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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3182a92dc3
Review Articles

Modern Approaches to the Treatment of Amyloidosis: The Critical Importance of Early Detection in Surgical Pathology

Picken, Maria M. MD, PhD, FASN

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Author Information

Department of Pathology, Loyola University Medical Center, Maywood, IL

The author has no funding or conflicts of interest to disclose.

Reprints: Maria M. Picken, MD, PhD, FASN, Department of Pathology, Bldg 110, Rm 2242, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153 (e-mails: mpicken@lumc.edu; mmpicken@aol.com). All figures can be viewed online in color at http://www.anatomicpathology.com.

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Abstract

The amyloidoses comprise a group of disorders of diverse etiology, in which different proteins undergo abnormal folding, leading to their deposition in tissues and concomitant tissue toxicity. This process ultimately leads to tissue destruction, with organ failure and progressive disease. Recent progress in the treatment of the systemic amyloidoses has dramatically changed the outlook for affected patients and their families. From a relatively rare and esoteric disorder that was typically diagnosed only at autopsy, or was invariably fatal if diagnosed during life, it has now become a disease for which, with modern therapies, durable responses and long-term survival can be achieved. The clinical symptoms are largely nonspecific, and therefore misdiagnosis, or late diagnosis, have been major detriments in achieving better treatment outcomes. Despite advances in laboratory medicine, amyloidoses are still diagnosed on the basis of the pathologic detection of deposits in tissues. Thus, effective primary screening for these diseases requires the active engagement of the pathology community at large, while specialized laboratories and treatment centers can offer secondary consultation and assistance with further steps. This review provides an update on pathogenesis, the clinical and pathologic features, and treatments of various amyloidoses, as well as the current terminology, classification, and practical considerations that are relevant to the diagnosis.

Amyloid means “starch-like.” Rudolf Virchow, a German pathologist, first introduced this term in 1853 in connection with certain tissue deposits, which, when stained with iodine, behaved in a manner similar to starch.1 However, the term amyloid is a misnomer, as the deposits that it is meant to denote are actually derived from proteins, which undergo abnormal folding and, as such, deposit in tissues where they exert a direct toxic effect.2 This process ultimately leads to tissue destruction, with organ failure and progressive disease. Although, initially, amyloid was thought to represent a single entity, recent decades have led to the discovery of different amyloid types, which are, in turn, associated with clinically different diseases, including neoplasia and inflammatory, degenerative, genetic, and iatrogenic processes. Currently, >28 different proteins, and many more variants, have been shown to be amyloidogenic. Despite the diversity of proteins that are capable of undergoing amyloidogenesis, all types of amyloids share a β-pleated sheet secondary structure, which confers stability under physiological conditions and imparts common staining properties and distinctive electron microscopic characteristics. Thus, amyloid deposits are Congo red positive and exhibit apple-green birefringence when viewed under polarized light (Fig. 1). By electron microscopy, amyloid deposits are distinctly fibrillar, consisting of rigid, nonbranching fibrils that are, on average, 7 to 10 nm in diameter. Despite advances in laboratory medicine, amyloidoses are still diagnosed on the basis of the pathologic detection of deposits in tissues, and hence the pathologist plays a critical role in patient management.3 This review provides an update on the classification, current terminology, pathogenesis, clinical and pathologic features, and treatment options for various amyloidoses, as well as practical considerations relevant to the diagnosis.

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NOMENCLATURE AND CLASSIFICATION

The current amyloid nomenclature is based on the chemical structure of the fibril protein.2 Thus, a letter A (for amyloid) is followed by a suffix that is an abbreviated form of the precursor protein’s name. In amyloidosis associated with an underlying plasma cell dyscrasia (PCD), amyloid is derived from immunoglobulin light chains, and the amyloid fibril is designated as AL and the disease is AL amyloidosis. In amyloidosis derived from the acute-phase reactant serum amyloid A protein (SAA), the amyloid type is designated AA. In hereditary (familial) amyloidoses that are associated with mutations in the amyloid protein, in addition to the general amyloid designation derived from the name of the involved protein (eg, ATTR=amyloidosis derived from transthyretin), the location of the mutation and the amino acid substitution are also indicated (eg, ATTRV30M). Older designations of amyloid of different types, which were based solely on clinical features, are ambiguous, and their use is not recommended.2,3 Amyloid deposits may be systemic or localized.4–9 Amyloidoses that affect the central nervous system, which are typically localized and generally not systemic to a clinically significant degree, are not included in this review. Table 1 lists the currently known systemic amyloidoses. A number of proteins are known to form localized cerebral (both acquired and hereditary) or extracerebral amyloid deposits.2,4–7 Alzheimer disease is the most prevalent form of cerebral amyloid; it is derived from a wild-type precursor of Aβ protein. Among extracerebral localized deposits, several types are derived from various hormones or are associated with various tumors and/or ageing.4–7

TABLE 1
TABLE 1
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PATHOGENESIS OF AMYLOID FORMATION: GENERAL COMMENTS

Under normal circumstances, the conformation and function of the proteome is regulated by a network of protein chaperones, which protect the proteins from misfolding.10–12 This latter process, which leads to protein aggregation and fibrillogenesis, is the essence of amyloidogenesis and may also be associated with many clinical aspects of our lives, ranging from neoplasia, inflammation, genetics, and neurodegeneration to ageing.

