Figure 1. The patient developed progressive symmetrical hyperpigmentation with interposed areas of hypopigmentation.
A 39-year-old man of Native American and Iberian descent currently living in El Paso, TX, noticed increasing pigmentation on his back and extremities for approximately 6 to 7 years. The pigmentation was unassociated with pruritus. He denied any history of blistering sunburns, use of tanning beds, or known family history of pigmentation disorders.
On examination, the patient had extensive, somewhat symmetrical and reticulated hyperpigmentation studded with hypopigmented macules on his lower back, buttocks, and proximal extremities (Figure 1). The patient was concurrently noted to have a heart murmur and was thought to possibly have mitral valve regurgitation. Urine electrophoresis and serum total protein electrophoresis were both normal. The pattern of the urine protein factions was consistent with a glomerular proteinuria.
At no point did the patient develop purpura of the skin, including the eyelids. His tongue did not have macroglossia. The patient had had open heart surgery to repair the valve, and was noted to have premature calcification of the coronary arteries. He had mild hearing loss on the left, which he attributed to being a drummer. The results of a magnetic resonance imaging study were normal.
Figure 2. A hematoxylin-eosin stain (1000×) shows an increase in epidermal keratinocytes accentuated in the basal layer but involving the spinous layer as well. The basal layer shows basilar vacuolar change and focal basilar dyskeratosis. Pink globular material compatible with keratin-derived amyloid is noted in the papillary dermis.
Figure 3. A crystal violet preparation highlights the amyloid deposits within the papillary dermis. The staining pattern is a metachromatic one, resulting in the slightly pinkish hue as opposed to the background bluish quality (1000× crystal violet stain).
A biopsy was performed of the reticulated hyperpigmented skin. There was focal epidermal attenuation alternating with zones where the epidermal architecture was preserved. The epidermis was surmounted by a scale that exhibited melanin pigment and contained cytoid bodies. Randomly disposed scattered dyskeratotic cells primarily situated in the basal layer and spinous layer of the epidermis were present and unaccompanied by lymphocyte satellitosis. Scattered melanophages were also noted within the superficial dermis reflective of antecedent epidermal apoptosis. An irregular and increased pattern of epidermal melanization was observed. Within the dermal papillae, eosinophilic globules most compatible with keratinocyte derived amyloid were present singly and in small clusters (Figure 2). This material was highlighted in a metachromatic fashion by the crystal violet stain, corroborating its categorization as amyloid (Figure 3). In addition, the amyloid deposits stained positively for cytokeratin 5/6 (Figure 4) and as its basis was one derived from prematurely apoptotic keratinocytes, significant nuclear staining for caspase 3 was also observed (Figure 5).
Figure 4. The keratinocyte-derived nature of the amyloid is revealed by the cytokeratin stain (400× diaminobenzidine stain).
Figure 5. Caspase 3 is an excellent immunohistochemical stain for the detection of apoptosis. It is quite obvious at this power that the amyloid exhibits an enriched caspase 3 staining pattern consistent with an apoptotic milieu (400× diaminobenzidine stain).
The patient had a long-standing history of a striking, somewhat generalized reticulated hyperpigmentation that likely commenced as early as adolescence. The basis of the hyperpigmentation was captured histologically, representing in part increased epidermal melanization and melanophage accumulation in the dermis. Additionally, the biopsy showed dyskeratotic cells in the basal and spinous layers. It was a distinctive dyskeratotic pattern that was unaccompanied by lymphocyte satellitosis around keratinocytes, indicating that its basis was not immunologically mediated. The material was discovered to represent keratin-derived amyloid based on the distinctive metachromatic staining pattern with the crystal violet stain and its highlighting by a cytokeratin stain.
The combined clinical presentation and light microscopic findings are diagnostic of amyloidosis cutis dyschromica, a rare form of dyschromia with less than 50 reported cases. The presentation is well exemplified by this case. From a clinical perspective, fairly widespread symmetric reticulated hyperpigmentation and guttate hypopigmented macules are observed more commonly in patients of southeast Asian extraction, but can occur in patients of diverse ethnicity. It is less pruritic than conventional macular amyloidosis.1-5
The histology of the lesions varies according to whether a hyperpigmented or hypopigmented lesion is biopsied. When a hyperpigmented lesion is analyzed, there is basilar hypermelanosis. Dyskeratosis will be observed. Amyloid will be present in the dermal papillae. In examining the hypopigmented areas, similar changes are noted in dyskeratosis and amyloid deposition; however, there is no discernible pigmentation and/or it is significantly diminished with a commensurate reduction in melanocyte density.
