There are probably few conditions that have resulted in so many case reports as localized AL amyloidosis. It is uncommon but not extremely rare and can cause some diagnostic problems, particularly in the sense that it has to be distinguished from the systemic form. The amyloid deposits often cause a tumor-like process, where the type is sometimes known as “amyloidoma,” and the microscopic diagnosis is usually a surprise. In most cases, the alteration is initially suspected to be a tumor and the diagnosis becomes clear only after microscopic analysis of a biopsy, where more or less cell-free hyaline areas are seen. A Congo red stained section, examined in polarized light, reveals the amyloid diagnosis. A more diffuse localized pulmonary amyloidosis has also been described, but the AL nature was not proven [2]. Diffuse pulmonary amyloidosis should always be suspected of being part of a systemic disease [3]. Among the localized forms, localized AL amyloidosis is probably the one that is most easily mistaken for systemic amyloidosis. The distinction is very important since, although systemic amyloidosis is often life-threatening, in most cases, localized AL amyloidosis is not. Localized AL amyloid can develop at any site, including the central nervous system, or even multiple sites of the same organ, e.g., bronchi. Deposits are most commonly seen in the respiratory tract (paranasal sinuses-larynx—bronchi-lungs), the urinary tract (renal pelvis-urethra), skin, and conjunctiva. In the urinary tract, the bladder is most commonly involved, followed by the ureter, the urethra, and the renal pelvis [4]. There is most often one mass, but bilateral amyloid deposits may occur, e.g., in the bronchi or in the conjunctiva. These lesions are still designated as localized. As in systemic AL amyloidosis, the amyloid is composed of a monoclonal immunoglobulin light chain, which is usually C-terminally truncated [5]. This specific light chain, varying from case to case, is synthesized at the site of deposition by a local clone of plasma cells that are usually benign. Why this happens is not clear but, initially, it may be a result of antigenic stimulation causing a chronic inflammation [6]. Sometimes, clonality is quite obvious from an immunohistochemical staining for light chains (Fig. 7.1), but very often there is a mixture of kappa- and lambda-producing plasma cells, making the clonality less evident. However, clonality may be demonstrated by analysis of immunoglobulin heavy chain gene rearrangements [7–9]. There is not the same strong predominance of lambda chains as in systemic AL amyloidosis, and localized AL kappa amyloidosis is comparably common. The reason for this is unknown but may point to important differences in pathogenesis. Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) often contains deposits of amyloid, and the distinction between this neoplasm and “amyloidoma” is not always sharp [10, 11].

The microscopic findings vary with the localization. Deposits may be quite small, as is often seen in the larynx and in the conjunctiva. On the other hand, deposits at some other locations, such as the lungs or urinary bladder, may be quite large. Typically, there are almost acellular amyloid areas intermingled with spots with inflammatory cells, notably plasma cells (Fig. 7.1). An almost constant feature of localized AL amyloidosis is the presence of multinucleated giant cells of foreign body type, mentioned in many of the great number of case reports of this kind of lesion. These cells are usually interpreted as a sign of tissue reaction of the deposited material. However, as an alternative, it is possible that the giant cells directly participate in the generation of fibrils by processing the monoclonal immunoglobulin light chain, produced by plasma cells in the vicinity [12, 13]. Amyloid, close to giant cells, is often more brightly stained with Congo red and shows a particularly bright green birefringence, probably indicating extensive organization of the fibrils (Fig. 7.2). Calcifications and metaplastic bone formation are commonly found, particularly in bronchial deposits.

Appearance of abnormal nodules, bleedings, and results of obstruction are the most common symptoms of localized AL amyloidosis. Localized AL amyloidosis of the urinary tract most commonly presents with macroscopic hematuria, but other symptoms such as anuria or acute renal failure may occur [4]. Very often, the lesions are initially strongly suspected for cancer. This is particularly true for lesions in the trachea-bronchial region and in the urinary tract. The rare localized AL amyloidosis of the breast is also very easily mistaken for malignancy and may even show micro-calcifications visible at X-ray examination [14]. In most cases, localized amyloidosis is not life threatening, but there are exceptions. In the respiratory tract, where the deposits often are multiple and bilateral [15], the amyloid can cause severe hemorrhages and even death [16, 17]. In most instances, the condition is long-lasting and not curable but may be kept under control by repeated endoscopical intervention [4, 15, 18]. However, a more radical surgical treatment is sometimes necessary and may even include cystectomy for urinary bladder amyloid or nephrectomy for localized amyloidosis in the renal pelvis. The risk of progression to systemic amyloidosis is very small [4], but AL amyloid tumors may appear in patients with systemic amyloidosis [19]. A careful clinical investigation is therefore important.

Small deposits are common in certain endocrine organs and their tumors. In general, these amyloid deposits are composed of specific polypeptide hormones or fragments thereof. The importance of the deposits themselves may vary, but it is likely that most of them are fairly innocent, at least when small. However, there is strong evidence that some of them are pathogenically important, both when appearing as large deposits and during their formation, then as toxic oligomers. The best studied example is the amyloid in the islets of Langerhans, but there are other deposits which may play a pathogenic role.