Amyloid formation usually involves a combination of several factors such as increased and prolonged protein supply and/or a propensity of the protein to acquire a β-pleated sheet conformation, which may be caused by a mutation or be acquired during proteolytic cleavage or may be intrinsic to a normal protein, making it susceptible to environmental factors that favor amyloidogenesis (Fig. 2). In addition to the amyloid protein, which is the main element of the fibril, several additional components are present in all types of amyloid deposits, such as amyloid P-component (SAP), proteoglycans, and glycosaminoglycans.10–12 These components contribute to the formation and stabilization of amyloid fibrils. It is also postulated that these components may influence the specific organ/tissue localization of amyloid deposits through their interaction with the extracellular matrix. In recent years, it has been realized that the pathogenicity of amyloid is not purely mechanical—that is, a consequence of atrophy caused by expanding deposits—but that the actual process of amyloid formation, in particular the prefibrillar species, is also implicated in direct tissue toxicity.

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In systemic disease, the amyloid protein is synthesized remotely by the bone marrow cells or the liver and circulates in the blood with deposition at multiple organ sites. In contrast, localized deposits of amyloid are typically limited to 1 site (or organ system), and the protein is not detectable in the circulation.4–7 In several systemic amyloidoses, deposits are also present in the subcutaneous fat, and hence fat biopsy is typically performed to ascertain whether the disease is systemic or localized.8,9 This latter distinction is clinically important, as treatments for systemic amyloidoses differ from those used for localized forms. Although the majority of localized deposits of amyloid are derived from immunoglobulin light chains, other proteins can also be involved.

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INCIDENCE

Systemic amyloidosis is a rare disease. According to estimates by the Mayo Clinic, the incidence of amyloidosis is 8 cases per million people per year in the United States (or 3000 people in total).1 However, the disease may be underdiagnosed, both in the United States and worldwide.

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TYPE-SPECIFIC AMYLOIDOSES

Immunoglobulin Amyloidoses

Amyloidoses associated with an underlying PCD include those with deposits derived from immunoglobulin light chain (AL) or heavy chain (AH), with AL accounting for the majority of cases.10–15 Recently, it was also proposed that, on rare occasions, amyloid fibrils may be derived from both light and heavy chains.16 Formerly, AL was referred to as either “primary amyloidosis” or “amyloidosis associated with multiple myeloma.” However, only 5% of AL patients present with an accompanying multiple myeloma, whereas the majority are diagnosed with PCD.

It is noteworthy that PCD is broadly defined as a proliferation of monoclonal plasma cells/B lymphocytes with plasmacytic differentiation producing a monoclonal protein (M-component).17 Thus, when broadly defined, PCD includes a wide spectrum of diseases ranging from overt myeloma to conditions with a small burden of monoclonal cells.17–19 Although, as a generic term, PCD is frequently used to encompass the entire spectrum of monoclonal proliferation by plasma cells, there are actually 3 defined clinical entities associated with this process, which include multiple myeloma, PCD (sensu stricto), and monoclonal gammopathy of unknown significance (MGUS) (Table 2). By definition, MGUS is associated with an isolated M-component in the serum in the absence of clinically apparent disease. In patients with multiple myeloma, the clinical manifestations are primarily due to the large tumor burden, whereas in patients with PCD the morbidity is mainly caused by the M-component, which is produced by a relatively small clone of plasma cells (Fig. 3).10–13 Thus, in the latter condition, the bone marrow biopsy frequently fails to show plasmacytosis, and many patients diagnosed with AL cannot be demonstrated to have a circulating M-component by serum and urine electrophoretic or immunofixation methods. Hence, formerly, the term “primary” amyloidosis was used when referring to such patients. However, the serum free light-chain (sFLC) assay, introduced in the early 2000s, which allows the detection and measurement of the concentration of free monoclonal light chains that are unbound to heavy chains, allows the detection of M-component in most (but still not all) patients with AL.20–22 As the concentration of sFLCs is several orders of magnitude lower than that of light chains bound to heavy chains, in the earlier testing methods the circulating sFLCs were frequently obscured by the polyclonal chains bound to heavy chains (Fig. 4).

TABLE 2
TABLE 2
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It is important to stress that AL amyloidosis primarily develops in patients with a small tumor burden and that the clinical manifestations are dominated by end-organ damage caused by the amyloidogenic light chains (M-component). Despite being small, this clone is very dangerous as it produces a very toxic protein, leading to a devastating systemic disease (Fig. 2). In addition to AL, the damage caused by the M-component can result in light-chain deposition disease (LCDD), crystal-storing histiocytosis, monoclonal cryoglobulinemia, and other disorders.18,19 Thus, in such patients, the diagnosis of amyloidosis, or other evidence of damage caused by the M-component, is an important trigger for aggressive therapy, which would not otherwise be considered for patients with a similarly sized small clonal plasma cell proliferation.18,19 These latter patients would belong to the MGUS category, which carries a relatively low potential for malignancy and is therefore managed conservatively.

