Abstract
The assessment of gastrointestinal specimens from immunosuppressed patients can be challenging, particularly because of the increased likelihood of multiple diseases and of rarer diseases. This chapter documents and presents the wide range of luminal gastrointestinal pathologies that can develop in the three main groups of immunosuppressed patients, i.e. HIV/AIDS patients, individuals with primary immunodeficiencies, and patients receiving iatrogenic immunosuppression. These gastrointestinal pathologies include infections, neoplasms, drug-related injuries, and diseases that are more specific to certain groups of immunosuppressed patients such as graft versus host disease in bone marrow transplant recipients.
Introduction
The assessment of gastrointestinal (GI) specimens from immunosuppressed patients can be challenging, particularly because of the possibility of multiple diseases. Further, these specimens may potentially contain rarer diseases and/or unusual variants of more common diseases. This chapter aims to document and present the wide range of luminal GI pathologies that can develop in immunosuppressed patients. It will focus more on diseases that may potentially be diagnosable histopathologically.
This review will consider three main groups of immunosuppressed patients: HIV/AIDS patients, individuals with primary immunodeficiencies, and patients receiving iatrogenic immunosuppression (Fact Sheet 4.1). The latter include those receiving immunosuppressant therapies for inflammatory or neoplastic disease and particularly include transplant patients. These transplant patients have traditionally been subdivided into solid organ transplant recipients and bone marrow transplant recipients. This chapter does not discuss biopsies from transplanted small bowel because of their relative rarity, the possibility that they may show compounded features of organ rejection, and the fact (certainly in the UK) that such biopsies are predominantly centralised for reporting at the transplant centres themselves.
Fact Sheet 4.1 Categories of Immunosuppression Considered in this Chapter
1. HIV/AIDS patients
2. Primary immunodeficiencies
3. Iatrogenic immunosuppression
Immunosuppressant therapies for inflammatory or neoplastic disease
Transplant patients include solid organ transplant recipients and bone marrow transplant recipients
The chapter will focus on luminal GI pathologies and concentrate more on pathological features of these diseases than on general epidemiological and management-based aspects. The review will restrict the histological details especially to newer or evolving entities and entities that are potentially more difficult to diagnose. The review will first outline pathologies that may occur in one or more of the three groups of immunosuppressed patients mentioned earlier. The review will then consider GI pathologies that are more restricted to specific groups of immunosuppressed patients.
Infections
Bacteria
All immunosuppressed patients will be susceptible to the usual spectrum of bacteria that can cause so-called infective colitis, for example, Salmonella, Escherichia coli, and Campylobacter.1–3 This author is not aware of any conclusive evidence that the histological appearances of such bacterial colitides differ in immunosuppressed patients compared with immunocompetent individuals. It is worth noting that certain primary immunodeficiencies with aberrant antibody production (e.g. X-linked agammaglobulinaemia) predispose to bacterial overgrowth,4 though such overgrowth has no known specific histological features.
Particular bacterial infections of the GI tract to consider among immunosuppressed patients are Clostridioides difficile (Figures 18.11 and 23.8), spirochaetosis (Figure 18.15), Chlamydia, and mycobacteria. Clostridioides difficile infection and the pseudomembranous colitis that it can cause are potentially more prevalent among immunosuppressed patients in view of their common use of antibiotics. The relationship between spirochaetosis and HIV infection is well recognised. Chlamydial infection can cause a proctitis (Figure 22.3) and this can particularly be seen in HIV/AIDS patients (see also Chapters 18 and 22). Prominent lymphoid aggregates/follicles may be present in this proctitis whereas granulomas may be uncommon. This author has previously confirmed chlamydia infection in some cases of ‘follicular proctitis’ by polymerase chain reaction (PCR) analysis of formalin-fixed paraffin-embedded biopsy tissue.
