CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Nodular localized primary cutaneous amyloidosis: a bullous variant A. LaChance,1 A. Phelps,1 J. Finch,1 J. Lu,1 Z. Elaba,2 W. Rezuke2 and M. J. Murphy1 1
Division of Dermatopathology, Department of Dermatology, University of Connecticut Health Center, Farmington, CT, USA; and 2Department of Pathology, Hartford Hospital, Hartford, CT, USA doi:10.1111/ced.12305
Summary
Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin-restricted amyloidoses. We present an unusual case of NLPCA in a 51-year-old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.
The term ‘primary cutaneous amyloidosis’ (PCA) refers to a group of conditions that show skin-restricted intracellular and extracellular deposition of amyloid fibrils and oligomers, derived from a variety of protein sources.1–10 Several subtypes of PCA have been described, including lichen amyloidosus, macular amyloidosis, amyloidosis cutis dyschromica (ACD) and nodular localized PCA (NLPCA).1–10 In the lichen, macular and ACD variants, the amyloid is derived from degenerated basilar keratinocytes, and is generally confined to the papillary dermis.1,2 In NLPCA, the amyloid is largely derived from clonal immunoglobulin light chains produced by tissue-infiltrating monotypic plasma cells.1,3–6 Bullous change has rarely been described in primary cutaneous forms of amyloidosis, and most commonly in the lichen variants.8–10 Of note, cutaneous blistering is more often associated with systemic forms of amyloidosis.1 Bullous change in NLPCA has not been reported previously. We describe an unusual case of NLPCA with subepidermal bullous formation.
Report A 51-year-old man presented with a 2-month history of a solitary, slightly erythematous, smooth-surfaced papule, 6 mm in size, with overlying tense blister, on his right third toe (Fig. 1). The patient reported no history of trauma to the site. Whole-body skin examination did not reveal any other cutaneous lesions. An incisional biopsy was taken, and on histopathological review, focal subepidermal clefting was seen, with otherwise normal-appearing epidermis (Fig. 2). Basilar keratinocytes did not show degenerative cytological changes. A subjacent superficial perivascular and interstitial mature-appearing plasma cell infiltrate
Correspondence: Dr Michael J. Murphy, Division of Dermatopathology, Department of Dermatology, University of Connecticut Health Center, 21 South Road, Farmington, CT 06030, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 10 November 2013
344
Clinical and Experimental Dermatology (2014) 39, pp344–347
Figure 1 Solitary, slightly erythematous, smooth-surfaced,
papule, 6 mm in size, with overlying tense blister on the right third toe.
ª 2014 British Association of Dermatologists
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
(a)
(c)
(b)
(d)
(e)
Figure 2 (a,b) Superficial dermal perivascular and interstitial predominantly plasma cell infiltrate, with adjacent aggregations of amor-
phous, acellular, faintly eosinophilic material. Focal subepidermal clefting is visible. Haematoxylin and eosin, original magnification (a) 9 20; (b) 9 40. (c) Amorphous, acellular, strongly staining material (Congo red, original magnification 9 100). Apple-green birefringence was visible under polarized light (not shown). (d,e) In situ hybridization studies for (d) kappa and (e) lambda light-chains show evidence of kappa light-chain restriction, consistent with a monoclonal plasma cell proliferation.
with prominent intranuclear inclusions (Dutcher bodies) was identified. The adjacent dermis showed aggregations of amorphous, acellular, faintly eosinophilic material, which stained strongly with Congo red, and demonstrated apple-green birefringence under polarized light, consistent with amyloid. In situ hybridization studies revealed kappa light chain restriction, consistent with a monoclonal plasma cell proliferation. Follow-up evaluation did not reveal any clinical or laboratory evidence of systemic amyloidosis or an autoimmune disorder. The patient had no family history of amyloidosis. A diagnosis of NLPCA was made. The lesion was subsequently excised completly. At follow-up approximately 1 year later, the patient showed no evidence of local recurrence or related systemic disease.
