binds to the f-actin microfilaments of the cytoskeleton, directly or through α-catenin [12]. p120-catenin also associates with E-cadherin’s cytoplasmic tail at a different site, the juxtamembrane domain, and acts to both strengthen the adhesion between cells and regulate cadherin membrane trafficking and degradation [13, 14]. E-cadherin is considered to have an invasion suppressor role, where decreased expression permits cells to dissociate from each other in order to migrate and invade [15]. In cancers, this manifests as increased infiltrative and metastatic potential [16]. E-cadherin is also thought to act as a tumour suppressor, potentially through its interaction with the multipurpose β -catenin molecule which is an effector of the WNT signalling pathway [17]. Loss of E-cadherin can result in β-catenin release from the membrane and translocation to the nucleus where it complexes with Tcf/Lef-1 transcription factors to initiate transcription of WNT responsive genes [18]. Activation of these genes have been implicated in tumourigenesis through the WNT signalling pathway as seen in adenomatous polyposis coli (APC) [19]. In support of the role of E-cadherin as a tumour suppressor is the observation of abnormal or absent E-cadherin expression in precursor lesions of DGC and LBC, where the phenomenon is seen in in situ signet ring cell carcinomas found in prophylactic gastrectomy specimens from germline CDH1 mutation carriers [20] and the lobular carcinoma in situ lesions seen adjacent to invasive lobular breast cancers [21]. These examples suggest that loss of E-cadherin is an early or even tumour-initiating event, however the actual molecular basis of such a potential role of E-cadherin in such cases is unknown.
Inactivating CDH1 mutations are found in 50% of sporadic DGCs [22, 23] and cluster between exons seven and nine [11], in contrast with the low percentage of mutations seen in sporadic intestinal type GCs [23]. Decreased expression of E-cadherin in DGCs may account for morphologic differences between intestinal and DGC variants [24]. Unlike somatic CDH1 mutations, germline mutations associated with DGC are distributed throughout the gene [7] (Fig. 2). In the cancers from individuals with CDH1 mutations, CDH1 acts as a classic tumour suppressor gene with loss of expression of the wildtype allele [25, 26]. In a single study of 6 hereditary DGC cancers, inactivation of the wild-type allele could be attributed to promoter hypermethylation in 5 (83%) of cases [26]. This finding warrants verification in a larger cohort as abnormal promoter methylation in early cancers could potentially form the basis of a screening test.
Fig. 2DGC and LBC associated CDH1 germline mutations. Mutations shown above CDH1 gene schematic occur in families with DGC history and those below CDH1 occur in families with an additional or exclusive LBC history. In addition to the known CDH1 germline mutations compiled by Kaurah et al. [4], the recent mutation in an LBC family [9] and novel mutation from this paper are shown and identified below the symbol denoting mutation type. * Denotes the halfway point of the CDH1 coding sequence (1324 or the start of exon 10)
Lobular breast cancer and diffuse gastric cancer: loss of E-cadherin
Currently germline mutations in single genes account for approximately 5–10% of breast cancer [27]. High penetrance genes such as BRCA1 and 2 account for 3–8%, and TP53 and PTEN as seen in Li-Fraumeni and Cowden syndrome together only account for <0.1% of breast cancer diagnoses [28]. Other medium and low penetrance genes such as CHK2, BRIP1, PALB2 and ATM [29–32] have been identified, however, there still remains a proportion of hereditary breast cancer not yet determined. LBC accounts for approximately 10% of all breast cancers compared to the other major histologic subtype, invasive ductal carcinoma (IDC) [33]. Several factors suggest that LBC has a stronger hereditary basis relative to IDC, such as the higher frequency of bilateral disease [33], and also where excess familiality of LBC has been observed in population studies [34]. LBCs compose only 3% and 9% of the breast cancer tumour types seen in germline BRCA 1 and 2 mutation carriers, respectively [35], illustrating that the genetic risk factors for the majority of cases are unaccounted for by these genes.
The histology of LBC is characterized by infiltrative cancer cells which are isolated, highly dispersive and demonstrate a growth pattern with scattered and single files of tumor cells dispersed in stromal tissue [36]. This pathologic appearance is remarkably similar to DGCs and both LBC and DGC demonstrate characteristic mucinous, signet ring cells. This is not unexpected as E-cadherin staining is absent in 85% of sporadic invasive LBC [37] and somatic CDH1 mutations have been identified in 56% of sporadic LBCs [38]. Furthermore, in IDC, somatic CDH1 mutations are not found [38] and complete loss of E-cadherin expression is an uncommon feature. As loss of E-cadherin expression is a distinctive trait of both LBCs and DGCs, it likely contributes to the unique histopathologic features shared by the two cancers.
