A Review of Primary Cutaneous Amyloidosis Jared Heaton, DO,* Natalie Steinhoff, DO,** Brian Wanner, BA,*** Michael Krutchik, DO****
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A Review of Primary Cutaneous Amyloidosis Jared Heaton, DO,* Natalie Steinhoff, DO,** Brian Wanner, BA,*** Michael Krutchik, DO**** *Dermatologist, Legacy Dermatology, Bountiful, UT **Dermatology Resident, PGY-3, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL ***Osteopathic Medical Student, OMS-IV, Des Moines University College of Osteopathic Medicine, Des Moines, IA ****Dermatologist and Clinical Faculty, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL Disclosures: None Correspondence: Natalie Steinhoff, DO; [email protected] Abstract Primary cutaneous amyloidosis is characterized by amyloid deposition in the skin without systemic involvement. This article reviews the three main variants of primary cutaneous amyloidosis, lichen, macular, and nodular, and briefly discusses rare forms. shins, calves, ankles and dorsa of feet and thighs Introduction 4,8,9 Primary cutaneous amyloidosis (PCA) is (Figure 1). Hyperkeratotic plaques may be present and often appear similar to plaques of characterized by deposition of amyloid in the skin 8 with no extracutaneous involvement. The three lichen planus, lichen simplex or nodular prurigo. main variants are lichen, macular, and nodular Cases of lichen amyloidosis limited to the anosacral region or the auricular concha have been amyloidosis. Of these three, macular and lichen 8 amyloidosis are most common. They are clinically documented in the literature. distinguishable but have the same keratinocyte- In macular amyloidosis, small, gray-brown derived amyloid K (AK) protein deposited in macules may blend together to produce the papillary dermis, so they are often considered 1-3 hyperpigmented patches. These hyperpigmented different manifestations of the same disease. macules or patches are frequently found on the Classically, macular amyloidosis presents on the upper back and less commonly on the chest or upper back as poorly demarcated, hyperpigmented 10 extremities (Figure 2). Macular amyloidosis macules coalescing into pruritic patches and plaques. Figure 1. Hyperkeratotic, hyperpigmented has been described as appearing similar to fading On the lower extremities, lichen amyloidosis more lichenoid inflammation, post-inflammatory papules and plaques on bilateral shins of a often presents as discrete, hyperkeratotic papules hyperpigmentation, and the “dirty neck” of atopic patient with lichen amyloidosis. forming larger plaques. Biphasic amyloidosis 8,11 eczema. Unusual variants have been described occurs when macular and lichen variants present as periocular hyperpigmentation, nevoid simultaneously and has been reported in 18.75% of 2,4,11 hyperpigmentation following Blaschko’s lines, and PCA cases. diffuse macular amyloidosis with an incontinentia 8,12 The nodular variant is less common and involves pigmenti-like pattern. dermal and subcutaneous deposition of amyloid In both macular and lichen amyloidosis, chronic light chain (AL). AL is derived from immunoglobin scratching in susceptible individuals is thought light chain material created by infiltrating plasma to contribute to the mechanism of amyloid cells. It is the only form of primary cutaneous deposition. The process of amyloid deposition amyloidosis in which the amyloid deposits are of involves filamentous degeneration and apoptosis the light chain subtype. This is the same subtype of basal keratinocytes followed by conversion found in systemic amyloidosis associated with 5 of filamentous masses (or colloid bodies) into plasma cell dyscrasias and multiple myeloma. The 1,8,13 amyloid material in the papillary dermis. nodular type is typically found on acral sites but That lichen and macular amyloidosis have similar can also appear on the face or trunk. It generally Figure 2. Hyperpigmented patch on the upper amyloid deposition and can occur simultaneously appears as single, or less commonly multiple, back of a patient with macular amyloidosis. supports the idea they are different manifestations pink to tan, waxy papule or nodule that often 1,8,11,14 6 of a common etiology. Also, new insight hemorrhages with slight trauma. All three variants into amyloid diseases has shown the pathology is of PCA display apple-green birefringence under due not only to accumulation of fibrillar material polarized light due to the β-pleated sheet structure 2 but more so to the presence of smaller misfolded of the amyloid protein. 