Clinical and Experimental Dermatology 1994; 19: 159-162.

Primary nodular cutaneous amyloidosis-long-term follow-up and treatment

J.P.VESTEY, M.J .TIDMAN AND K.M.MCLAREN* University Departments of Dermatology and* Histopathology, Royal Infirmary of Edinburgh, Edinburgh, UK

Accepted for publication \0 March 1993

Summary

A case of facial primary nodular cutaneous amyloidosis isreported. This illustrates: the striking appearance of thisunusual condition; the investigations appropriate toestablish the diagnosis and to exclude underlying sys-temic amyloidosis or a condition which might contributeto amyloidosis; and the difficulty of successful manage-ment. Initial investigation failed to reveal any evidence ofsystemic amyloidosis or an associated internal illness.Two amyloid nodules were excised, but 7 years later thepatient developed further nodules on the adjacent facialskin and again sought dermatological advice. He wasreinvestigated and again no underlying condition wasfound. A trial of cryotherapy was unsuccessful, butcurrettage and cautery produced a cosmeticaily accept-able result.

The amyloidoses are a group of rare conditionscharacterized by extracellular deposition of several differ-ent unrelated proteins which share histological, im-munofluorescenee and ultrastructural features. They arecategorized according to their clinical features and thenature ofthe amyloid deposits. Three types of primarycutaneous amyloidosis are recognized. Lichen amyloido-sus and macular amyloidosis are the most common, andare associated with deposition ofa type of amyloid proteinin the upper dermis which appears to be derived fromepidermal cells.'-^ The third type, nodular or tumefactiveprimary cutaneous amyloidosis, is very rare, however,and only some 50 cases have been reported since it wasfirst described in 1950.''

Primary nodular cutaneous amyloidosis is thought tobe formed by deposition of amyloid I. protein in thedermis and subcutis produced by a local plasma celldyscrasia. The amyloid chains in this condition areindistinguishable from those which may be deposited in

Correspondence: Dr J.P.Vestey, DepartmenI of Dermatology,Level 4. Lauriston Building. Royal Infirmary of Edinburgh, Lauri.stonPlace, Edinburgh EH3 9YW, Midlothian, LK.

the skin and other tissues as a complication of primarysystemic amyloidosis, which is usually associated withevidence ofa systemic plasma cell dyscrasia or of multiplemyeloma. Investigation of patients with nodular cuta-neous amyloidosis may reveal evidence of systemicamyloidosis, paraproteinaemia, a plasma cell dyscrasia ormyeloma;'-'' occasional patients presenting with primarynodular cutaneous amyloidosis develop multiple mye-loma several years later.'- '̂̂ However, at least 38 cases ofprimary nodular cutaneous amyloidosis have beenreported without evidence of systemic involvement. Veryrarely, clinically apparent cutaneous amyloid depositsmay occur in secondary .systemic amyloidosis which maycomplicate infective or inflammatory conditions, orfamilial diseases such as Mediterranean fever or Muckie-Wells' syndrome.'** Usually, however, such cutaneousdeposits are asymptomatic or only present because ofmild haemorrhage from adjacent cutaneous blood ves-sels.'̂ -"

Therefore patients with nodular cutaneous amyloido-sis should be investigated and followed up, to excludeassociated systemic amyloidosis or an underlying diseasewhich might contribute to it. We report a case of primarynodular cutaneous amyloidosis which illustrates thestriking clinical appearance of this condition, and thedifficulty of managing it successfully in the absence of anytreatable underlying cause.

Case report

A 35-year-oId man was referred to the dermatology clinicwith a 1-year history of two slowly growing pearlynodules affecting the upper right nasolabial fold and theleft side ofhis chin (Fig. la and b). The lesions had aglistening, gelatinous appearance with a translucentattenuated epidermis stretched over the surface and fociof telangiectasia within. The clinical differential diagnosisincluded nodular amyloidosis, acquired haemangioma,basal cell carcinoma, adnexal tumours, infiltration by alymphoma or sarcoidosis. He was otherwise well andhis previous medical history had been uneventful, apart

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160 J.P.VESTEY, M.J.TIDMAN AND K.M.MCLAREN

Figure 1. (a) Nasal and (b) chin lesium of nodular cutaneous amyloidosis at presentation.

Figure 2. Section through a nasal lesion showinjiexpansile deposition of boniopeneous amyloid witbsome attenuation of appendages. Small foci ofplasma cells are related to the amyloid deposits.

from mild rosacea 7 years previously which had res-ponded to systemic oxytetracycline and topical 0 5%sulphur in calamine lotion, both of which he haddiscontinued 3 years later.