Amyloidosis cutis dyschromica represents one of the classic forms of keratinocyte-derived amyloidosis along with the more common variants, which fall under the designation of lichen amyloidosis and macular amyloidosis, respectively. The most common variant of keratinocyte-derived amyloidosis is lichen amyloidosis, which is characterized by pruritic, brownish lichenoid papules distributed over the extensor surface of the legs, forearms, and upper back. Macular amyloidosis presents as a larger, often single area of dyschromia, typically one exhibiting hyperpigmentation. In general, cases of macular and lichen amyloidosis are unassociated with extracutaneous stigmata, although CMM has seen one case of macular amyloidosis in a patient who subsequently developed pulmonary insufficiency attributable to septal amyloid deposition.6
Amyloidosis cutis dyschromica can occur sporadically, but an autosomal dominant and recessive pattern of inheritance has been demonstrated. In one study, cells taken from a patient with amyloidosis cutis dyschromica exhibited the same pattern of sensitivity to UV-C compared with normal cells, although a greater degree of sensitivity was noted with UV-B exposure.7 Unscheduled UV-C irradiation in patient cells was also lower than that noted in normal cells. Unscheduled DNA synthesis after UV-B irradiation was lower than in normal cells. Although UV light exposure via sunlight has always been held to be an integral feature of amyloidosis cutis dyschromica and intrinsic to its pathogenesis, the cutaneous alterations which are quite extensive extend to involve photoprotected areas as well. The pathogenesis of amyloidosis cutis dyschromica was largely thought to be linked with defective repair of damaged keratinocytes mediated exclusively by UV light exposure. The underlying mechanisms in keratinocyte repair following UV light exposure remained an elusive topic until decades later, when the genetic defect as outlined above was discovered in patients with amyloidosis cutis dyschromica.7
Recently, a biallelic gene defect in the glycoprotein nonmetastatic melanoma protein B (GNMPB) has been identified in patients with the autosomal recessive form of this condition.8 This protein is found in diverse cell types exhibiting many critical and diverse functions; thus, one might link this genetic defect with other unusual aspects of the patient’s clinical presentation specifically as it applies to mitral valve laxity and premature calcification of coronary vessels. In the skin, it has its highest expression in melanocytes but is also expressed in keratinocytes at lower levels. This genetic defect leads to reduced function of this protein and may result in paradoxical melanocyte overactivity, interference with melanosome formation, and inhibited apoptotic body clearance as well as attenuate melanocyte keratinocyte interaction. Whether or not this genetic defect is operational in nonhereditary sporadic cases is not known.8,9
Human GNMPB has a characteristic composition comprising 560 amino acids, representing a highly glycosylated type I transmembrane. It was initially isolated from metastatic melanoma cells and is a regulator of tumor growth. This protein is localized in the melanosomes, lysosomes, and early endosomes. GNMPB appears to be critical for melanosome formation; therefore, a mutation in the expression of this protein would cause irregularities in melanization. It is unclear how this protein leads to pro-apoptosis and secondary amyloid formation.
The differential diagnosis of this unique form of dyschromia encompasses xeroderma pigmentosum, poikilodermatous amyloidosis, and dyschromatosis universalis hereditaria. In xeroderma pigmentosum, the skin changes are exclusively photodistributed. Patients have supervening severe actinic damage, and various forms of UV light-induced cutaneous neoplasia are an intrinsic feature of xeroderma pigmentosum.10 In poikilodermatous amyloidosis, the onset is in early childhood. The patients have photosensitivity, short stature, palmar plantar keratosis, and blisters.11 The hallmarks of dyschromatosis universalis hereditaria include generalized small hyperpigmented and hypopigmented macules primarily involving the trunk and extremities with relative sparing of the face, palms, soles, and oral mucosa. The onset is in childhood. Some cases are associated with high tone deafness and short stature. Other, less common associations include ocular albinism, Dowling-Degos disease, and tuberous sclerosis. The condition shows both autosomal dominant and autosomal recessive modes of inheritance. The abnormality lies in the melanosome distribution in melanocytes while the melanocyte density is normal.12
In conclusion, amyloidosis cutis dyschromica, although rare, represents a unique form of dyschromia reflective of a disturbance in keratinocyte melanocyte interaction, localized intraepidermal proapoptotic state, and the tendency of released keratin filaments toward amyloid conversion. While defining a pathology reminiscent of macular amyloidosis, the clinical presentation and underlying pathogenetic mechanisms to this form of cutaneous amyloidosis is unique.
Dr Magro is a distinguished professor of pathology and laboratory medicine in the department of pathology at Weill Cornell Medicine in New York, NY.
Dr Goldman is an instructor in the department of dermatology at Weill Cornell Medicine and owner of Goldman Dermatology in New York, NY.
Disclosure: The authors report no relevant financial relationships.
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