There are some differences with regard to the nature of the mutations seen in LBC and DGC. Generally mutations associated with sporadic LBC have been found to be nonsense or frameshift mutations [39] which encode truncated, non-functional proteins, whereas in sporadic DGC, mutations have generally been found to be splice site and in-frame mutations [11]. In sporadic LBC, mutations in CDH1 are spread throughout the gene [11] compared with the mutations seen in sporadic DGC which tend to cluster. Germline CDH1 mutations associated with DGC and/or LBC occur throughout the gene (Fig. 2). However, when the DGC and LBC associated CDH1 mutations are tabulated and compared based on their 3′ or 5′ positions relative to the halfway point of the CDH1 coding sequence (1324 or the start of exon 10), LBC associated mutations show a statistically significant trend towards clustering at the 3′ end (Fisher’s exact test, two-tailed P-value equals 0.0467) (Fig. 2). As this association is of weak statistical significance, it is unlikely to impact clinical testing strategies. Future analyses of novel germline LBC-associated CDH1 mutations should help to confirm this observation. Another difference between the molecular genetics of the two types of cancers, is that in sporadic LBC, silencing of E-cadherin expression is generally accomplished by a mutation in one allele in combination with loss of heterozygosity (LOH) or promoter hypermethylation in the remaining allele [40]. This is in contrast to sporadic DGC, where biallellic inactivation is achieved by mutations in one allele in concert with promoter hypermethylation in the other [41].
We have recently identified a truncating germline CDH1 mutation in an LBC family where analysis of the tumour was suggestive of partial LOH in the WT allele [9]. Our current case demonstrates a germline CDH1 mutation (1565 + 1G > A) in a predominantly breast cancer family, which is predicted to disrupt splicing. The mutation is in the same conserved position as a previously reported mutation (1565 + 1G > T) which was found in an Arabian HDGC family with no recorded history of breast cancer [42]. Moreover, a previous study reported a germline missense mutation in a proband with LBC but did not detail family history, or functionally characterize the missense mutation [43]. These examples demonstrate the need for further studies of germline mutations in LBC families in order to determine the mutation frequency and potential genotype-phenotype correlations.
Lobular breast cancer and HDGC
Breast cancer has been observed in HDGC kindreds to the extent where clustering of LBCs within HDGC families has led to the misclassification of families as breast cancer kindreds who test negative for BRCA1/2 mutations [4]. In 1998, Keller described the first case of histologically defined LBC in association with HDGC [5]. Since then, several more HDGC families with associated breast cancer were reported where it was observed, that these cases were LBCs when pathology was available [4, 6–8].
Prior to establishment of the association between HDGC and LBC, several efforts to determine whether CDH1 was a breast cancer susceptibility gene were attempted in view of the well-recognised phenotype of loss of E-cadherin expression displayed by the breast cancer subtype. For various reasons these studies failed to demonstrate the link. Rahman et al. examined 65 cases of lobular carcinoma in situ, however did not pre-screen the cases based on family history and included a wide age range, from 26 to 71 years, not necessarily in keeping with the usual age of onset seen in hereditary cancer syndromes [44]. Salashor examined 19 breast cancer tumours exhibiting LOH at the CDH1 locus, however of those, only 3 were confirmed to be pure LBC or mixed LBC/IDC pathology [45]. Lei examined 13 familial LBC cases and found no mutations, however did not define the extent of the family history [46].
Penetrance data based on 11 HDGC families, estimated the cumulative risk for LBC for female mutation carriers to be 39% (95% CI, 12–84%) by 80 years of age [47]. More recently we have published an estimated cumulative risk for breast cancer for females by the age of 75 years as being 52% (95% CI, 29–94%) from analysis of 4 predominantly gastric cancer pedigrees from Newfoundland with the 2398delC CDH1 founder mutation [4]. This is with the caveat that LBC risk for CDH1 mutation carriers has been assessed within high risk HDGC families, leading to a potential ascertainment bias and underestimation of the role of CDH1 mutations in LBC development. To accommodate for this we have begun analysis of CDH1 mutations within familial lobular breast cancer families or those families ascertained through a relatively young index case with confirmed LBC and have found germline CDH1 mutations in these kindreds [9].
Clinical implications of CDH1 associated LBC risk
At this time, it seems reasonable to conclude that at least four groups of women are at increased risk for LBC: women with LBC and a family history of breast cancer, women with a known CDH1 mutation, women from families with diffuse gastric cancer in whom no CDH1 mutation has yet been identified; and women with a germline BRCA2 mutation. Since there has not yet been a large population based study of the prevalence of CDH1 mutations among women with lobular breast cancer, it is premature to recommend genetic evaluation to women with a family history of breast cancer unless, at the very least, one of the breast cancers can be shown to have been lobular. Additional research can be expected to provide better guidance for these families.
