Brief Summary of the Condition

Sarcoidosis is a chronic multisystem disorder characterised by the presence of numerous granulomas within involved tissues and organs. The spectrum of clinical effects is very wide, ranging from no symptoms to severe clinical features that can be life threatening.

Epidemiology

The incidence of sarcoidosis is very difficult to ascertain, as it is commonly asymptomatic. There may be up to a 10-fold difference in prevalence in post-mortem studies compared to those based on other modalities, e.g. chest radiography.¹ The prevalence and incidence show geographical variation. For example, estimates of the prevalence include 3.7 per 100,000 in Japan and 28.2 per 100,000 in Finland. Corresponding annual incidences are 1.0 and 11.4 per 100,000 respectively.² Some studies have suggested that the mortality rate from this disease is increasing.³

Clinical Features, Including Systems Involved

Sarcoidosis is predominantly a disease of young adults and occurs more commonly in females than in males and in African Americans than in Caucasians.⁴ Sarcoidosis classically affects the lungs and hilar lymph nodes, with more than 90% of affected patients showing pulmonary involvement.⁵ However, it may affect almost any site. The skin, eye, liver, and peripheral lymph nodes are the next most commonly involved sites. Luminal GI tract involvement by sarcoidosis is relatively rare. The disease may be asymptomatic or can produce a wide range of symptoms according to the site(s) of involvement. Involvement of an organ or tissue may be diffuse or focal, and the latter can result in clinical features that raise the suspicion of neoplasia.⁶ Multifocal sarcoidosis may produce radiological features initially suggestive of disseminated malignancy.⁷ Cardiac and neurological involvement by sarcoidosis may cause sudden death.

Diagnosis, Including the Role of Histopathology

The diagnosis of sarcoidosis relies on identification of an appropriate clinical scenario, often supported by characteristic histological features. The former vary according to the anatomical pattern of disease involvement. However, because almost all patients with sarcoidosis have lung and/or hilar lymph node involvement, a chest radiograph can often provide useful supportive evidence of the condition. High serum levels of angiotensin converting enzyme (ACE) may occur in sarcoidosis, especially with extra-thoracic disease.¹³ More recent serological tests include soluble interleukin-2 receptor and neopterin.¹⁴ However, modern imaging techniques such as fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomography (PET) / computed tomography (CT) scanning appear to be even more sensitive than serological methods for detecting active disease.¹⁴ In the now outmoded Kveim–Siltzbach test, an extract of spleen tissue from a patient with sarcoidosis was injected into the skin of a patient suspected to have the condition. A positive result was characterised by the finding of granulomas within a biopsy from the injection area, 4–6 weeks later.¹⁵

The hallmark histological feature of sarcoidosis is the presence of numerous granulomas that contain giant cells (Fact Sheet 2.1) (Figure 2.1). Granulomas may be present within clinically involved sites or identified incidentally. The granulomas are characteristically well defined, and although some associated lymphocytic infiltrate is present, this is not usually dense in nature. The granulomas may contain inclusions such as Schaumann bodies (calcium and protein inclusions) and asteroid bodies (probably lipid inclusions) within the giant cells. Central necrosis is unusual and, especially in an appropriate clinical context, may raise suspicion for infective causes such as mycobacteria. However, there are descriptions of a variant of sarcoidosis characterised by the presence of necrotising granulomas.^{11, 16} In experienced hands, fine-needle aspiration cytology (e.g. endobronchial ultrasound-guided transbronchial needle aspiration [EBUS–TBNA]) can provide useful supporting evidence for a diagnosis of sarcoidosis.¹⁷

Figure 2.1(A) Liver biopsy in sarcoidosis showing a non-caseating granuloma with no surrounding cuff of chronic inflammation.

(B) A connective tissue stain (Masson’s trichrome) highlights the fibrosis associated with the granuloma.

Clearly, the index of suspicion for the presence of sarcoidosis at any particular site is significantly higher if the patient already has a condition at one or more other sites. Alternatively, a biopsy of liver, pancreas, or GI tract may contain granulomas, leading to a new diagnosis of sarcoidosis, and may act as the index biopsy even if the granulomas are ‘incidental’. In this circumstance, further clinical investigations often reveal asymptomatic disease at other sites.

Hepatic involvement by sarcoidosis may be identified on liver biopsy during the investigation of imaging-detected mass lesions, impaired liver function, portal hypertension, or, more rarely, cholestasis.