Immunosuppressed patients are at risk both of tuberculous and non-tuberculous mycobacterial infection of the GI tract. As HIV/AIDS patients become more immunocompromised, tuberculous infection may present histologically with less well-formed granulomas that nevertheless contain numerous acid-fast bacilli. The typical GI histological manifestation of non-tuberculous or atypical mycobacteria in HIV/AIDS patients is filling of the lamina propria by foamy macrophages containing the organisms (Figure 18.13). Non-tuberculous mycobacterial infection of the intestine may also affect transplant patients. Descriptions of the histological features of such infection in transplant patients are limited, but the data suggest that non-tuberculous mycobacterial infection in bone marrow transplant patients5, 6 is similar to that occurring in HIV/AIDS patients. By contrast, there are limited data to suggest that non-tuberculous mycobacterial infection in solid organ transplant patients may be more granulomatous.7, 8
Viruses
Cytomegalovirus
According to some authors, cytomegalovirus (CMV) infection in the absence of other contributory factors can cause GI epithelial apoptosis. However, an important practical question is whether an endoscopic biopsy requires investigation for CMV infection if it demonstrates gland apoptosis but no identifiable viral nuclear inclusions. An often quoted publication reported six patients with CMV (one AIDS patient and five renal transplant patients) whose biopsies all showed crypt apoptosis but also recognisable viral nuclear inclusions (Figures 18.1 and 23.1–23.6).9 Nonetheless, and more recently, PCR demonstrated CMV infection in GI biopsies without viral nuclear inclusions or even CMV immunopositivity.10 Further, a study of reproducibility in diagnosing GvHD reported two HIV patients with CMV gastritis whose gastric biopsy changes were misinterpreted as graft-versus-host disease (GvHD) when the pathologist was blinded to the clinical details, mainly because gland apoptosis was present.11 Thus, this author’s routine practice is to request CMV immunohistochemistry on any transplant patient endoscopic biopsy showing gland apoptosis, regardless of the patient’s CMV blood copy number and even if no viral nuclear inclusions are seen. CMV infection can rarely present as localised disease such as polyps.12 Finally, there may be an association between mycophenolate mofetil (MMF) therapy and CMV GI infection.13, 14 However, others argue that this simply represents ascertainment bias in that the GI tracts of patients who have received MMF are more likely than usual to be investigated because of the risk of GI toxicity from the drug itself.15
Adenovirus
There are only a few previous publications of the histological features of adenovirus infection of the GI tract in transplant patients. Further, all these studies comprised small bowel transplant recipients and the descriptions of the histology of adenovirus infection were confined to the changes that occur in transplanted small bowel specimens.16–19 A consistent finding across the studies was crypt epithelial apoptosis.16–19 Several of the studies described increased chronic inflammatory cells in the lamina propria16–18 and some studies also reported acute inflammation, which was defined in one study as neutrophils within the lamina propria and crypts.17 One study described nuclear atypia among regenerative surface epithelial cells.18 These epithelial changes are consistent with reports of adenovirus GI infection in HIV patients; in one study of such patients, colonic biopsies with adenovirus infection showed disorganised surface nuclei with loss of polarity, inverted goblet cells, and abundant cellular degeneration and debris.20 Further, the study authors proposed that such epithelial changes, together with a neutrophil and eosinophil infiltrate and nuclear inclusions, suggest pathogenic adenovirus infection. This author’s experience includes two bone marrow transplant recipients with diarrhoea (but no other clinical features of GvHD) and adenovirus demonstrated in stool and/or peripheral blood. Both patients’ large bowel biopsies showed a mixture of crypt epithelial apoptosis and acute inflammation with scattered adenovirus immunopositive cells (Figure 4.1). These decorated nuclei typically occurred within or just below the surface epithelium and were occasionally shed into the overlying lumen (Figure 4.1).
(A) There is focal acute inflammation, in the form of neutrophilic cryptitis (example arrowed), combined with
(B) crypt basal apoptosis.
(C) Immunohistochemistry demonstrates infected nuclei both just below the surface epithelium but also free-floating above this epithelium.
Figure 4.1 Adenovirus infection in a colonic mucosal biopsy from a bone marrow transplant patient.
Other Viruses
Herpes simplex virus infection (Figure 18.3) is a well-recognised cause of oesophagitis particularly in HIV/AIDS patients and patients who have been iatrogenically immunosuppressed. The virus may also cause anal ulceration.