ª 2014 British Association of Dermatologists
NLPCA is a rare variant of PCA, with only around 60 cases reported in the literature.1–7 It is characterized by a focal cutaneous accumulation of predominantly light-chain immunoglobulins (AL-type amyloid), secondary to a localized monoclonal proliferation of plasma cells.1,3–6 A predilection for acral sites has been reported,1,7 sometimes leading to the clinical impression of a callus.6 By definition, patients with NLPCA do not show evidence of underlying haematological dyscrasia or amyloid deposition in internal organs at diagnosis.1–7 It has been proposed that NLPCA may represent either a form of ‘localized plasma cell dyscrasia’4 or ‘extramedullary plasmacytoma’ with local production of amyloid by plasma cells.5 An association between NLPCA and several autoimmune conditions has been described, most
Clinical and Experimental Dermatology (2014) 39, pp344–347
345
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
commonly Sj€ ogren syndrome (about 25% of reported cases).1–7 Under light microscopy, NLPCA typically appears as amyloid deposits in the papillary and reticular dermis.1–7 Involvement of the subcutaneous tissue, cutaneous blood vessel walls, nerve sheaths and adnexal structures has also been described. Deposits are highlighted by Congo red staining with applegreen birefringence under polarized light. Thioflavin S, crystal violet, Sirius red and metachromatic stains have also been used to highlight amyloid in tissue sections.1–7 Immunohistochemistry and surface receptor gene rearrangement studies have been used to confirm monoclonality of plasma cell populations in lesions of NLPCA,1–7 as identified in our case. Currently, immunostaining is the preferred method for amyloid typing in NLPCA and other cutaneous amyloidoses.1 In NLPCA, antibodies targeting kappa and lambda light chains have been used to confirm the composition of AL-type amyloid deposits.1 The clinical and histopathological features of NLPCA may be indistinguishable from those of systemic amyloidosis with cutaneous involvement,1–7 prompting the need for thorough investigations at the time of diagnosis. Surgical excision, cryotherapy, electrodesiccation and curettage, intralesional steroid injection, localized radiation and CO2 laser therapy have been used with variable success.1–7 Reported local recurrence rates are high, and may be secondary to the extent and depth of amyloid deposition in this form of cutaneous amyloidosis compared with lichen and macular variants. Progression from NLPCA to systemic amyloidosis is believed to be uncommon. Although early investigations suggested progression rates as high as 50%, recent studies have reported a much more conservative rate of around 7%.1–7 Outcomes in patients with systemic amyloidosis are improved with early detection, therefore long-term follow-up of patients with NLPCA is prudent.1–7 Cutaneous blistering is most commonly associated with the systemic forms of amyloidosis.1 Bullous change has been rarely described in PCA, with most examples being the lichen variant.8–10 Bullous lesions of cutaneous amyloidosis typically demonstrate subepidermal (or superficial intradermal) clefting on light microscopy, raising the differential diagnosis of bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, porphyria cutanea tarda, pseudoporphyria, bullous drug eruption, bullous lupus erythematosus or epidermolysis bullosa.8–10 To our knowledge, bullous change in NLPCA has not been reported previously.
346
Clinical and Experimental Dermatology (2014) 39, pp344–347
The exact mechanism by which bullae are formed in cutaneous amyloidosis is not currently understood. It has been suggested that bullous change may be induced by trauma, with shearing forces resulting in either the fracturing of fragile cutaneous amyloid deposits or their engulfment and transepidermal elimination by keratinocytes.8 Furthermore, recent studies have reported that oligomers (i.e. small, misfolded protein species), in addition to amyloid fibrils, are detectable in NLPCA and other variants of PCA.2,3 Importantly, immunoglobulin-derived amyloid oligomers are known to be toxic to epidermal keratinocytes.3 We speculate that the possible presence of such oligomers in close proximity to basilar keratinocytes could have compromised their function, and played a role in the subepidermal bullous change seen in our case. In conclusion, we report an unusual presentation of NLPCA with clinical and histopathological evidence of subepidermal bullous formation. Evaluation of cutaneous bullous lesions by light microscopy should include a search for underlying amyloid deposits.