It is understood that the amyloidogenicity of immunoglobulin light chains is dependent on their specific structural features. Thus, in most cases (75%), AL amyloid is derived from the λ light chain, which is in contrast to other plasma cell disorders and to localized AL amyloidosis. In addition, in AL, there is restricted usage of a small subset of genes with overrepresentation of certain families, 1 of which (eg, the λVI family) is almost invariably associated with AL amyloidosis. It is believed that mutations in immunoglobulin light chains may have a destabilizing effect on their structure and, consequently, increase their propensity to undergo misfolding and aggregation. In AL amyloidosis, amyloid fibrils are composed of immunoglobulin light-chain fragments containing the V region, or the V and C regions, or a combination, including also a seemingly intact light chain. Rare cases of AH, amyloid derived from a truncated heavy chain, have also been reported, and recently it has been reported that in some patients amyloid deposits may contain both light and heavy chains.

Although both systemic and localized AL amyloidoses are derived from an N-terminal segment of a monoclonal immunoglobulin light chain, there are notable differences. Typically, in localized AL amyloidosis, the deposits occur in proximity to the clonal plasma cells and giant cells. Thus, localized AL amyloidosis (amyloidoma) represents a true plasma cell neoplasm and not a pseudotumor. It has been proposed that the giant cells in AL amyloidosis directly participate in the transformation of the soluble full-length light chains into insoluble fibrils. However, the genesis and function of multinuclear giant cells, which are typical of certain infections/inflammation, are still poorly understood.

Although AL/AH amyloidosis primarily affects older individuals, average age at diagnosis being 65 years, the disease may be diagnosed over a wide age range, from 23 to 91 years. The clinical manifestations of AL/AH amyloidosis, in general, are typically rather nonspecific and virtually always include fatigue and weight loss. Renal involvement is seen in 70% of patients, whereas cardiac involvement is seen in 60%. Thus, proteinuria and/or cardiac failure are the most common clinical presentations. Other sites involved include peripheral and autonomic neuropathy, liver enlargement, soft tissues deposits with macroglossia, periorbital purpura, submandibular swelling, “shoulder pad,” carpal tunnel syndrome, and nail lesions.11

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Nonimmunoglobulin Amyloidoses

AL amyloidosis is the most common type of systemic amyloidosis in the United States and the western world, where it constitutes 85% of all cases of systemic amyloidosis. AA amyloidosis, the second most common type of renal amyloidosis, accounts for 5% to 7%, and other types collectively account for approximately 10%.24

AA amyloidosis may occur in either sporadic or familial settings, including familial Mediterranean fever and other autoinflammatory diseases.25–28 Amyloid fibrils are derived from a truncated SAA, which is a major acute-phase reactant. Although its normal physiological function is largely unknown, it is understood that SAA plays a role in inflammation and pathogen defense. Thus, AA amyloidosis develops in association with an enhanced and prolonged inflammation that leads to a sustained upregulated production of SAA and, subsequently, to its incomplete degradation, misfolding, and deposition in the tissues. In familial Mediterranean fever and other autoinflammatory diseases (including Crohn disease) upregulated production of SAA is due to genetic defects in proteins involved in the modulation of the inflammatory response. AA amyloidosis involves the kidney and gastrointestinal tract, and nephrotic syndrome/proteinuria is the most frequent clinical presentation (97%).25 In one large European series, the median age at diagnosis was 50 years, but the age range was wide, from 9 to 87 years.25

ALect2 amyloidosis, derived from leukocyte chemotactic factor 2, was recently recognized. It has emerged as the third most common form of renal amyloidosis, typically associated with renal failure in the absence of significant proteinuria.29–32 ALect2 may also involve the liver and spleen. Although no specific mutation has thus far been demonstrated, this amyloidosis type is seen mainly among Mexican and Punjabi individuals.

Hereditary systemic amyloidoses include, thus far, amyloidoses derived from transthyretin (ATTR), fibrinogen (AFib), apolipoproteins AI and AII (AApoAI and AApoAII, respectively), lysozyme (ALys), gelsolin (AGel), and cystatin (ACys); it is also possible that other types may be discovered in the future.33–39 Although hereditary (also termed familial) systemic amyloidoses are individually rare, collectively as a group they are relatively common and constitute approximately 10% of systemic amyloidoses. It is also postulated that these disorders may be underdiagnosed. In hereditary amyloidoses, a mutation is considered to predispose to amyloidogenesis; however, despite the inheritance of the predisposing mutation, the disease is typically not clinically apparent until later in life. Moreover, even though these mutations are all inherited as autosomal dominant traits, because of variations in genetic penetrance a family history may not be present. Phenotypically, hereditary amyloidoses may be similar to AL, and hence diagnosis of the amyloidosis type on clinical grounds is not possible. Thus, amyloid protein typing is now mandatory for this disease, as treatments are markedly different (please see below). Genetic testing is recommended to support a tissue diagnosis of hereditary amyloidosis but not to make it.40 Regrettably, it has been shown that some patients with hereditary amyloidoses were misdiagnosed as AL and given inappropriate and, frankly, detrimental treatment.41,42 Finally, although certain hereditary amyloidoses are concentrated in particular geographic locations, or affect defined ethnic groups, these various diseases have been diagnosed in many patients throughout the world. In the United States 85% of familial amyloidosis is due to ATTR and 5% is due to AFib, whereas in Europe AFib is the most frequent hereditary amyloidosis.

