Immunohistochemical studies on fibrillin in amyloidosis, lichen ruber planus and porphyria.

The pathogenesis of macular amyloidosis and lichen amyloidosis remains unsolved and the primary amyloid fibril protein(s) has not yet been identified. Ultrastructural association of skin amyloid with elastin associated microfibrils has been noted earlier. The presence of fibrillin in conjunction with such microfibrils was recently demonstrated immunohistochemically. The presence of fibrillin immunoreactivity in the amyloid deposits in skin biopsies from 3 patients with macular amyloidosis and 3 patients with lichen amyloidosis was studied, using monoclonal anti-fibrillin antibodies. For comparison, skin specimens were studied from five patients with lichen ruber planus, four patients with erythropoietic protoporphyria and from a patient with myeloma-associated cutaneous amyloidosis. Renal specimens from two cases of the amyloid A type of renal amyloidosis also were investigated. There was no immunostaining either of the keratin bodies in specimens of lichen ruber planus, the cutaneous PAS-positive vascular deposits in patients with erythropoietic protoporphyria, or the amyloid deposits in specimens of systemic amyloidosis and it was faint or absent in amyloid deposits in the specimens from patients with lichen amyloidosis. In contrast, distinct fibrillin immunoreactivity could be demonstrated in amyloid deposits in specimens from patients with macular amyloidosis. It was sometimes absent in deposits located in the upper part of the papillary dermis, close to the dermal epidermal junction zone, while consistently strong in deposits located lower down in the dermis. The results suggest that fibrillin or part of the fibrillin molecule may be present in some of the amyloid deposits in specimens of macular amyloidosis.     

Trauma-induced bullae; the presenting feature of systemic amyloidosis associated with plasma cell dyscrasia

Two patients who presented with skin fragility and a bullous eruption were found to have amyloid deposits along the epidermal basement membrane. In both cases a basement membrane similar to that observed in pemphigoid was seen on direct immunofluorescence resulting from the non-specific absorption of immunoglobulins by the amyloid deposits. Evidence of a plasma cell dyscrasia was found in both patients, one of whom developed nephrotic syndrome.     

Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies

Please cite this paper as: Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies. Experimental Dermatology 2010; 19 : 904–911. Abstract: In the skin, amyloidosis can be found with or without systemic disease. Primary cutaneous amyloidosis defines those amyloidoses restricted to the skin without involvement of other systems. Here, we used conformation‐specific antibodies to characterise both fibrillar and oligomeric amyloid aggregates in the skin from patients with cutaneous amyloidosis. Localised cutaneous amyloidosis with different morphology was reproduced in mice by intra‐dermal (i.d.) and subdermal administration of amyloid‐enhancing factor. Moreover, we demonstrated that conformational antibodies were effective in clearing amyloid deposits caused by localised intra‐lesional injections without the necessity of an immune response. Given the accessibility and amyloid localization in this disease, direct i.d. injections of conformational antibodies could be a convenient and direct method for treatment.     

Immunohistochemical studies on vitronectin in elastic tissue disorders, cutaneous amyloidosis, lichen ruber planus and porphyria

Vitronectin, identical with serum-spreading factor and S-protein of complement, is a glycoprotein present in both plasma and tissue. It stimulates cell adhesion and spreading and affects the complement and coagulation pathways. Vitronectin immunoreactivity was recently found in conjunction with dermal and renal elastic fibres, in renal amyloid deposits in cases of AL- and AA-amyloidosis, and in sclerotic glomerular lesions. Skin specimens from lesions of patients with selected skin diseases were investigated with an avidin-biotin peroxidase technique using both monoclonal and polyclonal anti-vitronectin antibodies and an alkaline phosphatase anti-alkaline phosphatase technique using monoclonal anti-vitronectin antibodies. Vitronectin immunoreactivity was found in association with the abnormal elastic tissue in solar elastosis and pseudoxanthoma elasticum. It was also found in conjunction with dermal amyloid deposits in primary localized cutaneous amyloidosis and in Civatte bodies in cases of lichen ruber planus. In cases of erythropoietic protoporphyria and porphyria cutanea tarda, hyaline perivascular deposits also demonstrated positive vitronectin immunoreactivity. The presence of vitronectin immunoreactivity not only in normal and degenerated elastic fibres but also in various pathological tissue deposits suggests that vitronectin occurs both in elastic fibres and in different types of abnormal protein deposits.     