Learning points Cutaneous blistering is often associated with
systemic amyloidosis. Bullous change has rarely been described in
PCA, and most commonly in lichen variants. This report illustrates bullous change in nodu-
lar localized PCA. Evaluation of cutaneous bullous lesions by light
microscopy should include a search for amyloid deposits.
References 1 Fernandez-Flores A. Cutaneous amyloidosis: a concept review. Am J Dermatopathol 2012; 34: 1–14; quiz 15. 2 Clos AL, Lasagna-Reeves CA, Kelly B et al. Role of oligomers in the amyloidogenesis of primary cutaneous amyloidosis. J Am Acad Dermatol 2011; 65: 1023–31. 3 Clos AL, Lasagna-Reeves CA, Castillo-Carranza DL et al. Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis. Br J Dermatol 2011; 165: 1349–54. 4 Schwendiman MN, Beachkofsky TM, Wisco OJ et al. Primary cutaneous nodular amyloidosis: case report and review of the literature. Cutis 2009; 84: 87–92. 5 Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J Dermatol 2001; 145: 105–9.
ª 2014 British Association of Dermatologists
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
6 Borrowman TA, Lutz ME, Walsh JS. Cutaneous nodular amyloidosis masquerading as a foot callus. J Am Acad Dermatol 2003; 49: 307–10. 7 Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol 2003; 139: 1157–9. 8 Kuroda K, Mizoguchi M. Lichen amyloidosus with subepidermal blister formation. Eur J Dermatol 2004; 14: 262–3.
ª 2014 British Association of Dermatologists
9 Chandran NS, Goh BK, Lee SS et al. Case of primary localized cutaneous amyloidosis with protean clinical manifestations: lichen, poikiloderma-like, dyschromic and bullous variants. J Dermatol 2011; 38: 1066– 71. 10 Cho TH, Lee MH. A case of lichen amyloidosus accompanied by vesicles and dyschromia. Clin Exp Dermatol 2008; 33: 291–3.
Clinical and Experimental Dermatology (2014) 39, pp344–347
347
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Nodular localized primary cutaneous amyloidosis: a bullous variant A. LaChance,1 A. Phelps,1 J. Finch,1 J. Lu,1 Z. Elaba,2 W. Rezuke2 and M. J. Murphy1 1
Division of Dermatopathology, Department of Dermatology, University of Connecticut Health Center, Farmington, CT, USA; and 2Department of Pathology, Hartford Hospital, Hartford, CT, USA doi:10.1111/ced.12305
Summary
Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin-restricted amyloidoses. We present an unusual case of NLPCA in a 51-year-old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.
The term ‘primary cutaneous amyloidosis’ (PCA) refers to a group of conditions that show skin-restricted intracellular and extracellular deposition of amyloid fibrils and oligomers, derived from a variety of protein sources.1–10 Several subtypes of PCA have been described, including lichen amyloidosus, macular amyloidosis, amyloidosis cutis dyschromica (ACD) and nodular localized PCA (NLPCA).1–10 In the lichen, macular and ACD variants, the amyloid is derived from degenerated basilar keratinocytes, and is generally confined to the papillary dermis.1,2 In NLPCA, the amyloid is largely derived from clonal immunoglobulin light chains produced by tissue-infiltrating monotypic plasma cells.1,3–6 Bullous change has rarely been described in primary cutaneous forms of amyloidosis, and most commonly in the lichen variants.8–10 Of note, cutaneous blistering is more often associated with systemic forms of amyloidosis.1 Bullous change in NLPCA has not been reported previously. We describe an unusual case of NLPCA with subepidermal bullous formation.
Report A 51-year-old man presented with a 2-month history of a solitary, slightly erythematous, smooth-surfaced papule, 6 mm in size, with overlying tense blister, on his right third toe (Fig. 1). The patient reported no history of trauma to the site. Whole-body skin examination did not reveal any other cutaneous lesions. An incisional biopsy was taken, and on histopathological review, focal subepidermal clefting was seen, with otherwise normal-appearing epidermis (Fig. 2). Basilar keratinocytes did not show degenerative cytological changes. A subjacent superficial perivascular and interstitial mature-appearing plasma cell infiltrate
Correspondence: Dr Michael J. Murphy, Division of Dermatopathology, Department of Dermatology, University of Connecticut Health Center, 21 South Road, Farmington, CT 06030, USA E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 10 November 2013
344
Clinical and Experimental Dermatology (2014) 39, pp344–347
Figure 1 Solitary, slightly erythematous, smooth-surfaced,
papule, 6 mm in size, with overlying tense blister on the right third toe.
