Report
Primary Localized Amyloidosis in One Family Hiroyuki Hashimoto, M.D., Satoshi Itami, M.D., Sotaro Kurata, M.D., Susumu Takayasu, M.D., and Tadaaki Yokota, M.D.
Abstract: Primary localized amyloidcsis was found in a family. A 66-year-old woman had suffered from hoarseness for 18 years. A biopsy specimen from the larynx showed amyloid deposits in the submucosal connective tissue. Her 40-year-old daughternoticed a subcutaneous nodule on herphiltrum. Histologic examination showed the deposition of amyloid in the middle and lower dermis, which also encased the blood vessels and epidermal appendages. In both cases the amyloid deposits were positively stained with Congo red and the staining was resistant to potassium permanganate treatment. These amyloid deposits were strongly positive against the anti-amyloid antibody of the X light chain. These results indicate that the amyloid substance is derived from protein AL. There was no clinical or laboratory evidence of systemic amyloidosis or multiple myeloma in either patient.
Primary familial localized amyloidosis is a rare disease.' This report describes the occurrence of primary localized amyloidosis of X light chain origin, involving the larynx of a mother and the skin of her daughter. Case Reports
Case 1 • A 66-year-old woman was admitted to our hospital because of hoarseness and dyspnea of 18 years' duration. Fifteen years before, a thickening of the laryngeal mucosal membrane and dysfunction of tbe false vocal code were detected laryngoscopically at a local hospital. Furthermore, the histologic examination performed at that time revealed amyloid deposits in the submucosal area of the larynx. These symptoms were gradually aggravated. She received tracheotomy several times without any beneficial results. The bronchofibroscopy performed at our hospital showed a thickening of the false vocal code and constriction of trachea. There was no clinical or laboratory evidence suggestive of systemic amyloidosis or multiple myeloma. The laboratory data were normal except for the positive RA test and antinuclear From the Department of Dermatology, Medical College of Oita, Oita-Gun, and the Department of Pathology, Yamaguchi University School of Medicine, Ube City, Japan. Address correspondence to: Satoshi Itami, M.D., Department of Dermatology, Medical College of Oita, 1-1, Idaigaoka, Hazama-cho, Oita-Gun, Oita Pref., 879-55 Japan. 632
antibody (1:40). Bence-Jones proteins were not detected in urine. The result of quantitative determination of immunoglobulins was normal. Biopsy specimens of the rectum and stomach were free of amyloid deposits. Histologic examination of the larynx disclosed faintly eosinophiiic, fractured homogeneous masses under the laryngeal mucosa (Fig. 1). Numerous plasma cells and lymphocytes were scattered around the mucous glands (Fig. 2). These materials were intensely stained with Congo red, and the stain was resistant to potassium permanganate treatment. Immunohistochemical studies were carried out with rabbit antisera to AA, Ak, AX,^ prealbumin, /32-microglobulin, and keratin. The amyloid material was stained only with the anti-amyloid antibody of the X light chain (Fig. 3), and was negative for the other antibodies used. Most of the infiltrating plasma cells were positively stained with anti-AX antibody, and some were stained with anti-A/c. Case 2 A 40-year-old woman, a daughter of the patient in case 1, had a subcutaneous nodule on her philtrum (the depression above the upper lip and below the nasal septum), which had been noticed for 3 months before presentation. The lesion was neither painful nor pruritic. The nodule gradually increased in size. She had suffered from Raynaud phenomenon for several years before she visited our hospital in March, 1988. The cutaneous examination revealed afirmsubcutaneous nodule measuring 1 cm in diameter on her philtrum. The overlying skin was normal. Her general condition appeared to be good. The normal or negative laboratory findings included a complete blood cell count, as well as the results of urinalysis, serum protein electrophoresis, and fluorescent antinuclear antibody test. No M-protein was detected in the serum. Roentgenographic examination of the skull demonstrated no punched-out lesions. Biopsy of the bone marrow showed no abnormal or neoplastic plasma cells. There was no amyloid deposit in hiopsy specimens from the stomach and rectum. Histologically, the nodule on the philtrum consisted of hyaline-like amorphous masses in the middle and lower dermis, which encased the blood vessels and epidermal appendages (Fig. 4). At the periphery of the masses, a small number of lymphocytes and plasma cells was observed. The overlying epidermis was normal. The amorphous material was positively stained with Congo red, and the staining was September 1991, Vol. 30, No. 9
No. 9
Primary Localized Amyloidosis • Hashimoto et al.
633
Figure 3. Plasma cells and amyloid surrounding the blood vessels are stained with anti-X light chain amyloid antibody (ABC method, original magnification X2OO).