Bullous poikilodermatitic amyloidosis of the skin with junctional bulla development in IgG light chain plasmacytoma of the lambda type. Histology, immunohistology and electron microscopy]

A 75-year-old patient presented with bullae, poilokilodermatic skin and nail dystrophy as signs of systemic amyloidosis 1 year before an IgG myeloma of the lambda type was diagnosed. The skin lesions appeared at mechanically irritated locations on the trunk and at the tensor sites of the extremities. Histology showed a subepidermal blister and necrotic keratinocytes in the epidermis. There were amyloid deposits in the papillary dermis perivascular, and in the deep dermis around eccrine glands and in arrectores pilorum muscles. Polyclonal antibodies allowed classification of the deposits as amyloid composed of lambda light-chain immunoglobulins. Electron microscopy revealed globoid deposits of non-branching filaments typical of amyloid. The blister was formed at the level of the lamina lucida, with the lamina densa at the base of the bottom of the bulla. So far, junctional blister formation in bullous amyloidosis of the skin has been described only once. Our case is the second report of this blister type, and to our knowledge the first published report of a junctional blister in myeloma-associated systemic amyloidosis.     

Notalgia paraesthetica—report of an association with macular amyloidosis

We report three patients with notalgia paraesthetica. In two of our cases amyloid deposits were found on skin biopsy. Symptoms had been present in both cases for a number of years. It is well recognized that the amount of amyloid present in macular amyloid is often very small and difficult to detect. We suggest that many cases of long-standing notalgia paraesthetica may result in the formation of amyloid, possibly secondary to chronic friction.     

Cutaneous lymphatic amyloid deposits in "Hungarian-type" familial transthyretin amyloidosis: a case report

Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of a 59-year-old woman carrying the "Hungarian-type" mutation of TTR (Asp18Gly). Clinical symptoms involved severe central nervous system dysfunction without signs of polyneuropathy, also referred to as the "central form" of TTR-related systemic amyloidosis. Skin biopsy was also evaluated as a tool in order to diagnose this type of TTR amyloidosis. Biopsy samples were collected from the infra-axillary region. Light microscopy using Congo red and polarized light was used to diagnose amyloid deposits. Subsequently, electron microscopic analysis was performed to correlate the amyloid deposits with vicinal dermal structures. The amyloid class was determined by means of immunocytochemistry. TTR amyloid was primarily localized to lymphatic microvessels in the present case, whereas arterioles were devoid of TTR amyloid deposits. In addition, the well-known association of TTR amyloid with neural structures along the erector pilorum and around the sebaceous and serosal (sweat) glands was also evident. Electron microscopic analysis of amyloid deposits revealed characteristic amyloid fibrils that were irregular in shape, and exhibited a heterogeneous density and a random deposition pattern. Immunocytochemistry confirmed the cutaneous accumulation of TTR amyloid. In conclusion, amyloid deposits were abundantly present in the skin of a patient with "Hungarian-type" TTR amyloidosis; skin biopsy seems to be appropriate for the diagnosis of this disorder. We showed that besides the erector pilorum, sweat glands and nerve terminals, lymphatic microvessels are also severely infiltrated by TTR amyloid. Whether these pathological alterations can exclusively be found in "Hungarian-type" TTR amyloidosis should still be investigated. If such changes are not specific for the Asp18Gly mutation, they may be considered as diagnostic markers for "central" TTR amyloid disorders.     

Amyloid elastosis: analysis of the role of amyloid P component.

We report the second case of amyloid elastosis. Our patient had an underlying primary systemic amyloidosis with lambda light chain paraproteinemia. Salient clinical features included a sclerodermatous facial appearance, cordlike thickening of superficial blood vessels, neck skin resembling that in pseudoxanthoma elasticum, livedo reticularis-like changes on the trunk, Raynaud's phenomenon, arterial and venous thromboses, and the nephrotic syndrome. Amyloid deposits were present in the dermis, around appendages, in blood vessel walls, and in a striking distribution surrounding individual elastic fibers, that appeared shortened and fragmented. Immunofluorescence, electron microscopic, and immunoultrastructural studies with antibodies to lambda light chain, localized the amyloid deposits to the region of the elastic fiber microfibrils, with which amyloid P component (AP) is invariably associated in normal tissues. Because AP binds amyloid fibrils, codistribution of amyloid deposits and AP in amyloid elastosis strongly supports the theory that elastic fiber-associated AP may act as a nidus for amyloid deposition.     

Friction melanosis, friction amyloidosis, macular amyloidosis, towel melanosis: many names for the same clinical entity.