ATTR, amyloidosis derived from transthyretin, is typically associated with cardiac involvement and peripheral neuropathy. Transthyretin, a carrier protein for thyroid hormone and retinol binding protein, is synthesized primarily by hepatocytes. Transthyretin is composed of 127 amino acids, and 4 of these monomers form a tetramer, which circulates in the blood. In vitro studies have demonstrated that mutations in the TTR gene compromise the stability of the tetramer and, thereby, lead to the formation of monomers, which are prone to misfolding and aggregation (Fig. 5).43 It is these intermediates rather than the mature fibrils themselves that are toxic. While familial ATTR is concentrated in Portugal, Sweden and Japan, the disease has been documented worldwide. Almost 4% of African Americans carry a mutation that probably originated on the west coast of Africa.44 However, even wild-type transthyretin, which inherently has an extensive β-pleated sheet structure, can undergo fibrillogenesis in older patients, who then develop senile systemic amyloidosis (SSA).45,46 The latter affects predominantly the heart and has been referred to colloquially as “cardiac Alzheimer’s.” The median survival time in SSA is 60 months. SSA is found as “an incidental autopsy finding” in approximately 25% of persons over the age of 80 years. Although many patients have clinically silent or insignificant deposits, some patients suffer from massive deposition of wild-type TTR, which typically manifests itself clinically in the seventh decade of life as congestive heart failure or arrhythmia. Symptomatic SSA occurs almost exclusively in men.

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AFib, amyloidosis derived from fibrinogen, is characterized by predominantly renal involvement and manifests itself as nephrotic syndrome and hypertension.35–37,39 However, more recent reports also suggest a systemic involvement. Fibrinogen is produced exclusively by the liver.

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DIALYSIS-ASSOCIATED AMYLOIDOSIS

Dialysis-related amyloidosis develops in patients with chronic renal failure who are undergoing long-term hemodialysis.47 The amyloid fibril is derived from β2-microglobulin, a small, 11,800 Da protein with a predominantly β-pleated sheet secondary structure, which is primarily eliminated by the kidney. This protein is not efficiently removed during dialysis, and hence its serum concentration increases markedly in patients receiving maintenance hemodialysis. Although there is no direct correlation between the absolute concentration of β2-microglobulin and amyloidosis-related symptoms, high serum levels of this protein are believed to be the basis of amyloid deposition in tissues. Although kidney transplantation has been effective in the management of this disease, newer generations of dialysis membranes also show some promise in addressing this issue.

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TREATMENT OF SYSTEMIC AMYLOIDOSES

From the point of view of patient treatment, and in the absence of dialysis, the diagnosis of renal amyloidosis should be considered to comprise 3 main categories: AL, AA, and hereditary types (Table 3).48–57 The treatment of patients with systemic AL targets the underlying PCD, whereas in patients with AA control of the acute-phase response is the ultimate goal of therapy.48–54 In several hereditary amyloidoses, liver transplantation is performed to eliminate the source of the abnormal protein but other, pharmacologic therapies are also currently being tested.55–57 In general, the overall prognosis in untreated amyloidosis varies with the type and the extent of clinical organ involvement. The last 2 decades have been associated with major advances in the treatment of systemic amyloidoses. In general, in all types of systemic amyloidosis, survival time has been shown to be extended by early intervention.

TABLE 3
TABLE 3
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Introduction of high-dose Melphalan and autologous blood stem cell transplantation for the treatment of AL amyloidosis in the mid-1990s has led to a marked improvement in overall survival. The immunomodulatory drugs, such as thalidomide and its derivatives, and, more recently, proteasome and aggresome inhibitors have further expanded the treatment options. Currently, rates of overall median survival of between 5 and 6.3 years are being reported, with a subset of patients surviving >10 years. However, late diagnosis, after advanced organ dysfunction has occurred, remains a major impediment to improving outcomes, and 30% of patients still die within a year of diagnosis.

In AA amyloidosis, control of the acute-phase response is currently the standard of care. Thus, disease-modifying antirheumatic drugs, antitumor necrosis factor therapies, and other biological agents have been used to treat inflammatory arthritides and autoinflammatory diseases (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Antibiotics and surgery have been used in the control of chronic sepsis.