Differential Diagnosis

The differential diagnosis includes other conditions characterised by the presence of granulomas (Table 2.1). Some of these are also multisystem diseases. The potential causes of hepatic granulomas are particularly diverse, and Table 2.1 includes only the more common entities. Awareness of the clinical setting may well help to confirm or exclude certain differential diagnoses. For example, the patient may already have an established diagnosis of sarcoidosis or another granulomatous condition, e.g. Crohn’s disease. As hepatic sarcoidosis may be associated with damage to bile ducts, differentiation from primary biliary cholangitis (PBC) is often difficult. Additional histochemical stains, e.g. Ziehl–Neelsen (ZN) and periodic acid–Schiff (PAS), help to exclude infective organisms, particularly if there is no existing diagnosis of sarcoidosis or of any other non-infective granulomatous disease. It is also important to remember that the absence of infective organisms, e.g. acid-fast bacilli on ZN staining, does not exclude infection. In this setting, careful clinicopathological discussion together with ancillary tests (e.g. serology, molecular-based techniques such as polymerase chain reaction–based tests) may help exclude infectious disease.

Course and Treatment

The clinical outcome depends to a large degree on the pattern and distribution of the disease. GI tract involvement may determine the course of the disease, e.g. if widespread hepatic involvement is present. However, luminal GI tract involvement, especially as it is often asymptomatic, is less likely to be the dominant determinant of outcome. The inflammatory component of sarcoidosis usually responds well to immunosuppressant therapy. Steroids are the mainstay of treatment, although other immunosuppressants may be required in severe and/or longstanding disease (e.g. methotrexate, azathioprine). In cholestatic liver involvement, ursodeoxycholic acid can be useful for symptomatic relief. Hepatic sarcoidosis may not require specific treatment when mild. In chronic cases, the associated fibrosis can remain and lead to persistent problems, e.g. portal hypertension. Liver transplantation may be required in severe cases. In luminal GI involvement, surgery is sometimes required, e.g. if there is bowel obstruction or haemorrhage.

Brief Summary of the Condition

Amyloid is a group of proteins with a common, β-pleated sheet structure in which the constituent protein subunit may be one of several different types. Within amyloid, these precursor proteins are associated with a glycoprotein called the P-component. Amyloidosis is a condition characterised by the deposition of amyloid protein in an anatomically localised or diffuse distribution. Amyloid deposition occurs in the extracellular space and imparts a waxy texture to the tissue when advanced. Various types of clinicopathological scenario may underlie the development of amyloidosis.

Epidemiology

The underlying conditions that may be associated with amyloidosis are protean and therefore its incidence and other epidemiological factors vary according to other patient factors. Rare hereditary forms of amyloidosis may have geographical associations. For example, familial Mediterranean fever usually (but not exclusively) occurs in people of Mediterranean origin.

Clinical Features, Including Systems Involved

The clinical features of amyloidosis are very varied and depend on the distribution and severity of amyloid deposition. Deposition may occur in almost any tissue or organ, classically involving blood vessel walls but commonly also the interstitial compartment. Typically, amyloid deposition is diffuse within the affected site(s), leading to organ dysfunction such as cardiac failure or nephrotic syndrome. Sometimes amyloid deposition can form a mass that simulates a tumour. Clinical manifestations of amyloidosis may be superimposed on those of an underlying condition that is the reason for the development of amyloidosis, e.g. a B-cell lymphoma or a connective tissue disease (Table 2.2). Alternatively, amyloidosis may have few or no symptoms – even when there is relatively extensive deposition – and may therefore be an incidental finding. Within the GI tract, amyloid deposition may be associated with a range of symptoms, including diarrhoea, steatorrhoea, anorexia, weight loss, nausea/vomiting and gut dysmotility/pseudo-obstruction.^{18, 19}

Gastrointestinal Tract and Liver Involvement

The liver and luminal GI tract can show a wide spectrum of involvement by amyloidosis. Within the liver, amyloid deposition occurs particularly within the sinusoids and may be very extensive in advanced disease. The degree of amyloid deposition within the liver can be surprisingly marked before biochemical liver function becomes significantly impaired.

Within the luminal GI tract, amyloid deposition starts within blood vessel walls, with advancing disease characterised by more widespread deposition, e.g. within the lamina propria. Subepithelial amyloid deposition may require differentiation from collagenous colitis using additional histochemical stains.