The role of certain viruses in the pathogenesis of neoplasms, particularly in immunosuppressed patients, is the subject of further discussion (see later). In summary, the associations are human papilloma virus (HPV) and squamous neoplasia; human herpes virus 8 infection and Kaposi sarcoma; and Epstein–Barr virus (EBV) and both post-transplant lymphoproliferative disorder (PTLD) and smooth muscle tumours.
Fungi and Parasites
Oesophageal candidiasis is a common complication of HIV infection as well as several primary immunodeficiencies including severe combined immunodeficiency. Both Cryptococcus neoformans (Figure 4.2) and Pneumocystis jirovecii (formerly Pneumocystis carinii) (Figure 4.3) can involve the GI tracts of immunosuppressed individuals, particularly HIV/AIDS patients. Unexplained nodular or ulcerative lesions in immunosuppressed patients may represent fungal infection. Therefore, the assessment of biopsies from such lesions should always include at least a fungal stain.
(A) H&E stain showing yeast forms with narrow-based budding giving rise to a ‘soap bubble’ appearance.
(B) The yeast capsule, partly deficient here, stains magenta with mucicarmine.
Figure 4.2 Cryptococcal infection (affecting the liver in this example).
(A) H&E stain showing submucosal amorphous material and foamy casts that comprise cell debris and fungi.
(B) GMS stain showing yeast cells without a capsule. Terms for their appearance include cup-shaped, boat-shaped, or reminiscent of a squashed ping-pong ball.
Figure 4.3 Pneumocystis jirovecii infection involving the ileum.
The parasitic infections that can occur in HIV/AIDS patients as well as in patients with primary immunodeficiency (including combined variable immunodeficiency [CVID] and X-linked hyper-IgM syndrome) include Cryptosporidium and Entamoeba histolytica. Cryptosporidial infection can present with the typical histological finding of spores lying just above surface or crypt epithelium (Figure 4.4), but in addition is a recognised cause of increased crypt apoptosis.21, 22 Entamoeba infection of the large bowel (also known as amoebic colitis or amoebiasis) is characterised histologically by PAS-positive histiocyte-like organisms which often ingest red blood cells and lie above flask-like ulcers (Figures 18.20 and 23.7). Other parasites that are worth considering, particularly in HIV/AIDS patients, are Microsporidium (Figure 14.4) and Cystoisospora belli (Figure 18.23). Giardia lamblia infection, particularly of the small intestine, may occur both in HIV/AIDS patients and in patients with primary immunodeficiencies, including X-linked hyper-IgM syndrome, X-linked agammaglobulinaemia, and CVID.23
Neoplasia
Lymphoreticular Proliferations
Nodular Lymphoid Hyperplasia
Nodular lymphoid hyperplasia (NLH) can occur particularly in the setting of several primary immunodeficiencies, including IgA deficiency, X-linked hyper-IgM syndrome, and CVID.23 The usual histological appearance is multiple lymphoid aggregates/follicles located in the lamina propria and/or superficial submucosa. These changes are most likely to affect the small intestine but can also occur in the stomach and large bowel. If prominent, NLH can lead to intestinal obstruction. Finally, there is a recognised association between NLH and Giardia infection.
Post-transplant Lymphoproliferative Disorder
Post-transplant lymphoproliferative disorder (PTLD) develops particularly in patients who have been iatrogenically immunosuppressed. Among transplant patients, it is well recognised that PTLD is more common among solid organ transplant recipients than bone marrow transplant recipients.24 As such, there are numerous publications describing the features of GI PTLD in solid organ transplant recipients.25, 26 However, there are also a few case reports of PTLD involving the GI tract of bone marrow transplant recipients. Three reports described a monomorphic population of lymphoid cells, consistent with monomorphic PTLD24, 27, 28 and two describe PTLD with polymorphic rather than monomorphic features (one gastric and one small intestinal).29 The small intestinal case showed ‘mucosal erosion, glandular destruction and apoptosis in residual glands’.29 This author has seen three cases of adult bone marrow transplant recipients who presented with diarrhoea and whose colorectal biopsies showed changes that were initially interpreted as Crohn’s disease-like inflammation (Figure 4.5) with granulomas, but further tests revealed numerous EBV–encoded small nuclear RNAs (EBER)-positive B lymphoid blasts in the granulomas (Figure 4.5). All three patients demonstrated either elevated blood EBV copy numbers preceding their endoscopic biopsies or an elevation soon after, and their GI symptoms all resolved with PTLD-targeted therapies.
