Basal Plasmacytosis and the Plasma Cell Gradient

The normal mucosa has a plasma cell gradient, with a higher density of plasma cells in the upper third than in the lower third (Figure 21.5). Basal plasmacytosis requires the density of plasma cells in the lower third of mucosa to be similar to or greater than the density in the upper third. In other words, there is loss of the plasma cell gradient (Practice Points 21.2). Excess plasma cells are easiest to detect beneath crypt bases but also occupy the deep part of intercrypt spaces.^{9, 23, 28, 29} Schumacher refers eloquently to ‘crypts with their feet in pools of plasma cells’ while acknowledging the variations on this picture.²⁸ Plasma cells are easier than lymphocytes to identify and quantify.

Basal plasmacytosis in initial biopsies is the strongest predictor of a future diagnosis of IBD. Demonstration of its value as a discriminator between IBD and non-IBD is consistent.^28–30 Basal plasmacytosis may subside in chronic/treated disease but is usually present at least focally at diagnosis. Depending partly on whether the IBD is of UC or Crohn’s type, basal plasmacytosis may be diffuse, extensive, patchy, or focal. A search to exclude focal basal plasma cells is advisable before rejection of a diagnosis of IBD.

There are some caveats. Basal plasma cells may occur in the normal right colon, particularly the caecum, and may be sufficiently dense to cause loss of the plasma cell gradient (Figure 17.9). In addition, basal plasmacytosis is not unique to IBD and is not diagnostic in isolation. It can occur in diverticular colitis, diversion proctocolitis, and less often in other chronic mucosal inflammatory conditions such as chronic infection, drug-induced colitis, radiation colitis. Lamina propria plasmacytosis is common in microscopic colitis and may lead to loss of the plasma cell gradient, but the architectural changes and other features of IBD are not usually present.

Figure 21.11 Basal plasmacytosis may be focal in Crohn’s disease (arrow). Note also the smooth mucosal surface, a feature that favours Crohn’s disease over ulcerative colitis.

Abnormal Architecture/Crypt Distortion/Crypt Branching

Crypt distortion is a broad term for abnormally shaped crypts and includes branching, loss of ‘parallelism’, irregularity of outlines, tortuosity, dilatation, and inter-crypt variation in shape and size (Figure 21.4). One definition of crypt branching requires the presence of two or more branched crypts in a well oriented biopsy (without mention of the size of the biopsy). Branching between mucosal hillocks/at innominate grooves is normal.^{19, 23, 29, 31, 33, 34} Branching may be vertical or horizontal, but this distinction probably has little value in routine diagnostic practice (Figure 21.12).

Figure 21.12 Crypt branching is sometimes classified as vertical (as in this biopsy) or horizontal. The distinction has limited diagnostic value.

Assessment of crypt architecture is unreliable in some circumstances. Adjacent to crypt abscesses and lymphoid aggregates/lymphoid follicles there may be distortion of the crypts. The anal transition zone/columnar cuff is unsuitable for assessment, because crypt distortion is quite common in this location.^{9, 23, 29–33, 41}

Demonstration of the discriminant value of crypt architectural abnormalities for IBD is highly consistent between studies.^{28–32, 35, 39, 42} However, crypt changes are more likely than basal plasmacytosis to be present in non-IBD colitides. They are usually less extensive and less severe in non-IBD than in IBD. Perhaps surprisingly, interobserver variability for the assessment of crypt architectural abnormalities is higher than for the assessment of basal plasmacytosis.²

Crypt Atrophy

Diagnosis of crypt atrophy usually requires crypt shortening, i.e. an increase in the gap between the base of the crypt and the muscularis mucosae (Figure 21.4B and C). Normally, this gap is small or non-existent. Wider spacing of crypts is further evidence of atrophy, and definitions include ‘more than one crypt diameter between crypts’. Caution is necessary in some areas of the mucosa, e.g. near lymphoid follicles and near aggregates of muciphages, and there may be a larger space beneath or between crypts in the anal transition zone/columnar cuff, the rectum and the caecum (Figure 17.7C).^{9, 20, 23, 29, 31, 32, 34, 35, 39} Crypt atrophy is a reliable marker of IBD. In one report, a count of less than five crypts per mm was unique to IBD. However, moderate or severe atrophy may occasionally occur in other settings. There is moderate interobserver variability for the assessment of crypt atrophy.

Irregular/Villous Mucosal Surface

This refers to an undulating or broadly villiform surface that is partly a consequence of widening of crypt mouths (Figure 21.4A). Separation of crypts yields a surface consisting of broad villous projections. It is a reliable marker of IBD with moderate interobserver variability.^{9, 28, 29, 31, 32, 35, 42} It is generally more common and better developed in chronic disease than in new IBD.

Granulomas

A granuloma is a discrete collection of macrophages. In the setting of IBD, one definition refers to a discrete collection of at least five epithelioid macrophages (Figure 21.9).^{29, 31} Granulomas are strongly discriminant between Crohn’s disease and UC. They are also a pointer towards IBD, largely because they discriminate between Crohn’s disease and many other causes of colorectal inflammation. Therefore, a GI mucosal granuloma should always raise the possibility of Crohn’s disease unless there is another suspected or established cause of granulomas. Many other causes of granulomas require exclusion, e.g. infection, drugs, sarcoid, foreign material, and rarer conditions (Fact Sheet 21.4).⁴³ Overall, granulomas favour IBD over infection but are of no value in distinguishing UC from infective colitis.^{28, 29, 31, 32, 42} ‘Cryptolytic granulomas’ are a result of rupture of a crypt abscess or cryptitis into the adjacent lamina propria, and can occur in any setting (see later) (Figure 21.13A).