Figure 1. Larynx of case 1. Heavy deposits of faintly eosinophiiic amorphous materials are seen in the submucosal tissue (H&E, X4O).
resistant to potassium permanganate treatment. Immunohistocbemical studies revealed tbat the amyloid material was stained only with anti-amyloid antibody of the X light chain, as in case 1 (Fig. 5).
Discussion Familial primary localized amyloidosis is an extremely rare disease, but several familial occurrences have been reported in endocrine, senile, cutaneous, and corneal
Figure 2. Amyloid deposition around the blood vessels and dense plasma cell infiltration (Congo-red, original magnification X2OO).
amyloidosis.' The nature of amyloid fibrils has been biochemically and immunohistochemically characterized in the first two types of amyloidosis.^ Unfortunately, however, the immunohistochemical characteristics of amyloid fibrils still remain to be clarified in the remaining two types.*"* To our knowledge, this is the first report of familial localized amyloidosis of immunoglobulin light chain origin. The mother (case 1) had deposits of amyloid in the larynx, which later involved the lower respiratory tract. The larynx is the most frequently affected site in primary localized amyloidosis'''^; amyloid deposits extend to the bronchi in some cases.* In this patient the amyloid material and plasma cells infiltrating the lesion were positively stained with anti-amyloid antiserum of the X light chain. These findings suggest that precursor light chains were locally produced by the plasma cells.'-"
Figure 4. Cutaneous nodule of case 2. Hyaline-like amorphous masses are seen in the entire dermis (H&E, original magnification XlOO).
634
International Journal of Dermatology • September 1991
Vol. 30
volved systemically,'*'" and because familial occurrence of primary systemic amyloidosis has been reported.'* References
Figure 5. Massive amyloid stained with anti-X light chain amyloid antibody (ABC method, x40).
The daughter (case 2) had a nodule on the philtrum without systemic involvement of amyloidosis. Primary localized cutaneous amyloidosis can be classified into three types: macular, lichenoid, and tumefactive types.'^ In the first two types, the amyloid protein is derived from epidermal keratin.'^ On the other hand, amyloid deposits are stained with anti-AL antiserum in the tumefactive or nodular type,''''' of which this case was an example. Our patients must be carefully followed up, because some cases once diagnosed as primary localized amyloidosis of light chain origin later proved to be in-
1. Thomas PK. Genetic factors in amyloidosis. J Med Genet. 1975;12:317-326. 2. Fujihara S, Balow JE, Costa JC, et al. Identification and classification of amyloid in formalin-fixed, paraffin-embedded tissue sections by the unlabeled immunoperoxidase method. Lab Invest. 1980;43:35S-365. 3. Cohen AS, Shirahama T, Sipe JD, et al. Amyloid proteins, precursors, mediator, and enhancer. Lab Invest. 1983;48:l-4. 4. Vasily DB, Bhatia SG, Uhlin SR. Familial primary cutaneous amyloidosis. Arch Dermatol. 1978; 114:1173-1176. 5. Newton JA, Jagjivan A, Bhogal B, et al. Familial primary cutaneous amyloidosis. BrJ Dermatol. 1985;112:201-208. 6. Stock EL, Kielar RA. Primary familial amyloidosis of the cornea. Am J Ophthalmol. 1976;82:266-27I. 7. Jepsen O, Nielsen K. Primary localized amyloid tumours of the upper respiratory tract. Acta Med Scand. I955;l51:312-328. 8. McAlpine JC, Fuller AP. Localized laryngeal amyloidosis: A report of a case with a review of the literature. J Laryngol Otol. 1964;78:296-314. 9. Nagata H, Yoshihara T, Nomoto M, et al. Light and electron microscopic studies of localized laryngeal amyloidosis. Arch Otorhinolaryngol. 1987;244:180-184. 10. Hui AN, Koss MN, Hochholzer L, et al. Amyloidosis presenting in the lower respiratory tract. Arcb Pathol Lab Med. 1986;110:212-218. 11. Glenner GG. Amyloid deposits and amyloidosis: The /3-fibrilloses. N Engl J Med. I980;302:1333-1343. 12. Ratz JL, Bailin PL. Cutaneous amyloidosis. J Am Acad Dermatol. 1981;4:21-26. 13. Lever WF, Schaumberg-Lever G. Histopathology of the Skin. Philadelphia: JB Lippincott, 1989:452-457. 14. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosis involving the vulva. Arch Dermatol. I985;121:518-521. 15. Kitajima Y, Seno J, Aoki S, et al. Nodular primary cutaneous amyloidosis. Arch Dermatol. 1986; 122:1425-1430. 16. Brownstein MH, Helwig EB. The cutaneous amyloidosis. Arch Dermatol. 1970;102:8-19. 17. Franklin EC. Amyloid and amyloidosis of the skin. J Invest Dermatol. 1976;67:451-456. 18. Gerts MA, Garton JP, Kyle RA. Primary amyloidosis (AL) in families. Am J Hematol. 1986;22:193-198.