The skin is one of the principal sites for localized AL amyloidosis, described above, but other forms of amyloid deposits are even more common. Small, or sometimes very small, amyloid deposits occur subepidermally in the two related and, most probably, biochemically identical amyloid forms, lichen amyloidosus (LA) and macular amyloidosis (MA). LA, MA, and some related variants are in the dermatological literature collectively often referred to as “primary localized cutaneous amyloidosis” (PLCA). LA appears as slightly elevated, irregular papules, or plaques, often affecting the shins, but it may also appear elsewhere. Amyloid is seen as irregular, small masses in the papillary dermis. Very often the amyloid is seen to contain a number of macrophages with engulfed melanin (melanophages) (Fig. 7.8). There is no amyloid in the reticular dermis or in the walls of blood vessels. Transepidermal elimination of amyloid may occur [76]. The deposits are moderately Congophilic. MA appears as irregular areas with a rippled hyperpigmentation, and is most commonly encountered on the upper back, between the shoulder blades or over one of them. In this form, the amyloid is sometimes so scanty that the deposits are difficult to see, particularly since their affinity for Congo red is weak and green birefringence is difficult to demonstrate. Staining methods other than Congo red are therefore often used, e.g., the fluorescent dye thioflavin S (or T). In Japan, the dye Pagoda red (Dylon, Japan) is often used, although its properties when complexed with amyloid are less well known than Congo red. Also, in MA, melanophages are quite typical and are of help for diagnosis. There are usually no other inflammatory cells, unless there are secondary changes due to scratching. LA and MA are closely related and are sometimes seen in the same patient where they are then referred to as “biphasic amyloidosis.” Both types tend to run a chronic course and generate an intractable pruritus.

In addition to LA and MA, there are other very rare clinical forms of localized subepidermal amyloidosis, sometimes with the appearance of poikiloderma [77].

Morphological studies on the origin of the amyloid have indicated a close relationship between the basal cell layer and the amyloid fibrils, strongly indicating a keratinocyte origin of the fibril protein [78]. A direct, secretory mechanism has been suggested from electron microscopic findings [79, 80] as an alternative to the possibility that the amyloid derives from degenerative keratinocytes [81]. Most studies on the biochemical nature of the fibrils in LA and MA have been performed by the application of antibodies against known proteins. These studies have repeatedly reported reactions with antibodies against basic keratin variants, and CK5 antibodies have been suggested for diagnostic work [82, 83]. A pathogenesis involving processing of keratin from apoptotic keratinocytes has also been suggested [84]. However, recent research including mass spectrometric analysis of extracted amyloid has indicated that the fibril protein is not derived from keratin but from galectin-7 [85, 86]. Galectin-7 is a carbohydrate binding protein specifically expressed by keratinocytes. It is a small protein of 136 residues arranged as a β-sandwich [87], which makes it a good amyloid fibril protein candidate.

LA and MA are relatively rare in the Western world but are more prevalent in Southeast Asia and in South America. It has been repeatedly suggested that LA and MA may be induced by long-term scratching, particularly with a nylon towel or brush. This may be doubtful since these conditions sometimes do not produce itching. There is often a family history, and also a connection between LA and multiple endocrine neoplasia syndrome 2A has been established [88, 89]. The mutated gene is RET located on chromosome 10. A linkage study in Chinese families with LA and/or MA has indicated a locus on chromosome 1 [90] and another in a Brazilian family identified a mutated oncostatin M (OSM) receptor β which is a receptor for OSM and interleukin-31 [91]. A number of families with LA and mutations in the interleukin-31 receptor protein genes have been described [92]. Interleukin-31 is involved in the genesis of itching, but the precise connection between mutations in this gene and the pathogenesis of amyloid is still unknown. The recent discoveries of amyloid protein and mutations in LA and MA indicate that the pathogenesis may be complicated.

MA belongs to a group of related conditions which, in addition, include notalgia paresthetica and macular posterior pigmentary incontinence (also called “posterior pigmented pruritic patch”) [93]. These latter conditions have similarities in symptoms and clinical appearance but lack amyloid. Interestingly, macular posterior pigmentary incontinence (without amyloid) was present in several members of a kindred with multiple endocrine neoplasia syndrome 2A [94].

Calcifying epithelial odontogenic (Pindborg) tumor is a rare mandibular or maxillar benign neoplasm that typically contains amyloid deposits in association with the tumor cells [101]. Analysis of the purified main protein revealed a previously unknown sequence, showing that the amyloid is unique [102]. The 264 amino acid residue protein has been given the name “odontogenic ameloblast-associated protein” and the amyloid protein, therefore, AOAAP. OAAP is believed to be important in odontogenesis and, remarkably, small amyloid deposits of AOAAP can be found in unerupted tooth follicles [103]. OAAP is expressed in other tissues as well but is not known to form amyloid deposits and has been suggested as a breast cancer biomarker [104].