(A) A cryptolytic granuloma adjacent to a ruptured crypt in a patient with known ulcerative colitis (UC). Cryptolytic granulomas are less discriminant than non-cryptolytic for Crohn’s disease versus UC but are probably more likely to occur in Crohn’s disease (image courtesy of Dr V Simanskaite, London, UK).

(B) A biopsy from a patient with established UC containing a granuloma (arrow). This lies close to a crypt and could be a consequence of crypt rupture. However, because it is not demonstrably cryptolytic it raises the alternative possibility of Crohn’s disease.

Figure 21.13 Cryptolytic granulomas.

Basal Giant Cells

Basal multinucleate giant cells (Figure 21.9E) are more common in IBD than in infective colitis, but many studies do not assess them as a separate feature. Therefore, there is sparse information about giant cells.^{31, 32, 42} In isolation, they probably have little discriminant value because they could alternatively reflect crypt rupture or a reaction to foreign material.

Basal Lymphoid Aggregates

Lymphoid aggregates are collections of lymphocytes, usually nodular (Figure 21.6). If they have a germinal centre, the term ‘lymphoid follicle’ is preferable. They usually occupy the deep part of the lamina propria and may lie between the muscularis mucosae and crypts. In normal mucosa, there may be a small number of transmucosal lymphoid nodules. They can also extend across the muscularis mucosae (Figure 17.10A).^{9, 29, 31, 33}. Lymphoid aggregates are more numerous in IBD than in normal mucosa, but in the absence of other histological abnormalities they have limited discriminant value because pathological aggregates are difficult to distinguish from normal aggregates. There is no definition of the acceptable maximum number in normal mucosa.^{29, 31, 32, 39, 42}

Lamina Propria Chronic Inflammation/Lamina Propria Hypercellularity

There are various terms to describe an increase in lamina propria chronic inflammatory cells, but they are less precise or less well defined than the term basal plasmacytosis. In addition, plasma cells are easier than lymphocytes to identify, meaning that loss of the usual plasma cell gradient is a more objective sign of chronic inflammation than an increase in lymphocytes or other inflammatory cells. ‘Transmucosal chronic inflammation’ suggests chronic inflammation occupying the full thickness of the mucosa and correlates broadly with basal plasmacytosis. An increase in lamina propria lymphocytes is difficult to confirm objectively, but in many cases there is an obvious increase in the number and density of lymphocytes. Regardless of definitions, such an increase is less specific than basal plasmacytosis for IBD. In some conditions, unequivocal lamina propria chronic inflammation occurs with no basal plasmacytosis and no loss of the plasma cell gradient. Interobserver reproducibility for diagnosing this feature is low. Bearing these many caveats in mind, an increase in lamina propria chronic inflammatory cells, with or without identifiable basal plasmacytosis, is more likely in IBD than in other colitides.^{32, 39, 42}

Paneth Cell Metaplasia

Paneth cells are common in the caecum and proximal colon and diminish in frequency with more distal anatomical location. They are more significant if present distal to the splenic flexure.^{31, 33} Several studies have challenged the assertion that they are largely or wholly absent in the left colon and rectum. In fact, their presence at distal locations, albeit in low numbers, has been recognised for some time.⁴⁴ Not surprisingly, the likelihood of detection increases if sampling is thorough. For example, there were Paneth cells in the rectal mucosa in 17% of young patients in one report.³⁷ Despite these observations, Paneth cells distal to the splenic flexure are worth noting and are more likely in this location to be significant (Figure 21.8). They probably favour a diagnosis of IBD over other causes, although the association is weak in some studies.^{20, 28, 42, 44, 45} Paneth cells also occur in GvHD, radiation colitis, and other chronic conditions, and were present in 44% of collagenous colitis biopsies in one report.⁴⁶ They may be more common in chronic IBD than new IBD but the evidence is again inconsistent.⁴⁵

Surprisingly, there is moderate interobserver variability for the recognition of Paneth cells. Distinction from endocrine cells is important. Paneth cells are pyramidal crypt epithelial cells with supranuclear brightly eosinophilic granular cytoplasm. Compared to Paneth cell granules, endocrine cell granules are smaller and less brightly eosinophilic and are subnuclear or perinuclear rather than supranuclear (Figure 9.23B). In addition, endocrine cells are usually ovoid or rectangular rather than pyramidal.³⁷

Activity

The term ‘activity’ includes neutrophil cryptitis, neutrophil crypt abscesses, neutrophil infiltration of the surface epithelium, erosion, and ulceration.⁷ It does not usually include lamina propria acute inflammation. Activity is certainly not specific for IBD. There are a few studies of the relationship between severity or pattern of activity and the likelihood of IBD. For example, deeply located (rather than superficially located) crypt abscesses may favour IBD over other aetiologies³¹ while high counts of crypt intraepithelial neutrophils/crypt luminal neutrophils (defined as>10 per crypt or per crypt lumen when assessed in 10 crypts) favoured IBD in one study.³⁹ Other studies also identify widespread activity as a feature favouring UC over Crohn’s disease (see later). A misconception that persists among some clinicians is that crypt abscesses are specific for UC or that their presence favours UC over Crohn’s disease.

Variation in crypt diameter favoured IBD over other causes in one study.²⁸

Table 21.4 and Practice Points 21.3 summarise the features favouring a diagnosis of IBD over other diagnoses.