Figure 4.5 (A, B) Two different transplant patients who developed polymorphic post-transplant lymphoproliferative disorder involving the large bowel. In both cases, mucosal biopsies show granuloma-like clusters of pale cells (arrowed) which destroy or replace gland crypts. (C) EBER in situ hybridisation study of the biopsy in (B) shows that several of these cells are, in fact, Epstein–Barr virus-infected B blasts.
Lymphomas
Several lymphomas are associated with HIV infection. Both Hodgkin lymphoma and non-Hodgkin lymphoma can present within the GI tract of HIV/AIDS patients. Subtypes of the latter include Burkitt lymphoma and diffuse large B-cell lymphoma. While primary effusion lymphoma does not arise specifically from the tubular GI tract, it is worth pointing out that this lymphoma is a more specific complication of HIV infection and can involve the peritoneum and therefore the serosal surfaces of GI organs.
Epithelial Neoplasms
The increased incidence of anal dysplasia and squamous cell carcinoma in particular is a known feature of transplant patients and HIV/AIDS patients; HPV infection is the usual driver of such neoplasia. Both gastric and colorectal adenocarcinomas have been reported in X-linked agammaglobulinaemia patients30, 31 and there is an increased risk of gastric adenocarcinoma in CVID patients.23
Mesenchymal Neoplasms
HIV patients have an increased incidence of Kaposi sarcoma, which can present within the GI tract. Kaposi sarcoma of the GI tract may also occur in solid organ transplant patients and even more rarely in bone marrow transplant recipients.32, 33
Both HIV/AIDS patients and transplant patients are also predisposed to EBV-driven smooth muscle tumours; these neoplasms may arise along the luminal GI tract, within abdominal soft tissue, and in solid organs such as the liver.34 A typical histological picture of these EBV-driven smooth muscle tumours comprises minimal nuclear atypia and low mitotic activity but with primitive round cell foci and prominent T-cell infiltrates.34
Table 4.1 summarises neoplasia in the setting of immunosuppression.
| Lesion | Typical setting | Typical GI site(s) | Predisposing infection(s) |
|---|---|---|---|
| NLH | Primary immunodeficiency | Small bowel | Giardia |
| PTLD | Transplantation | Any | EBV |
| Lymphoma | HIV/AIDS | Any | EBV, human herpes virus 8 |
| Squamous dysplasia and carcinoma | HIV/AIDS, transplantation | Anus | Human papilloma virus |
| Adenocarcinoma | Primary immunodeficiency | Stomach and large bowel | n/a |
| Kaposi sarcoma | HIV/AIDS, transplantation | Any | Human herpes virus 8 |
| Smooth muscle neoplasm | HIV/AIDS, transplantation | Any | EBV |
EBV, Epstein–Barr virus; NLH, nodular lymphoid hyperplasia; PTLD, post-transplant lymphoproliferative disorder.