The treatment of hereditary amyloidosis is evolving with regard to its form (from surgical to pharmacologic) and with regard to the timing of the intervention (from, historically, intervention at an advanced stage of the disease to the recent shift toward preemptive intervention).56 In hereditary amyloidoses, wherein the liver is the predominant (transthyretin), exclusive (fibrinogen), or partial (apolipoprotein AI) source of abnormal protein, liver transplantation has been offered to affected patients as a form of “surgical” gene therapy. In this therapy, replacement of the variant gene with a normal gene is achieved by replacement of the liver. Thus, in the early 1990s, the first patients with hereditary ATTR were treated in this manner (see the website tracking this activity at: http://www.fapwtr.org).55 Moreover, to alleviate organ shortage, the explanted livers have been offered to patients who otherwise would not qualify for transplantation, predominantly due to malignancy (this is termed “domino transplantation”). Currently, liver transplantation is an acceptable treatment option, which halts progression of the disease; however, long-term outcomes are variable, and other, pharmacologic therapies are currently being tested for ATTR. In AFib, initially kidney transplantation alone was offered to patients who developed renal amyloidosis with organ failure. However, solitary renal allografts ultimately failed because of the recurrence of the amyloidosis; thus, combined liver/kidney transplantation was introduced. However, the issue of precisely when to intervene, in a patient with an inborn defect that may potentially lead to amyloidosis in later life, is still under debate.56,57 In general, transplantation performed at the early stages of clinically apparent amyloidosis offers a better outcome than that performed at advanced stages of the disease; moreover, in AFib, early liver transplantation may reverse the renal failure and, hence, eliminate the need for renal transplantation. However, others now argue that preemptive liver transplantation, before the appearance of overt signs of disease, may prevent not only kidney failure but also the development of other systemic pathologies that may be associated with the mutation and which, hitherto, have not been fully understood (Fig. 6).57 Ultimately, however, only gene therapy, when it becomes available, may offer a fully satisfactory solution.

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DIAGNOSIS OF AMYLOIDOSIS

Although treatment options are expanding, the most critical step in patient management is the initial detection of amyloid in tissues.3,58 This generic diagnosis of amyloid must be done by the general surgical pathologist and is very challenging as the diagnosis of amyloid requires a special stain and an increased index of suspicion for this rare disease. This constellation of impedimenta poses a particular challenge in the diagnosis of early disease.

Regardless of the amyloid type, the light microscopic features are similar. In hematoxylin and eosin-stained sections, amyloid may be seen as eosinophilic, amorphous, “hyaline-like” extracellular material present in the interstitium and/or vascular wall. However, definitive diagnosis of any type of amyloid deposits must be based on the examination of a Congo red-stained slide, viewed under polarized light, with the demonstration of “apple-green” birefringence (Figs. 1, 7). Although, in bright light, amyloid deposits stained with Congo red appear pink, this in itself is not diagnostic. Moreover, it must be stressed that early deposits of amyloid may be inconspicuous in hematoxylin and eosin-stained sections, and hence Congo red staining must be performed not only to confirm suspicion of amyloid but also to rule out its presence (Fig. 7).

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A detailed technical description of the Congo red stain is beyond the scope of this review (the reader is referred to several reviews dealing specifically with this issue: Picken58 and Linke59); however, a few points need to be briefly mentioned. Although some pathologists use thicker sections (cut at 4 to 8 µm) for Congo red staining, this is not absolutely necessary. It is true that in thicker sections small deposits are less likely to be missed. However, the sensitivity of birefringence depends on the intensity of the transmitted light, pupil accommodation, and awareness of the “polarization shadow.” Owing to the latter, at any given time, only a portion of the amyloid deposit shows green birefringence, and specimen rotation is required to visualize the entire area containing deposits. Conversely, if excess Congo red dye is retained by the tissue, it can lead to false birefringence.

Admittedly, the evaluation of Congo red birefringence is not easy, and a certain amount of experience is needed. In this context, 2 additional methods may be considered helpful, namely Congo red fluorescence and thioflavin stains (Fig. 7).59,60 Although ultimately confirmation with Congo red birefringence is needed, both of these alternative methods are more sensitive and easier to interpret. However, they both require familiarity with fluorescence microscopy. Congo red dye itself is also a fluorochrome and can be examined under fluorescent light. Although different filters may be used, in the author’s own experience a tetramethylrhodamine isothiocyanate filter gives the best results (Fig. 7D). The thioflavins (T or S) are also widely used for staining amyloid fibrils, both in vivo and in vitro.61 Thioflavin derivatives have also been tested as alternative amyloid stains in the medical imaging of amyloid in living patients and have been used extensively in research. Other stains, such as crystal violet, methyl violet, Sirius red, and sulfated Alcian blue, are less sensitive and less specific and should not be used.

In systemic amyloidosis, deposits are also typically present in the abdominal fat pad. Hence, if amyloidosis is suspected clinically, a fat biopsy may be used as a surrogate tissue biopsy to screen for amyloid (Fig. 1).8,9 A fat biopsy can be obtained by fine-needle aspiration or as a small surgical biopsy (Fig. 8). Although both procedures can be performed at the bedside with only local anesthesia, a surgical biopsy offers a better yield of diagnostic material, which can be used not only to establish the generic diagnosis of amyloid but also for the determination of the amyloid type. Indeed, the detection of amyloid deposits should always prompt subsequent investigations as to the amyloid protein type and a determination of whether this is a systemic or localized process.