Macular or friction amyloidosis is a cutaneous entity characterized by a brownish pigmentation distributed on the skin over bony regions of the trunk and limbs after the use, for many years, of a nylon towel or scrub brush to clean the skin. Electron microscopy is necessary for the diagnosis of this dermatosis and reveals deposits of amyloid in the papillary dermis. This condition is relatively unknown in Western countries. In this report, we describe 24 Italian patients affected by friction amyloidosis which was caused by the use of cotton towels, horse-hair gloves or artificial and rough sponges to clean their skin.     

A study of cytokeratin profiles in localized cutaneous amyloids

The major component of localized cutaneous amyloids may be derived from cytokeratin (CK). However, the CK profiles of primary cutaneous amyloidosis (PCA) and secondary cutaneous amyloidosis (SCA) remain obscure. Paraffin-embedded sections of skin tissue from 64 patients with PCA, 111 with SCA and 3 with systemic amyloidosis were analyzed immunohistochemically using 12 different polyclonal or monoclonal anti-CK antibodies (34βE12, MNF116, LP34, AE1/AE3, anti-CK1, CK5, CK6, CK7, CK10, CK14, CK16 and CK17). In addition, frozen skin tissues from 12 patients with PCA were analyzed for comparison with the paraffin-embedded tissue. In all 64 PCA paraffin sections, the amyloid deposits were immunopositive for anti-CK5 antibody and 34βE12. In all 12 frozen sections of PCA, the amyloid deposits were immunopositive for anti-CK5 antibody, 34βE12, MNF116 and LP34, and seven (58.3%), three (25%) and one (8.3%) were immunopositive for anti-CK1, CK14, and CK10 antibodies, respectively. In all SCA sections, the amyloid deposits were immunopositive for CK5 and 34βE12. In addition, MNF116 immunolabeled amyloids of all sections from patients with basal cell carcinoma and trichoepithelioma, and MNF116 and LP34 immunolabeled amyloids of sections from patients with porokeratosis. Our results indicate that CK5 is the major CK present in the amyloid deposits of PCA and SCA, and “amyloid-K” is mainly derived from basal keratinocytes.     

Ultrastructural localization of amyloid P component in primary localized cutaneous amyloidosis

Amyloid P component (AP) was specifically localized to dermal amyloid deposits in the papular and nodular variants of primary localized cutaneous amyloidosis by an immunoperoxidase technique using an antibody to serum amyloid P component (SAP). Specific staining with anti-SAP of elastic fibre microfibrils which has previously been observed in normal skin, was also present and was noted in close proximity 10 deposits of amyloid material. AP associated with normal elastic fibre microfibrils may be involved in the deposition of amyloid fibrils in vivo.     

Extensive variant of cutaneous amyloidosis: report of a case with electron-microscopic and immunohistochemical studies of the basement membrane zone at sites of amyloid production.

A 60-year-old Japanese female developed widespread lichenoid eruptions with pigmentation, which initially appeared in preceding erythematous skin lesions due to dermatomyositis. Thioflavine T and Dylon stainings, electron microscopy and immunohistochemistry revealed that thick amyloid deposits were present in the papillary dermis particularly beneath the epidermis. Autopsy showed no evidence of systemic amyloidosis. Electron microscopy of the lesional skin disclosed the disturbance of lamina densa formation in the epidermal basement membrane zone (BMZ). There was disruption and dissociation of the lamina densa from the basal cell, and a lamina-densa-like substance was found in the amyloid deposits. Immunofluorescence and immunoelectron microscopy showed that type IV and VII collagens, LDA-1 antigen (a noncollagenous component of the BMZ) and laminin were distributed in irregular thick deposits along the BMZ and were also present within the amyloid itself. These findings indicate that morphological and immunohistochemical abnormalities of the lamina densa may be involved in amyloid production at the interface of the epidermis and dermis, at least in this case.     

Microangiopathy, connective tissue changes and amyloid deposits in chronic renal failure

Skin biopsies were taken from 59 patients with chronic renal failure (52 patients were on regular dialysis treatment, and seven patients were predialytic). The histological examination of the skin biopsies revealed microangiopathy and pericollageneous deposition of a substance with the histochemical behavior of amyloid. In electron microscopy studies these deposits were found to be fine granular, but microfibrillar structures could also be detected. The alterations of the vessel walls are obviously caused by a non-reactive deposition of immunoglobulins, complement components, and fibrinogen. The alteration of the connective tissue mainly imposes as actinic elastosis. These findings could be demonstrated in both predialytic patients and patients on regular dialysis. The extent of the observed alterations seemed to be dependent on the duration of uremia. Atrophy of sweat and sebaceous glands also characterizes the skin lesions of patients with chronic renal failure.     