Although there are not yet definitive data available on surveillance or risk reduction programs for women with known CDH1 mutations or untested women from CDH1-positive families, the high lifetime risk of LBC (39–52%) [4, 47] that these women face mandates their careful management. We suggest that they follow the recommendations for other high-risk women with hereditary breast cancer predisposition. This subgroup should be advised to practice breast self-examination; and to have annual mammograms, and semiannual clinical breast examination, beginning at least by age 30. There is certainly interest in regular bilateral breast MRI, as lobular breast cancer are known to frequently elude mammographic detection because they do not form masses or develop calcifications. These women can also be counseled to consider hormonal chemoprevention, since most LBCs are estrogen receptor positive [33], and both tamoxifen and raloxifene reduce the risk of estrogen receptor positive [48, 49] breast cancers in randomized trials. In addition, the risk reduction was greatest with both agents in women with lobular carcinoma in situ [50].
Prophylactic mastectomy may also be considered an option by some CDH1-positive women, particularly those who have been previously diagnosed with breast cancer in one breast or those who have had to undergo multiple biopsies for abnormal clinical findings. Several studies have reported a 90% reduction in breast cancer incidence with prophylactic mastectomy among women with a strong family history or with a germline BRCA1 or BRCA2 mutation [51, 52]. The published series include some lobular breast cancers, but not at numbers sufficient to permit meaningful subset analysis at this time.
Management of hereditary diffuse gastric cancer
Penetrance studies examining data from HDGC families, have estimated the lifetime risk of developing gastric cancer by age 75 and 80 respectively, to be from 40–67% in men, to 63–83% in women [4, 47]. Although identification of germline CDH1 mutations has enabled a significant proportion of HDGC families to utilise predictive testing to determine their individual risks of GC within CDH1 mutation positive pedigrees, unfortunately screening for DGC is ineffective and the current recommendation is for consideration of prophylactic gastrectomy in mutation positive individuals. Positron emission tomography [53] and chromoendoscopic-directed biopsies [54] have been proposed over basic endoscopy as more sensitive means of screening carriers, however screening methods have been consistently undermined by the recurrent discovery of multifocal DGC lesions underlying normal mucosa in prophylactic gastrectomy specimens of individuals with recent negative screening [4, 55, 56]. Regardless of the current limitations of screening, it is currently recommended that consideration for genetic testing and screening begin in at risk individuals in the late teens or early twenties [4] and that prophylactic total gastrectomy be considered in the early twenties for mutation carriers. Female mutation carriers will need specialized counseling to the potential nutritional effects on pregnancy following gastrectomy [57]. Further studies are currently underway to examine the quality of life impact of prophylactic gastrectomies. In the case report herein, although there was a GC in the maternal grandfather, the family history was more striking for the large number of breast cancer cases. This highlights the particular challenges we currently face with regard to counseling these families which appear to be mainly breast cancer, as it is unknown if the penetrance of DGC in this family is as high as it is in other HDGC pedigrees.
Conclusion
HDGC is one of a number of hereditary cancer syndromes that feature both an increased breast and gastric cancer risk (Table 1). In general, a lack of shared genetic risks for most breast and GI cancers was suggested through a recent study of 13,023 genes in 11 breast and 11 colon cancer cell lines in which the only commonly mutated gene between these two cancer types is p53 [58]. This likely reflects underlying differences in the biology of these diseases, however also highlights the unique nature of germline mutations in the CDH1 gene which are strongly associated with specific histologically defined subtypes of breast and GI cancer, namely LBC and DGC which are both part of the HDGC syndrome.