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Although the clinical picture may be amyloid protein type-dependent, with some types being dominated by cardiac and/or peripheral nerve involvement and others by renal signs and symptoms, the clinical phenotype alone is insufficient to diagnose the amyloid type. The latter must be based on the identification of amyloid protein in tissue deposits.62

Currently, precise identification of the amyloid protein type (referred to as “amyloid typing”) is the standard of care because currently available therapies are amyloid type-specific. Various antibody-based techniques [immunofluorescence stains on frozen tissues (Fig. 9), immunoperoxidase stains on paraffin sections (Fig. 10), immuno-electron microscopic labeling procedures, and Western blot methods] and biochemical methods, including the more sophisticated mass spectrometry (MS)-based proteomics techniques, have been applied to amyloid typing.63–69 The currently available proteomics methods are applicable to small biopsy samples and also to paraffin-embedded tissue.69 An important rationale for the application of proteomics methods to amyloid typing lies in the relative abundance of amyloid protein in the tissue, where it is frequently the dominant protein. Although specialized laboratories are available to perform proteomic amyloid type studies, antibody-based methods continue to be widely used. It must be stressed that the immunohistochemistry of amyloid differs significantly from that encountered in other areas of general surgical pathology, and caution and experience are necessary for its interpretation. Amyloid immunohistochemistry presents the pathologist with a major challenge because of (i) the lack of commercially available amyloid-specific antibodies (as opposed to the native proteins); (ii) the heterogeneity of amyloid proteins (and their variants); (iii) the lack of amyloid type-specific antibodies; and (iv) serum contamination, resulting in a background stain that competes with the signal from the amyloid protein. This latter feature is particularly apparent in paraffin sections. Thus, amyloid typing is best performed by experienced laboratories, specializing in such testing (Fig. 10).

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FIGURE 10
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Amyloid typing using immunofluorescence on frozen sections is superior to immunohistochemistry on paraffin sections, as the issues of altered antibody reactivity and background staining are less of an impediment to successful amyloid typing (Fig. 9).66 The immunohistochemistry results must be interpreted in the context of a prior Congo red stain. The direct combination of a traditional Congo red stain together with immunohistochemistry—the soi-disant “overlay technique”—has also been used in some laboratories.

Although MS-based proteomics is gaining popularity, the question remains whether the technique should replace, or complement, the existing methods.70 Currently, the complementary approach would seem to be the safer and more reasonable choice. In this connection, the discovery of new amyloid types, as a consequence of the use of MS techniques, is being validated by immunohistochemistry. In addition, at the present time, antibody-based methods would seem to be better suited to the detection of very small deposits, as the effectiveness of the MS-based proteomics technique is currently limited by the abundance of amyloid in the tissue examined. Now that emphasis has shifted decidedly toward the early detection of amyloid in patient specimens, wherein very small deposits are the rule rather than the exception, this may be to the relative disadvantage of MS-based proteomics.

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FUTURE PERSPECTIVES

The typing of amyloid proteins using luminescent conjugated polythiophenes, fluorescent probes that bind selectively to protein aggregates, is currently being tested.71 More importantly, well-defined probes called luminescent conjugated oligothiophenes have been devised, which can be used for real-time in vivo imaging of amyloids. It has even been postulated that such probes may allow the detection of early species involved in the formation of amyloids.71

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DIFFERENTIAL DIAGNOSIS AND PITFALLS

Among various proteinaceous deposits found in tissues, only amyloid is positive with the Congo red stain; other organized deposits (cryoglobulins, immunotactoid deposits, fibrillary deposits) and other disease entities, such as nonorganized monoclonal LCDD and hyalinosis, are negative.72 It is noteworthy that deposits found in LCDD, which are also associated with PCD, may mimic AL. Thus, in such cases, a negative Congo red stain should prompt further investigations to also rule out the presence of LCDD deposits. Note also that, although the kidney is the organ most frequently affected by LCDD, other organs may be affected, in particular the liver and heart. Deposits of LCDD are truly systemic and have been reported in the lymph nodes, bone marrow, spleen, pancreas, thyroid gland, submandibular glands, adrenal glands, prostate, testes, gastrointestinal tract, abdominal vessels, lungs, skin, along the nerve fibers, and in the choroid plexus. Similar to AL, LCDD may be responsible for peripheral neuropathy, gastrointestinal disturbances, pulmonary nodules, amyloid-like arthropathy, and sicca syndrome. These deposits are typically seen along basement membranes, which may be thickened. The demonstration of light-chain restriction by immunohistochemical stains is needed for diagnosis.72,73

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ORGAN SYSTEM INVOLVEMENT

Kidney and Genitourinary Tract

Essentially all systemic amyloidoses can involve the kidney, and, conversely, the kidney is the organ most commonly involved by clinically significant amyloid deposits, which are virtually always a part of systemic disease (Fig. 10).73,74 Extrarenal amyloid deposits, involving other segments of the genitourinary tract, are not commonly reported.73–77 When present, however, deposits of amyloid may be part of a systemic or localized process. Whereas systemic deposits are usually either clinically silent or less prominent, localized deposits may mimic tumors, both clinically and radiologically.75 Their clinical management therefore includes conservative surgery. There is extensive literature pertaining to systemic amyloidoses involving the kidneys, and a detailed description of these entities is beyond the scope of this review.73,74

Traditionally, renal amyloidosis has been detected more readily than amyloid occurring elsewhere. In addition, renal amyloidosis is more likely to be associated with clinically detectable symptoms and/or laboratory abnormalities, which are likely to prompt a kidney biopsy; as a matter of routine, the latter are more extensively investigated than other biopsies in surgical pathology. The differential diagnosis of proteinuria/nephrotic syndrome also includes renal amyloidosis. Conversely, kidneys are the most frequently involved organ in AL amyloidosis (70%), AA amyloidosis (>95%), and AFib (virtually 100%). Routine testing of kidney biopsies for light chains, in particular using immunofluorescence in frozen sections, has been very helpful in the typing of many cases of AL amyloid and is also critical in the detection of other kidney pathologies associated with an underlying PCD/B-cell lymphoproliferative disorder that are Congo red negative.