Amiloidosis cutánea localizada secundaria a poroqueratosis. Estudio histopatológico retrospectivo de 30 pacientes

IntroductionPorokeratosis is a rare disorder of keratinization. The presence of amyloid deposits has been observed in inflammatory and tumoral skin diseases.ObjectivesThe aim of this study was to determine the frequency of cutaneous amyloidosis in histology samples from various types of porokeratosis diagnosed in our department from 1988 to 2005.Material and methodsThirty patients were selected and 34 biopsies of lesions clinically and histologically compatible with porokeratosis were performed. Sections were stained with hematoxylin-eosin and thioflavin T.ResultsAmyloid deposits were observed in 11 biopsies from 9 patients. Most were women in their sixties, with disseminated superficial actinic porokeratosis that had begun at least 5 years earlier. No notable histologic differences were observed between porokeratosis specimens with and without amyloid deposits.ConclusionsThe coexistence of porokeratosis and amyloidosis is a rare occurrence but may be underdiagnosed. In our opinion, the advanced age of the patients and the chronic nature of the lesions would have been predisposing factors for amyloid deposition. The possibility of racial or genetic influences, however, cannot be ruled out.     

Non‐Hodgkin's lymphoma and auricular hypoplasia: associated with juvenile colloid milium or ligneous conjunctivitis?

The exact nature of amyloid‐like hyaline material deposits in the skin is not well understood in some disorders. Three of those – ligneous conjunctivitis, ligneous periodontitis and colloid milium – have been rarely reported in a same patient. We report a case of mucosal and skin deposits of an amyloid‐like homogeneous material associated with non‐Hodgkin's lymphoma and congenital auricular hypoplasia. We discussed and reviewed the literature on these unique associations to determine whether these are the same pathological process. We also noted whether this case represents a new syndrome or a coincidental association.     

A study of apolipoproteins E and A-I in cutaneous amyloids

BACKGROUND: Apolipoprotein E (apoE) is present in a variety of biochemically different amyloid deposits, including Alzheimer's disease, systemic amyloidosis and primary cutaneous amyloidosis (PCA). Among the three closely related alleleic forms of apoE, the epsilon4 allele is linked to Alzheimer's disease. Apolipoprotein A-I (apoA-I), another apolipoprotein, is also found in senile plaques of Alzheimer's disease and in amyloid of aortic atherosclerotic plaques. Furthermore, apoA-I has recently been found to be associated with hereditary cutaneous and cardiac amyloidosis. OBJECTIVES: To determine whether the apoE epsilon4 allele is associated with increased risk of PCA and whether apoE and apoA-I are present in PCA and common secondary cutaneous amyloidosis (SCA) (i.e. basal cell carcinoma, Bowen's disease and seborrhoeic keratosis). METHODS: We examined the apoE genotype in 57 Chinese patients with PCA and 58 normal healthy control subjects of similar age. In addition, immunohistochemical staining was performed to determine the localization of apoE and apoA-I in skin tissues from 15 patients with SCA and 15 with PCA. RESULTS: The frequency of the epsilon4 allele in the PCA group was not significantly higher than that in the control group (8.8% vs. 6.9%, P > 0.05). ApoE was present in amyloid deposits in both PCA and SCA, but apoA-I was not detected in these cutaneous amyloid deposits. CONCLUSIONS: ApoE is also a component of amyloid deposits in SCA. Although the genetic susceptibility of certain apoE isoforms may not be a crucial factor in the development of PCA and, although apoA-I is not associated with amyloid deposits of PCA and SCA, the role of apolipoproteins in amyloidogenesis deserves further scrutiny.     

Presence of basal lamina-like substance with anchoring fibrils within the amyloid deposits of primary localized cutaneous amyloidosis

The dermal-epidermal (DE) junction areas of skin specimens obtained from 16 patients with either lichen amyloidosis or macular amyloidosis were studied. In the dermal papillae where amyloid was deposited, elastic fibers frequently were absent, but periodic acid-Schiff reaction after diastase digestion was homogenously positive. Ultrastructural studies revealed that a basal lamina-like substance with anchoring fibrils was present between and within amyloid deposits. By indirect immunofluorescence technique using an anti-basement membrane zone antiserum obtained from a patient with bullous pemphigoid, specific linear fluorescence occurred at the DE junction, and in a reticular pattern in dermal papillae. It seemed that apoptotic keratinocytes of the epidermis brought down basal lamina and fine fibrous components attached to it when these cells dropped down to the papillary dermis and became the source of amyloid. These findings support the hypothesis that epidermal keratinocyte degeneration plays an important role in the histogenesis of cutaneous amyloidoses.     