Superficial incisional biopsies and subsequent exci-sional biopsies of both lesions revealed similar histologi-cal features (Fig. 2). There was a nodular expansion ofthepapillary and reticular dermis by homogeneous, eosino-philic material. The features, subsequently confirmed byCongo-red affinity with apple-green birefringence, weretypical of amyloid. The material lay in the upper dermis,as an irregular band at the dermo-epidermal junction, andin the walls of small blood vessels. The deeper dermalcomponent was more expansile and nodular with appar-ent compression of skin appendages. In the mid anddeeper reticular dermis there were aggregates of plasma

cells lying in association with the amyloid. These weremorphologically normal with a typical chromatin patternand cytoplasmic amphophilia with no blast transforma-tion. Within the nodular aggregates, there was a focalgranulomatous giant cell reaction to the amyloid deposi-tion.

The amyloid stained weakly with a monoclonal anti-body to kappa light chains and the plasma cells werepolytypic with a ratio of approximately 2:1 IgG kappa tolambda staining cells. There was no obvious heavy chainproduction, i.e. the pattern was 'non-secretory'. Electronmicroscopy revealed typical irregular, haphazard non-banded amyloid fibrils, approximately 7-10 nm indiameter. Potassium permanganate failed to remove thecongophilia, confirming that the amyloid was not ofsecondary 'inflammatory' type.

NODULAR CUTANEOUS AMYLOIDOSIS 161

Figure 3. Recurrent nodules of amyloid on the nose 7 years afterexcision of the index lesions.

The following itivestigations, performed to exclude thepresence of an underlying condition which might contri-bute to systemic amyloidosis, were normal: full bloodcount, erythrocyte sedimentation rate, plasma urea,glucose and electrolytes, liver function tests, prothrombinindex, thyroid function, serum electrophoresis, immuno-giobulin and complement levels, auto-antibody profile,rheumatoid factor, syphilis serology, hepatitis B surfaceantigen; urine dipstick analysis, microscopy, culture,electrophoresis and testing for Bence Jones proteins afterconcentration; intradermal tuberculin test (10 units);chest X-ray, abdominal ultrasound, electrocardiogramand a biopsy of normal-looking abdominal skin.

The patient was satisfied with the cosmetic results ofthe surgery and declined further investigation. However,further nodules of amyloid accumulated in skin adjacentto the excision sites over the subsequent 7 years (Fig. 3).He was therefore reinvestigated as before but again noevidence of systemic amyloidosis emerged nor of anyillness which might predispose to its development; hedeclined a rectal biopsy, bone marrow trephine oraspiration and a skeletal survey.

On this occasion it was felt that further radical surgerywas not appropriate since it was impossible to be certainthat the lesions might not recur. A preliminary trial ofcryotherapy was unhelpful and complicated by ininorhaemorrhage, and so the lesions were removed gradually,in three episodes of currettage followed by cautery underlocal anaesthetic, at 2-monthly intervals, which produceda satisfactory result (Fig. 4).

Discussion

The clinical and histological features were typical ofprimary nodular cutaneous amyloidosis in which the

Figure 4. A satisfactory cosmetic result was finally achieved bycurrettage and cautery uf the nasal lesions.

amyloid deposits contain amyloid L derived from im-munogiobulin light chains.' The precise source andnature of the amyloid fibril protein in the muscular andpapular (lichen amyloidosus) forms of primary cutaneousamyloidosis is, however, controversial but it appears to bederived from epidermal cells.'-^ Tn the nodular form thepresence of plasma cells suggests a localized form ofplasma cell dyscrasia, although full investigation isrequired to exclude primary systemic amyloidosis due toa systemic plasma cell dyscrasia or multiple myeloma. Inthis case there was no evidence of either systemicamyloidosis or of a condition which would predispose toit, but, although the subject was investigated on twooccasions, he declined several important investigationslisted above.

B-cell clonality of bone marrow cells has recently beendemonstrated by gene rearrangement in patients withnodular cutaneous amyloid deposits due to primarysystemic amyloidosis, either with or without associatedovert myeloma or parapn)teinaemia. Clonality of theamyloid-producing plasma cells from cutaneous nodulesin two further patients with primary localized nodular

162 J .P .VESTEY, M . J . T I D M A N AND K . M . M C L A R E N

cutaneous amyloidosis has also been demonstrated butwithout accompanying clonality of their bone marrowcells.'''^'' This confirms that the cutaneous amyloid de-posits in primary nodular cutaneous amyloidosis mayarise in relation to a localized plasmacytoma.^'" T-cellmarker studies ofthe cutaneous amyloid deposits in twosuch patients have also shown that many ofthe infiltrat-ing lymphocytes were T-cells (CD3, CD5, CD4> CD8),perhaps having a regulatory role in production of theamyloid.̂ *^ Unfortunately, similar studies were not poss-ible in our patient.