Drugs
Mycophenolate Mofetil
There is widespread acceptance that MMF can cause GI injury. Most previous studies of the histopathological features of MMF-related GI injury were based on solid organ transplant patients,35–39 presumably to avoid confusion with GvHD. However, one study has more recently investigated a group of bone marrow transplant patients to see whether there are histological features that might distinguish between intestinal GvHD and MMF colitis (see below).40
There is a limited record of the histological changes of MMF injury to the oesophagus and, to date, they appear to be non-specific.36 In the stomach, one study described only reactive gastropathy-like changes,37 two studies reported dilated damaged glands containing apoptotic debris39, 41 and a fourth study described balloon degeneration of parietal cells and epithelial cell apoptosis but questioned whether such changes were actually specific for MMF injury.36 Features of MMF injury to the small intestine include acute inflammation, dilated damaged crypts, villous atrophy, increased apoptosis, pyloric metaplasia, granulomas, and increased intraepithelial lymphocytes.36 37, 39 MMF colitis is a known cause of histological changes resembling GvHD (particularly as regards increased apoptosis) and/or inflammatory bowel disease (IBD; Figure 4.6), and there are rarer reports of histological features resembling those of infectious colitic or ischaemia.35, 37, 38 One report suggested that the histological changes of MMF colitis may be worse proximally.41 A study by Star and colleagues is particularly helpful in recording histological changes that help discriminate between GvHD and MMF colitis.40 In summary, absence of apoptotic microabscesses, absence of neuroendocrine cell clusters, and an eosinophil count of greater than 15 per 10 high-power fields were found to favour MMF colitis over GvHD.40 The same study reported that ‘hypereosinophilic crypts’ (defined as ‘small crypts, lined by atrophic, thin or hyper-eosinophilic epithelium’) were more common in GvHD than MMF colitis.40 Clarification is needed as to whether these hypereosinophilic crypts are different from the dilated damaged crypts (Figure 4.6) that are a characteristic histological feature of MMF GI toxicity.37
(A) Active chronic colitis with crypt distortion reminiscent of ulcerative colitis (UC). Other features of MMF colitis that are less characteristic of UC include
(B) prominent crypt epithelial cell apoptosis and
Figure 4.6 Colonic biopsies from a patient with mycophenolate mofetil (MMF) colitis.
Other Drugs
Two other immunosuppressants, tacrolimus and cyclosporine, may cause diarrhoea, though the mechanisms that mediate this side effect remain controversial.1
Diarrhoea is also a potential side effect of several forms of highly active antiretroviral therapy, e.g. protease inhibitors, but there are no known specific associated histological changes in intestinal mucosa.
Pathologies in Specific Groups of Immunosuppressed Patients
Transplantation
Acute Graft-versus-Host Disease
GvHD has traditionally been categorised into an acute phase and a chronic phase.43, 44 Although this categorisation is retained here, the clinical and pathological distinction between acute and chronic GI GvHD is not always clear (as discussed in the text that follows).
The hallmark histological feature of acute GI GvHD is epithelial cell apoptosis (Fact Sheet 4.2).43, 44 The apoptotic bodies form first within the proliferative compartments of the affected epithelia, and are thus present within the suprabasal/basal layers of oesophageal squamous epithelium, the mucous neck cell zone of gastric glands and the bases of small and large intestinal crypts (Figure 4.7). In the intestine, another term for these apoptotic bodies is ‘exploding crypt cells’.43, 45 An ‘apoptotic microabscess’ (defined as a group of five or more apoptotic bodies) may help distinguish GvHD from other histological mimics (see later).40 Reports of the histology of GI GvHD often describe little associated acute or chronic inflammation, but this dogma has been challenged more recently.46, 47 Chronic inflammation of the intestinal mucosa in GvHD typically has a pericrypt location and may comprise lymphocytes, plasma cells and eosinophils.43 The amount of chronic inflammation permissible for GI GvHD is the subject of controversy.47 Eosinophils are an acceptable feature of intestinal GvHD43, 46 although when numerous may favour a diagnosis of MMF colitis (see earlier).40 Also, the lymphocyte population of the intestinal lamina propria in GvHD increases as the post-transplant period lengthens and decreases with steroid therapy, according to one report.47 The extent of acute inflammation that is acceptable in GI GvHD is also controversial. Shidham and colleagues assessed colorectal biopsies from bone marrow transplant patients with diarrhoea and histologically proven cutaneous GvHD, and documented a mild neutrophilic lamina propria infiltrate in approximately a third of cases,48 while an earlier series reported acute inflammation in 40% of gastric GvHD biopsies.11 Shimoji and colleagues recorded ‘chronic active colitis’ in a third of intestinal GvHD cases; they defined this term only as a lymphoplasmacytic infiltrate though presumably the word ‘active’ indicates acute inflammation.49 All these data support the opinion that the presence of acute inflammation does not exclude GvHD.47
Fact Sheet 4.2 Potential Histological Features of Acute Gastrointestinal Graft-versus-Host Disease
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