ª 2014 British Association of Dermatologists
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
(a)
(c)
(b)
(d)
(e)
Figure 2 (a,b) Superficial dermal perivascular and interstitial predominantly plasma cell infiltrate, with adjacent aggregations of amor-
phous, acellular, faintly eosinophilic material. Focal subepidermal clefting is visible. Haematoxylin and eosin, original magnification (a) 9 20; (b) 9 40. (c) Amorphous, acellular, strongly staining material (Congo red, original magnification 9 100). Apple-green birefringence was visible under polarized light (not shown). (d,e) In situ hybridization studies for (d) kappa and (e) lambda light-chains show evidence of kappa light-chain restriction, consistent with a monoclonal plasma cell proliferation.
with prominent intranuclear inclusions (Dutcher bodies) was identified. The adjacent dermis showed aggregations of amorphous, acellular, faintly eosinophilic material, which stained strongly with Congo red, and demonstrated apple-green birefringence under polarized light, consistent with amyloid. In situ hybridization studies revealed kappa light chain restriction, consistent with a monoclonal plasma cell proliferation. Follow-up evaluation did not reveal any clinical or laboratory evidence of systemic amyloidosis or an autoimmune disorder. The patient had no family history of amyloidosis. A diagnosis of NLPCA was made. The lesion was subsequently excised completly. At follow-up approximately 1 year later, the patient showed no evidence of local recurrence or related systemic disease.
ª 2014 British Association of Dermatologists
NLPCA is a rare variant of PCA, with only around 60 cases reported in the literature.1–7 It is characterized by a focal cutaneous accumulation of predominantly light-chain immunoglobulins (AL-type amyloid), secondary to a localized monoclonal proliferation of plasma cells.1,3–6 A predilection for acral sites has been reported,1,7 sometimes leading to the clinical impression of a callus.6 By definition, patients with NLPCA do not show evidence of underlying haematological dyscrasia or amyloid deposition in internal organs at diagnosis.1–7 It has been proposed that NLPCA may represent either a form of ‘localized plasma cell dyscrasia’4 or ‘extramedullary plasmacytoma’ with local production of amyloid by plasma cells.5 An association between NLPCA and several autoimmune conditions has been described, most
Clinical and Experimental Dermatology (2014) 39, pp344–347
345
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
commonly Sj€ ogren syndrome (about 25% of reported cases).1–7 Under light microscopy, NLPCA typically appears as amyloid deposits in the papillary and reticular dermis.1–7 Involvement of the subcutaneous tissue, cutaneous blood vessel walls, nerve sheaths and adnexal structures has also been described. Deposits are highlighted by Congo red staining with applegreen birefringence under polarized light. Thioflavin S, crystal violet, Sirius red and metachromatic stains have also been used to highlight amyloid in tissue sections.1–7 Immunohistochemistry and surface receptor gene rearrangement studies have been used to confirm monoclonality of plasma cell populations in lesions of NLPCA,1–7 as identified in our case. Currently, immunostaining is the preferred method for amyloid typing in NLPCA and other cutaneous amyloidoses.1 In NLPCA, antibodies targeting kappa and lambda light chains have been used to confirm the composition of AL-type amyloid deposits.1 The clinical and histopathological features of NLPCA may be indistinguishable from those of systemic amyloidosis with cutaneous involvement,1–7 prompting the need for thorough investigations at the time of diagnosis. Surgical excision, cryotherapy, electrodesiccation and curettage, intralesional steroid injection, localized radiation and CO2 laser therapy have been used with variable success.1–7 Reported local recurrence rates are high, and may be secondary to the extent and depth of amyloid deposition in this form of cutaneous amyloidosis compared with lichen and macular variants. Progression from NLPCA to systemic amyloidosis is believed to be uncommon. Although early investigations suggested progression rates as high as 50%, recent studies have reported a much more conservative rate of around 7%.1–7 Outcomes in patients with systemic amyloidosis are improved with early detection, therefore long-term follow-up of patients with NLPCA is prudent.1–7 Cutaneous blistering is most commonly associated with the systemic forms of amyloidosis.1 Bullous change has been rarely described in PCA, with most examples being the lichen variant.8–10 Bullous lesions of cutaneous amyloidosis typically demonstrate subepidermal (or superficial intradermal) clefting on light microscopy, raising the differential diagnosis of bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, porphyria cutanea tarda, pseudoporphyria, bullous drug eruption, bullous lupus erythematosus or epidermolysis bullosa.8–10 To our knowledge, bullous change in NLPCA has not been reported previously.