Diagnosis, Including Role of Histopathology

Diagnosis relies on a combination of clinical assessment and the histological demonstration of amyloid deposition within tissues. Histopathology therefore plays a key role in the recognition of amyloidosis (Fact Sheet 2.2). There are several different scenarios. For example, GI tract mucosal biopsies may be taken specifically to look for evidence of systemic amyloidosis when the condition is suspected clinically. Biopsy of the rectum for this purpose is common, although there is evidence that gastric biopsies are associated with a better pick-up rate.¹⁹ Alternatively, the pathologist may diagnose amyloidosis as an incidental finding in biopsies from the liver or luminal GI tract in the absence of clinical suspicion for this condition. GI tract-related symptoms due to amyloidosis are usually non-specific (see earlier) but are within a group of clinical features that are very likely to result in GI tract–related investigations, including endoscopic mucosal biopsies.

Amyloid deposition has a characteristic glassy, eosinophilic appearance on haematoxylin and eosin (H&E) staining (Figures 2.2, 2.3, and 20.15). Evidence of early amyloid deposition should be sought in blood vessel walls (e.g. in portal tracts in liver biopsies) and in submucosa that is included in GI endoscopic biopsies. Amyloid deposition may occasionally be confused with other extracellular tissue depositions, e.g. thickening of the subepithelial collagen plate in refractory sprue and collagenous colitis. Additional histochemical and immunohistochemical stains may be particularly important in these circumstances to confirm the diagnosis. Congo red histochemistry is very useful for highlighting amyloid deposition, both under white light illumination and with the demonstration of ‘apple green’ birefringence under polarised light examination (Figure 2.2C). Immunohistochemistry for the P-component can also confirm amyloid deposition, while immunohistochemistry for amyloid A and light chains may help to differentiate between amyloid A and amyloid L. However, light-chain immunohistochemistry can be difficult to interpret and, in this respect, careful clinicopathological correlation is very useful. For example, additional clinical investigations may be instrumental in the identification of a monoclonal gammopathy, even if light-chain immunohistochemistry is inconclusive. Within the GI tract, AL amyloid (especially AL λ) is the most commonly found subtype, followed by AA and TTR-related amyloid in most series.^{20, 21} DNA extracted from formalin-fixed paraffin-embedded tissue is suitable for molecular assessment of the TTR genotype.²¹

Figure 2.2(A) Rectal mucosa and submucosa showing amyloid deposition that is most obvious in the submucosal blood vessels.

(B) Extensive dense accumulation of amyloid in the muscularis propria of the colon.

(C) A Congo red stain showing amyloid in the rectal muscularis mucosae, identifiable as ‘apple green’ birefringence under polarised light.

Figure 2.3(A) Liver biopsy in amyloidosis, showing extensive amyloid deposition within sinusoids and in a portal tract. The surviving hepatocytes are compressed and distorted.

(B) Immunohistochemistry for amyloid P-component confirms amyloid deposition.

Differential Diagnosis

Although the histological features of amyloid are characteristic and usually diagnostic, the differential diagnosis of amyloidosis is usually wider during initial clinical assessment, i.e. before the diagnosis is confirmed. This is also, in part, because the clinical manifestations of amyloidosis are so varied. For example, amyloidosis may lie within a wide clinical differential diagnosis in patients with malabsorption or with peripheral neuropathy.

While the histological appearance of amyloid is characteristic, it is important to recognise it where deposition is focal or subtle and in turn to confirm the disease using Congo red staining and/or immunohistochemistry. Light-chain disease is a condition characterised by the deposition of immunoglobulin light chains in, and sometimes beyond, the kidney, often in association with myeloma. This process may mimic amyloid deposition but is usually characterised histologically within the kidney by nodular sclerosing glomerulopathy.²² The deposited light chains can be highlighted using kappa or lambda immunohistochemistry but are negative on Congo red staining.

Course and Treatment

The identification of amyloidosis usually leads to a search for an underlying disease that predisposes to this condition. Histopathology can contribute to this process by subtyping the amyloid, where possible. The clinical course is often more dependent on the underlying condition, the diagnosis of which may have predated or followed the diagnosis of amyloidosis. The β-pleated sheet structure of amyloid results in the protein becoming insoluble. Therefore, reversal of most forms of amyloidosis probably does not occur, particularly when heavy deposition is present. Similarly, organ failure that is due primarily to heavy amyloid deposition is unlikely to recover significantly even if there is a treatable underlying condition.