Familial primary disseminated amyloidosis (a new clinical form?)

This report concerns two siblings we observed, one male the other female, who presented with primary disseminated amyloidosis. Repeated blood and urine examinations failed to demonstrate dysglobulinaemia. The brother developed, at the age of 51, extensive cutaneous amyloidosis with xanthochromia of the entire upper part of his body. His dermis contained a potassium permanganate-resistant amyloid substance. One year later, he presented with amyloid cardiomyopathy confirmed by biopsy. Owing to the intractable cardiac failure, heart transplantation was performed, but the patient died post-operatively. At autopsy, amyloid deposits were found to be present in the heart, liver, spleen and adrenal glands. His sister developed, at the age of 40, cutaneous amyloidosis in the form of yellowish and purpuric papules and plaques disseminated over the upper part of her body. Histological examination and electron microscopy of the skin showed large potassium permanganate-resistant amyloid deposits. In addition, endoscopy and histology demonstrated the presence of amyloid substance deposits in her larynx, oesophagus and rectum. Echocardiography revealed amyloid cardiomyopathy. She now has moderate cardiac failure, and heart transplantation is being contemplated. Like her brother, she has no renal of neurological amyloid lesions. There is no abnormality of serum or urinary globulins, and her SAA protein is present in normal concentrations. These cases do not fit in with the known nosological framework of amyloidosis. Clinically, both patients had disseminated amyloidosis of the AL type, and their disease clearly differed from familial systemic amyloidosis with neuropathy or nephropathy. To our knowledge, no case of familial primary amyloidosis of the AL type without dysglobulinaemia has yet been reported.     

Coexistence of beta2 microglobulin and lambda light chain in amyloid fibrils of dialysis-unrelated plasma cell dyscrasia-associated systemic amyloidosis

BACKGROUND: Systemic amyloidosis occurs as a result of amyloid deposition in various tissues. The amyloid fibrils in systemic amyloidosis have been reported to originate from immunoglobulin light chains. OBJECTIVE: We studied the composition of amyloid fibrils from two patients with plasma cell-associated systemic amyloidosis (PASA). METHODS: A double immunofluorescence study of the lesional skin of PASA was undertaken. Amyloid proteins were extracted with distilled water from one case of PASA. RESULTS: The double immunofluorescence study showed that anti-lambda light chain and anti-beta2 microglobulin antibodies mostly reacted with the same area of amyloid deposit. Amyloid deposits from two patients with PASA who had never undergone haemodialysis showed a positive reaction with the antibodies for beta2 microglobulin as well as immunoglobulin lambda light chain. By the use of immunoblot assay of amyloid fibril proteins, polypeptides immunoreactive with antigamma light chain antibody (29 kDa) and with anti-beta2 microglobulin antibody (12 kDa) were detected. CONCLUSIONS: These results indicate that beta2 microglobulin is a component of amyloid fibrils in PASA.     

Thermosensitive lichen amyloidosis

BACKGROUND: A 26-year-old male presented with a 3-year history of lichen amyloidosis. On examination, there was a pigmented papular eruption with a ripple pattern affecting the limbs and trunk but sparing the axillae, antecubital and popliteal fossae, central chest, neck and face. There was also prominent sparing of the skin overlying the superficial veins of the limbs. The sparing of the superficial veins of the limbs by lichen amyloidosis raised the possible role of cutaneous temperature in governing the distribution of amyloid deposits in our patient. OBSERVATIONS: Total body infrared thermography demonstrated consistent sparing of the amyloid deposits in areas with higher cutaneous temperatures such as the neck and axillae as well as the course of the superficial veins. The cooler areas such as the extensor surfaces of the arms and legs corresponded to areas of amyloid deposition. Narrow band ultraviolet B (NBUVB) phototherapy over a 5-month period resulted in a marked improvement of pruritus and clearing of the amyloid deposits. CONCLUSIONS: Our patient clearly demonstrated lichen amyloidosis in a thermosensitive distribution. This may be a gross manifestation of previous reports of in vitro thermosensitivity of amyloid fibril formation and may have potential implications in treatment at least in a subset of patients demonstrating this clinical feature.