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Cardiac Amyloidosis

Amyloid deposits can be detected in the ventricular or atrial myocardium, the sinoatrial and atrioventricular conduction system, the valves, and the intramural coronary arteries.78–82 In addition, cardiac amyloid deposits can be associated with systemic amyloidosis or be localized. Three major types of amyloid deposits can affect the heart: AL (Fig. 9) and 2 types of amyloids derived from transthyretin—mutant (hereditary ATTR) or wild type (wATTR); other forms are rare.45,46,78–82

In AL, cardiac involvement is seen in about 60% of patients. Although cardiac AL is typically associated with the involvement of other organs, cardiac symptoms usually dominate the clinical picture, and, despite a relatively mild burden of deposits, there is a rapid progression into cardiac failure. It is postulated that the prefibrillar amyloid precursors, rather than the mature fibrillar deposits, are directly cytotoxic to myocytes. Hence, diagnosis of cardiac AL calls for rapid and aggressive treatment targeting the precursor protein. Cardiac involvement in AL confers a poor prognosis, with a median survival of 1 year from the time of diagnosis, whereas in patients who manifest with heart failure the median survival time is only 6 months. Cardiac involvement is the leading cause of death in AL amyloidosis; death may be due to progressive heart failure or sudden cardiac death presumed to be the result of arrhythmia.

In hereditary ATTR, cardiac involvement may be associated with peripheral polyneuropathy and gastrointestinal symptoms. In wild-type ATTR, the heart is the predominant site of amyloid deposition, whereas systemic deposits are typically confined mainly to the walls of arteries of the different organs. Other forms of hereditary autosomal dominant systemic amyloidoses are rare but have been reported to involve the heart in some cases, and hence amyloid typing is mandatory before specific therapy can be considered.

Isolated atrial amyloidosis and isolated aortic amyloidosis are age related.5,6,78 The former, derived from atrial natriuretic factor produced by atrial myocytes, is seen in patients with left atrial dilatation and chronic atrial fibrillation. Cardiac valves are commonly infiltrated in systemic amyloidosis where deposits may be grossly visible and cause regurgitation, whereas localized small deposits of amyloid are incidental findings of no clinical importance. Medin, derived from lactadherin expressed by smooth muscle cells, aggregates into amyloids in certain arteries, particularly the thoracic aortic media layer, and may have a role in the generation of the potentially lethal conditions of thoracic aortic aneurysm and dissection.5

The main differential diagnosis of an expanded interstitium in the heart is fibrosis. Amyloid deposits may occasionally elicit a giant cell response, and this should not be misdiagnosed as giant cell myocarditis or even sarcoidosis. Cardiac LCDD has to be considered in patients with PCD.83,84

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Peripheral Nerve

Peripheral nerve involvement is a frequent presenting feature of systemic amyloidosis.85–90 However, because the clinical features may mimic different types of peripheral neuropathy, pathologic diagnosis of unsuspected amyloidosis is common. Peripheral nerve amyloidosis may be associated with AL, hereditary ATTR, AGel, and AApoA-1. Amyloid deposits may be seen in the interstitium of affected nerve fascicules and in the endoneurial microvessels. Typically, there is axonal degeneration at the level of the amyloid deposition, but there seems to be little correlation with the amount of amyloid deposition and the severity of neuropathy. Clinically, there is symmetric lower extremity sensorimotor peripheral neuropathy. In addition, usually there is involvement of the autonomic nerves and small fibers with painful acral paresthesias, thermanesthesia, erectile dysfunction, voiding dysfunction not related to direct organ infiltration, gastrointestinal dysmotility with gastric-emptying disorder, and pseudobstruction. Amyloid deposits may also form focal macroscopic aggregates, which are termed amyloidomas.91 In patients with PCD and Waldenstrom macrogobulinemia, intraneural deposits of IgM may mimic amyloids.89

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Gastrointestinal Tract

Amyloids affecting the gastrointestinal tract or liver may be relatively asymptomatic or associated with dysmotility, malabsorption with watery diarrhea that may be intractable, bleeding, or polypoid deposition, or with elevated alkaline phosphatase, hepatomegaly, and jaundice, respectively.92–98

Any segment of the gastrointestinal tract can be involved by amyloids. As with other sites, there does not appear to be any pattern of amyloid deposition that is characteristic of any particular amyloid type. The tongue, which is typically involved in AL, has also been shown to be involved in other amyloidoses. With endoscopic biopsies frequently being performed, and for diverse symptoms, it is important to keep amyloidosis in mind as a differential diagnosis, as endoscopic biopsies provide an important source of tissue for diagnosis (Fig. 11). Amyloid deposits can be seen in the lamina propria, muscularis propria, and the vasculature. Rectal (and gingival) biopsies, which were formerly performed in patients suspected of having amyloid, have been largely replaced by abdominal fat biopsies. Amyloid in the colon may also be deposited in the subepithelial space of the mucosa, in a manner reminiscent of collagenous colitis. Amyloidosis can also be mimicked by mucosal ischemic changes.