Dermabrasion," etretinate'^'-' and topical dimethylsulphoxide'** have been tried for the treatment of lichenamyloidosus with conflicting results. Most cases ofnodular cutaneous amyloidosis are treated with excisionwhich also provides material for histological and electronmicroscopical confirmation of this rare condition. How-ever, it has the tendency to recur,' as happened in ourpatient, presumably because the surgical procedure didnot remove all of the abnormal plasma cells. For thisreason, a less radical surgical approach was chosen on thesecond occasion. Carbon dioxide laser therapy has beenused successfully for treating this condition but may beassociated with recurrence,''' and variable results havebeen reported with cryotherapy"'''^ which was unhelpfulhere. Shave excision'" and electrodessication with curret-tage"* have also been reported to be suitable treatmentsfor nasal deposits of nodular cutaneous amyloidosis, and avery acceptable cosmetic result was produced in this case.

References

1. Breathnach SM. Amyloid and amyloidosis. Journal ofthe Ameri-can Academy of Dermatology 1988; 18: 1-16.

2. I Ioriguchi Y, Fine J-D, Lei[,'h IM, Yoshiki T, Ucda M, ImamuraS. Lamina densa malformation involved in histogtnesis ofprimary localised cutaneous amyloidosis. Journal of InvestigativeDermatology 1992; 99: 12-18.

3. Bizzozero E, Midana A. Sur 1'amyloidose cutanee. Annals deDermatologie 19.S0; 10: 18-24.

4. Gottron HA. Amyloidosis cutis nodularis atrophicans diabetics.Deutsche Medizinische Wochenschrift 1950; 75: 19-24.

5. Griinewald K, Sepp N, Weyrer K, Lhotta K, Feichtinger H,Konwaiinka G, Breathnach SM, Hintner H. Gene rearrangementstudies in the diagnosis of primary systemic and nodular primarylocalised cutaneous amyloidofi'ia. Journal of Investigative Dermato-logy 1991; 97: 693-596.

6. Brownstein Mil, Ilelwig EB. The cutaneous amyloidoses. I.Localized forms. Archives of Dermalology 1970; 102: 8-19.

7. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosisinvolving the vulva. Arehives of Dermatology 1985; 121: 518-521.

8. Brownstein Mil, Ilelwig EB. The cutaneous amyloidoses. II.Systemic forms. Archives of Dermatology 1970; 102: 20-28.

9. Rubinow A, Cohen AS. Skin involvement in generalised amyloi-dosis. A study of clinically involved and uninvolved skin in 50patients with primary and secondary amyloidosis. Annals ofInternal Medicine 88: 781-785.

10. Sepp N, Griinewald K, Soyer H-P, Kcrl H, Breathnach SM,Fritsch P, Hintner II. Typisierung von Intiltratzellen bei pri-marer, tocalisierter, nodularer, kutaner Amyloidose. Hautarzt1992; 43: 210-214.

11. Wong C-K, Li W-M, Dermabrasion for licben amyloidosus.Report ofa long-term study. Archives oj'Dermatology 1982; 118:302 304.

12. Aram H. Failure of etretinate (RO 10-9359) in lichen amyloido-sus. International Journal of Dermatology 1986; 25: 206.

13. MarschalkoM, DaroczyJ, Soos G. Ftrctinate for the treatment oflichen amyloidosis. Archives of Dermatology 1988; 124: 657-659.

14. F.ngel MF. Dimethyl sulfoxide (DMSO) in clinical dermatology.Southern Medical j'ourtial 1966; 59: 1318 1319.

15. Truhan AP, Garden JM, Roenigk III I. Nodular primary localisedcutaneous amyloidosis: immunohistochemical evaluation andtreatment witb the carbon dioxide laser. Journal of the AmericanAcademy of Dermatology 1986; 14: 1058-1062.

6. Bart RS, Kopf AW. Tumor conference 56. Localized cutaneousnodular amyloidosis. Journal of Dermatologic Surgery and Onco-logy 1985; I'l: 582-584.

17. Bourcier M, Raymond GP, Decroix G. In: Roerig J, ed.Challenges in Dermatology., no. 27. London: Pfizer, 1985.

18. Grattan CEII, Burton JL, Dabl MGC. Two cases of nodularcutaneous amyloid with positive organ-specific antibodies, treatedby sbave excision. Clinical and Experimental Dermatolog)' 1988;13: 187-189.