Table 1Other syndromes with familial susceptibility to breast and gastric cancersSyndromeMode of inheritanceAssociated gene(s)Sites of primary cancer(s)Evidence for association with the syndrome BRCA2 Hereditary Breast/Ovarian CancerADBRCA2BreastOvaryLarynxProstateBC is considered an integral tumor of the syndrome with an average cumulative risk in carriers by age 70 years of 45% (95% confidence interval (CI) 31–56%) [59]Familial aggregations of both BC and GC have been reported [60]In a study of 173 families, relative risk for GC was 2.6 [61]Among Ashkenazi Jewish GC patients, the frequency of 617delT mutation is five times that of the general Ashkenazi Jewish population frequency [62] Among other cancers, GC occurred in first degree relatives when mutations were located in the ovarian cancer cluster region of exon 11 of BRCA2 [63] BRCA1 Hereditary Breast/Ovarian CancerADBRCA1BreastOvary ProstateBC is considered an integral tumor of the syndrome with an average cumulative risk in carriers by age 70 years of 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) [64]There is a 4 times increased risk for GC [64]Peutz-Jeghers SyndromeADSTK 11Gastrointestinal (GI) tractGC is considered an integral tumor of the syndrome with a relative risk of 213 (95% confidence interval 96–368) [65] BC is considered an integral tumor of the syndrome with a relative risk of 15.2 (95% CI 7.6–27) [65] Cowden SyndromeADPTENBreastThyroidEndometriumBC is considered an integral tumor of the syndrome with an incidence of 22–50% [66, 67]GC in situ has been reported in a patient with Cowden Syndrome [68]Li-Fraumeni SyndromeADTP53CHK2BreastAdrenal cortexConnective tissueKidneyNervous systemPancreas White blood cellsBC is frequently found in families with this cancer susceptibility syndrome [69]Chompret expanded the spectrum of cancers to include GC [70]Germline TP53 mutations have been found in GC families without CDH1 mutations [71–73]The 1100delC CHK2 allele confers a 2.2 fold risk of BC to carriers [29], however germline mutations in GC kindreds have not been identified [74]Familial Adenomatous PolyposisADAPCColon and rectumDuodenumThyroidPancreasLiterature review by Shimoyama et al. totalled 30 reported cases of GC and FAP [76]47% to 49% of primary BCs had promoter hypermethylation at the APC locus [77, 78]23% of LBCs have been shown to have LOH of APC [43]Lynch Syndrome (Hereditary Nonpolyposis Colon Cancer (HNPCC))ADhMSH2hMLH1hMSH6hPMS1hPMS2Colon and rectumEndometriumStomach Small intestineUrotheliumKidneyOvarySkinPancreasBrainWhite blood cells Biliary tractGastric cancer accounted for 5% of cancers in families harboring MLH1 or MSH2 mutations [76]hMLH1 mutations in large kindred segregated with BCs exhibiting microsatellite instability (MSI) [79]A slight increased incidence of BC was seen in hMLH1 mutation carriers [80]Germline hMSH2 mutation carrier with BC exhibited LOH for hMSH2 in tumors analyzed [81]Analysis of primary invasive BCs demonstrated that 25% of tumours were immunonegative for MSH2 staining [82] Ataxia-telangiectasia (AT)ARATMWhite blood cellsMutations causing AT in homozygotes, confer susceptibility to BC in heterozygotes, where women with ATM mutations have a ∼2-fold risk of BC and ∼15% of these women will develop the disease [32]GC has been reported in association with the syndrome [83–85]There is evidence of excess risks of GC in heterozygotes (RR = 3.39, 95% CI = 0.86 to 13.4) [86]Xeroderma pigmentosumARXPAERCC3 (XPB)XPCERCC2(XPD)DDB2(XPE)ERCC4(XPF)ERCC5(XPG)POLH(XP-V)SkinEyesBC and GC have both independently been reported with the syndrome [87,88]Werner SyndromeARWRNConnective tissue SkinThyroidGC has been reported in association with the syndrome [89] There are no reports of BC in association with Werner syndrome. Although, there is evidence supporting WRN as a low-penetrance familial BC susceptibility gene, where patients harboring both WRN Cys1367Arg or TP53 MspI variants had an increased BC risk (OR = 3.39, 95% CI 1.19–9.71) [90] AD = autosomal dominant, AR = autosomal recessive
With the recent demonstration of a CDH1 mutation in a family ascertained through an index case of LBC and in view of the additional new mutation in a predominantly breast cancer family that we have described here, the evidence for establishing LBC as part of the HDGC syndrome is strong. There now is a need for establishing the prevalence of CDH1 mutations in LBC families to avoid the ascertainment bias generated from only looking at cases from families identified because of their family history of GC. It is not currently known what the risk of GC is in these families which present predominantly as having a susceptibility to breast cancer and therefore identification of CDH1 as a true susceptibility gene for LBC could result in CDH1 screening and effective risk reduction strategies for selected breast cancer families and further studies examining their risk for gastric and other cancers.
Most hereditary cancer syndromes are associated with cancer risk involving multiple organs. Here we have discussed germline CDH1 mutations and the risks with regard to DGC and LBC, however as the recognised spectrum of related cancers broadens, more affected families will be identified and successfully managed with regard to avoidance of specific cancer risks. Longer life expectancy in individuals with penetrant mutations could potentially lead to the development of different, later onset disease as yet to be identified in these kindreds. This represents a particular challenge in hereditary cancer practice as the clinical community tends to be segregated into organ specific specialties where as the cancer risks and the risk reduction strategies for germline mutation carriers require a variety of expertise. The medical needs of the HDGC families are therefore best served through an engaged multidisciplinary team.

hereditary diffuse gastric cancer (hdgc)