FIGURE 11
FIGURE 11
Image Tools

The liver is frequently involved in patients with systematic amyloids (up to 90% in some studies).92 The pattern may be sinusoidal, globular, or portal (also referred to as the “stromal pattern”) and arteriolar and/or capsular. In the portal pattern, acellular hyaline-like material may almost completely replace the portal tracts. The differential diagnosis includes entities that produce sinusoidal fibrosis and LCDD. Pancreatic amyloid deposits may also be seen in diabetes, wherein they involve pancreatic islets, and in chronic pancreatitis secondary to cystic fibrosis. Islet amyloid polypeptide aggregates and induces the depletion of islet β-cells in type 2 diabetes and in islets transplanted into type 1 diabetic subjects5,6

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Other Tissues

The lungs/upper respiratory tract may be affected by multifocal, and not uncommonly bilateral, deposits of amyloid, all of which may be part of a systemic or localized amyloidosis.99 In the latter case, the deposits of amyloid are limited to the respiratory system and are not associated with systemic amyloidosis.

Lymph nodes may be involved by amyloid, which may be localized and associated with a giant cell reaction mimicking necrotizing granuloma.100 Amyloid deposits in the bone marrow may be seen in the stroma, vessels, and peri-osseous soft tissues.101–104

Soft tissue involvement may be associated with arthropathy, claudication (presumed to be due to vascular amyloid), myopathy (with pseudohypertrophy), or carpal tunnel syndrome. Endocrine glands may be affected by localized amyloid deposits derived from locally produced hormones or may be involved by means of a systemic process.105 Lichen amyloidosis, as well as macular and nodular primary localized cutaneous amyloidosis, may affect the skin; in such cases, these amyloid deposits are seen in the dermis.

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LOCALIZED AMYLOIDOSIS

In some patients, amyloidosis is a purely localized phenomenon.4–7 The bladder, urinary tract, tracheobronchial system/lungs, larynx, oculi, and skin are the main organs or tissues involved in localized amyloidosis; however, breast and brain may also be involved to a minor extent.6,74,99 Localized amyloid deposits are most frequently (but not exclusively) of the AL type.7 Here, amyloid is derived from the monoclonal light chain synthesised by a local plasma cell clone, and most patients do not have evidence of monoclonal gammopathy. Localized AL deposits typically form a nonencapsulated mass; the involvement of vessel walls is common, but this only occurs at sites very close to the main deposit. Localized AL amyloidosis in the breast may form a mass that is associated with microcalcifications, and this may lead to a misdiagnosis of carcinoma.7 Localized AL deposits in the lymph nodes may mimic granuloma.

Although amyloid can be detected in various body fluids (urine, synovial fluid), the detection of unique urinary exosomes may, in the future, be potentially applicable to widespread screening for AL.106,107 At present, however, fat tissue continues to be the best choice of sample for screening.

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WHEN TO CONSIDER AMYLOIDS IN THE DIFFERENTIAL DIAGNOSIS, AND RECOMMENDATIONS FOR PATHOLOGIC REPORTING OF AMYLOIDS

It is apparent that certain tissues are more likely to be affected by amyloids and, therefore, should be investigated with an enhanced level of suspicion as a matter of routine. These tissues include: the kidney, myocardium, peripheral nerve biopsy, carpal tunnel specimens, and, of course, fat biopsy performed in patients suspected of amyloidosis. Moreover, bone marrow biopsy (or smear) from patients who are diagnosed with PCD should also be tested for amyloids, as well as specimens from patients diagnosed with PCD/lymphoproliferative disorder with plasmacytoid differentiation. Abdominal fat biopsies, as a screening procedure for amyloidosis, should be performed repeatedly in such patients, as deposits may initially be undetectable and become evident only at a later time. Certain pathologies that may mimic amyloids, such as those associated with “hyaline-like” deposits and collagenous colitis, as well as biopsies obtained for symptoms that remain unexplained (in particular liver), should also be tested for amyloids. A recent consensus meeting, organized by the International Society of Amyloidosis, concluded that a pathology report should include the following information:

  • Anatomic site (if known),
  • Histologic structure(s) involved and the pattern of involvement
  • Method (stain) by which the amyloid was diagnosed.3

In conclusion: early treatment of amyloidoses is critical. Although clinical staging and determination of the amyloid type are best performed at specialized centers, the generic detection of amyloid is dependent upon the expertise of general surgical pathologists. Hence, a wider awareness of the disease and a familiarity with its diagnosis in surgical pathology are increasingly of the highest importance.

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(In press)


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Keywords:

amyloidosis; pathogenesis; diagnosis; Congo red stain; thioflavin; treatment; light-chain amyloidosis; serum free light-chain assay; hereditary amyloidosis; liver transplantation

Copyright © 2013 by Lippincott Williams & Wilkins

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