346
Clinical and Experimental Dermatology (2014) 39, pp344–347
The exact mechanism by which bullae are formed in cutaneous amyloidosis is not currently understood. It has been suggested that bullous change may be induced by trauma, with shearing forces resulting in either the fracturing of fragile cutaneous amyloid deposits or their engulfment and transepidermal elimination by keratinocytes.8 Furthermore, recent studies have reported that oligomers (i.e. small, misfolded protein species), in addition to amyloid fibrils, are detectable in NLPCA and other variants of PCA.2,3 Importantly, immunoglobulin-derived amyloid oligomers are known to be toxic to epidermal keratinocytes.3 We speculate that the possible presence of such oligomers in close proximity to basilar keratinocytes could have compromised their function, and played a role in the subepidermal bullous change seen in our case. In conclusion, we report an unusual presentation of NLPCA with clinical and histopathological evidence of subepidermal bullous formation. Evaluation of cutaneous bullous lesions by light microscopy should include a search for underlying amyloid deposits.
Learning points Cutaneous blistering is often associated with
systemic amyloidosis. Bullous change has rarely been described in
PCA, and most commonly in lichen variants. This report illustrates bullous change in nodu-
lar localized PCA. Evaluation of cutaneous bullous lesions by light
microscopy should include a search for amyloid deposits.
References 1 Fernandez-Flores A. Cutaneous amyloidosis: a concept review. Am J Dermatopathol 2012; 34: 1–14; quiz 15. 2 Clos AL, Lasagna-Reeves CA, Kelly B et al. Role of oligomers in the amyloidogenesis of primary cutaneous amyloidosis. J Am Acad Dermatol 2011; 65: 1023–31. 3 Clos AL, Lasagna-Reeves CA, Castillo-Carranza DL et al. Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis. Br J Dermatol 2011; 165: 1349–54. 4 Schwendiman MN, Beachkofsky TM, Wisco OJ et al. Primary cutaneous nodular amyloidosis: case report and review of the literature. Cutis 2009; 84: 87–92. 5 Woollons A, Black MM. Nodular localized primary cutaneous amyloidosis: a long-term follow-up study. Br J Dermatol 2001; 145: 105–9.
ª 2014 British Association of Dermatologists
Nodular localized primary cutaneous amyloidosis A. LaChance et al.
6 Borrowman TA, Lutz ME, Walsh JS. Cutaneous nodular amyloidosis masquerading as a foot callus. J Am Acad Dermatol 2003; 49: 307–10. 7 Moon AO, Calamia KT, Walsh JS. Nodular amyloidosis: review and long-term follow-up of 16 cases. Arch Dermatol 2003; 139: 1157–9. 8 Kuroda K, Mizoguchi M. Lichen amyloidosus with subepidermal blister formation. Eur J Dermatol 2004; 14: 262–3.
ª 2014 British Association of Dermatologists
9 Chandran NS, Goh BK, Lee SS et al. Case of primary localized cutaneous amyloidosis with protean clinical manifestations: lichen, poikiloderma-like, dyschromic and bullous variants. J Dermatol 2011; 38: 1066– 71. 10 Cho TH, Lee MH. A case of lichen amyloidosus accompanied by vesicles and dyschromia. Clin Exp Dermatol 2008; 33: 291–3.
Clinical and Experimental Dermatology (2014) 39, pp344–347
347