21 protein species, termed oligomers. Clos et al. This article reviews the three main variants of PCA proposes that oligomers are formed intracellulary along with rarely reported types. The clinical and in the basal layer and can either cause immediate histological presentations and the diagnosis and cell death and amyloid formation or be released treatment of PCA will be discussed. from the basal cells into the dermis. The oligomers are then consumed and accumulate in dermal macrophages and fibroblasts, giving rise to the Lichen and Macular amyloid aggregates seen in PCA.21 Amyloidosis PCA is seen most often in persons of South In addition to the characteristic features seen Figure 3. Histological features of amorphous, 7 American, Middle Eastern or Asian ethnicities. by the naked eye, Chuang et al. did a study on eosinophilic amyloid deposited in the dermis. Most cases are sporadic, although an autosomal- the dermoscopic features of 35 cases of PCA. dominant family history is present in up to 10% The most common finding was a brown or white brown dots or a white rim. Of the cases with of cases. PCA is rare in children, but familial central hub surrounded by various patterns whitish central hubs, half also had the whitish forms commonly present during the second of pigmentation. Of the 18 cases of macular scar-like pattern for some lesions. This study decade of life.8 amyloidosis in the study, eleven patients showed helped demonstrate that dermoscopy may assist white central hubs, four patients showed brown in achieving an accurate diagnosis of PCA, but Lichen amyloidosis is most common in persons hubs, and three showed both.4 The 17 cases of more studies are needed to delineate the clinical of Chinese ancestry. It typically appears as red- lichen amyloidosis displayed whitish central usefulness of dermoscopy. brown, hyperkeratotic, pruritic papules on the hubs or whitish scar-like centers surrounded by HEATON, STEINHOFF, WANNER, KRUTCHIK Page 46 While the diagnosis of macular and lichen Another new treatment option targets IL-31 and amyloidosis relies on clinical identification of oncostatin M receptor b (OSMRb). Tanaka et characteristic skin findings, definitive diagnosis al. discuss the involvement of these receptors in requires histological confirmation.7 On hematoxylin mechanisms of pruritus in familial PCA. Missense and eosin (H&E) stain, both macular and lichen mutations have been identified in OSMRb, an amyloidoses demonstrate pink amyloid deposits interleukin (IL)-6 family cytokine receptor, and in the papillary dermis (Figure 3). Histologies are interleukin 31 receptor A (IL31RA) in patients similar as well, but lichen amyloidosis typically has with familial PCA.8 Tanaka et al. propose that more amyloid deposited. Lichen amyloidosis also signaling abnormalities from these receptors could commonly has secondary effects from rubbing, lead to keratinocyte apoptosis, subsequent amyloid causing it to demonstrate irregular acanthosis, accumulation, and changes in the number of hypergranulosis, and hyperkeratosis of the cutaneous nerves, leading to pruritus.8 Additional epidermis, features similar to macular amyloidosis research is necessary to further understand and and lichen simplex chronicus.7 Other common develop treatments aimed at these receptors. features seen on H&E include pigment loss, fissuring of the amyloid deposits, and extravasation Nodular Amyloidosis of red blood cells. Primary cutaneous nodular amyloidosis (PCNA) is very rare, with approximately 60 cases recorded The amyloid may be seen with several stains, in the medical literature up to 1994.16 In contrast including methyl violet, crystal violet, thioflavin to lichen and macular amyloidoses, nodular T and Congo red. Congo red is one of the most amyloidosis shows no predilection for certain 17 common staining techniques, as amyloid shows ethnic groups. Recent studies indicate nodular Figure 4. Tan to pink, waxy nodules on the scalp a characteristic apple green birefringence when amyloidosis occurs equally in both genders and and face of a patient with nodular amyloidosis. viewed under polarized light. An H&E stain may most commonly impacts patients between 50 years give suspicion for amyloid diagnosis, but Congo- and 60 years of age.5,18,19 It typically presents as red staining under polarized light has proved single or, less commonly, multiple pink to yellowish sensitive and definitive.2 Vijaya et al. helped brown, waxy nodules ranging from several demonstrate the importance of Congo red in a millimeters to several centimeters in size.8,17,20 study of 45 cases of suspected amyloidosis. The results showed that most patients tested positive While a definitive cause of PCNA is unknown, for apple-green birefringence under polarized it is understood that amyloid deposits in nodular light.11 The labelling of cytokeratin (CK) 5 might amyloidosis originate from immunoglobulin 6 also be useful in the diagnosis of both lichen and light chains secreted by local plasma cells. The macular amyloidoses.1,13 Studies by Huilgol et al. pathophysiology involves