Brief Summary of the Condition

The term ‘mastocytosis’ covers a spectrum of neoplastic conditions characterised by the presence of clonal mast cell infiltrates within involved tissues.²³ In urticaria pigmentosa, the infiltrate is centred on the skin. Systemic mastocytosis may be indolent or aggressive in nature and can be associated with the development of a range of leukaemias (Table 2.3).

Epidemiology

The prevalence of mastocytosis is difficult to determine because of the varied nature of the condition. While they remain rare, improved diagnostic techniques have led to greater awareness of mastocytosis and related conditions. Estimates of the prevalence in Europe range from 0.5 to 1 per 10,000.²³ Mastocytosis is most common in children, in whom cutaneous involvement is characteristic. Familial forms of mastocytosis also exist but are very rare.

Clinical Features, Including Systems Involved

Mastocytosis exists as a wide spectrum of conditions.²³ The clinical features may reflect the presence of mast cells themselves or of the mediators released from them, e.g. histamine and heparin. Urticaria pigmentosa occurs most commonly in children and is characterised by the development of erythematous macules, papules, and nodules, which often show dermographism (weal formation after rubbing the lesion). Systemic mastocytosis may be indolent and clinically silent, or an aggressive disease associated with the development of a range of leukaemic conditions. While indolent disease may be clinically occult, common symptoms of more aggressive systemic disease include pruritus, flushing, tachycardia, asthma, headache, and weight loss. Approximately 50%–80% of patients with systemic mastocytosis have GI tract–related symptoms. These include nausea and vomiting, abdominal pain, diarrhoea, and steatorrhoea.²⁴ Mastocytomas may present as cutaneous or deep-seated mass lesions and are often associated with systemic mastocytosis.

Gastrointestinal Tract and Liver Involvement

GI tract manifestations (Fact Sheet 2.3) include peptic ulceration. This and the clinical features listed in the preceding section are related to gastric hypersecretion and to the release of histamine and prostaglandins from mast cells. Histological features include mucosal villous atrophy, submucosal oedema, and variable but often marked mast cell infiltration within the lamina propria and submucosa. Mast cells may be present within glandular lumens, and degranulation is common. Eosinophils may also be prominent within the inflammatory infiltrate.

The liver is often involved in systemic mastocytosis. Hepatomegaly can occur. Histological features include mast cell infiltration of portal tracts and sinusoids (Figure 2.4). Fibrosis can occur but cirrhosis is uncommon.²⁵ Other possible manifestations include non-cirrhotic portal hypertension, cholestasis, and ascites.

Figure 2.4 (A, B) Liver biopsy in mastocytosis, showing portal tract expansion by a mixed inflammatory cell infiltrate including mononuclear cells and eosinophils. Immunohistochemistry for mast cell tryptase highlights mast cells within the portal tract (C) and parenchyma (D).

Diagnosis, Including Role of Histopathology

The diagnosis may be challenging, especially when the symptoms are mild and/or non-specific in nature. Many patients have characteristic skin lesions that may alert the clinician to the possibility of a mast cell disorder. Abnormalities of blood count, e.g. eosinophilia, may occur, particularly in more advanced disease. The serum tryptase concentration may be raised. Liver involvement leads to derangement of liver function tests and may result in ascites. Bone marrow involvement can lead to pancytopenia and/or to the features of a range of leukaemias, e.g. mast cell leukaemia and myelomastocytic leukaemia (Figure 2.5). Bone marrow smears can demonstrate prominent mast cell infiltrates, while marrow fibrosis may be apparent on bone marrow trephine (Table 2.4).

Figure 2.5(A) Bone marrow trephine in mastocytosis, showing a cluster of spindle-shaped cells (centre and left) together with numerous eosinophils.

(B) Immunohistochemistry for CD117 highlights the mast cell infiltrate.

Mastocytosis is a recognised cause of lymphoid infiltrates that are eosinophil-rich (Fact Sheet 2.4). In systemic mastocytosis, the neoplastic mast cells are commonly spindle shaped and this can lead to diagnostic confusion.

Mast cells can be difficult to identify on haematoxylin and eosin staining. Histochemical stains such as toluidine blue can highlight them, but immunohistochemistry (e.g. mast cell tryptase, CD117) is usually required. Differentiation between reactive and neoplastic mast cell infiltrates may also be facilitated using immunohistochemistry (e.g. CD25, which is expressed by neoplastic mast cells).²³ Measurement of the serum tryptase concentration and identification of the characteristic KIT gene D816V mutation using polymerase chain reaction (PCR)-based techniques is a very useful and relatively new test for confirmation of the diagnosis and monitoring of disease.^{26, 27}