Alleged Phthirophagy The idea tbat the Greeks were acquainted with the custom of eating lice seems to rest on very fragile grounds. Herodotus 4.109 mentions a tribe in the middle Volga who eat the phtheir, but in this context the word could mean 'fir-cone' and this is how most scholars bave taken it. Such an interpretation is by no means refuted by a iater passage of Herodotus (4.168) which recounts how women of the Adyrmacbidae in Libya, when they catch lice on themseives, bite them before throwing them away. Lice-eating has been reported in Scythia, for instance, and also among the Budini, the Hottentots (as described by P. Kolben, The Present State of the Cape of Good Hope (London 1738) 2.179), American Indians and fhose of the Amazon (A. R. Wallace, Transactions of the Ent. Soc. London 2 (1852/3) 244); also monkeys—accidentally, in the course of grooming. See in general Busvine pp. 86ff. who iists other alleged instances but cautiously concludes that what is actually involved is the disposing of the lice by cracking them between the teeth, a practice 'by no means uncommon among primitive peoples (which) when observed by divers imaginative travellers . . . gave rise to stories of the use of lice as food.'—Davies M, Kathirithamby J. Greek Insects. New York: Oxford, 1986:172.
Primary Localized Amyloidosis in One Family Hiroyuki Hashimoto, M.D., Satoshi Itami, M.D., Sotaro Kurata, M.D., Susumu Takayasu, M.D., and Tadaaki Yokota, M.D.
Abstract: Primary localized amyloidcsis was found in a family. A 66-year-old woman had suffered from hoarseness for 18 years. A biopsy specimen from the larynx showed amyloid deposits in the submucosal connective tissue. Her 40-year-old daughternoticed a subcutaneous nodule on herphiltrum. Histologic examination showed the deposition of amyloid in the middle and lower dermis, which also encased the blood vessels and epidermal appendages. In both cases the amyloid deposits were positively stained with Congo red and the staining was resistant to potassium permanganate treatment. These amyloid deposits were strongly positive against the anti-amyloid antibody of the X light chain. These results indicate that the amyloid substance is derived from protein AL. There was no clinical or laboratory evidence of systemic amyloidosis or multiple myeloma in either patient.
Primary familial localized amyloidosis is a rare disease.' This report describes the occurrence of primary localized amyloidosis of X light chain origin, involving the larynx of a mother and the skin of her daughter. Case Reports
Case 1 • A 66-year-old woman was admitted to our hospital because of hoarseness and dyspnea of 18 years' duration. Fifteen years before, a thickening of the laryngeal mucosal membrane and dysfunction of tbe false vocal code were detected laryngoscopically at a local hospital. Furthermore, the histologic examination performed at that time revealed amyloid deposits in the submucosal area of the larynx. These symptoms were gradually aggravated. She received tracheotomy several times without any beneficial results. The bronchofibroscopy performed at our hospital showed a thickening of the false vocal code and constriction of trachea. There was no clinical or laboratory evidence suggestive of systemic amyloidosis or multiple myeloma. The laboratory data were normal except for the positive RA test and antinuclear From the Department of Dermatology, Medical College of Oita, Oita-Gun, and the Department of Pathology, Yamaguchi University School of Medicine, Ube City, Japan. Address correspondence to: Satoshi Itami, M.D., Department of Dermatology, Medical College of Oita, 1-1, Idaigaoka, Hazama-cho, Oita-Gun, Oita Pref., 879-55 Japan. 632
antibody (1:40). Bence-Jones proteins were not detected in urine. The result of quantitative determination of immunoglobulins was normal. Biopsy specimens of the rectum and stomach were free of amyloid deposits. Histologic examination of the larynx disclosed faintly eosinophiiic, fractured homogeneous masses under the laryngeal mucosa (Fig. 1). Numerous plasma cells and lymphocytes were scattered around the mucous glands (Fig. 2). These materials were intensely stained with Congo red, and the stain was resistant to potassium permanganate treatment. Immunohistochemical studies were carried out with rabbit antisera to AA, Ak, AX,^ prealbumin, /32-microglobulin, and keratin. The amyloid material was stained only with the anti-amyloid antibody of the X light chain (Fig. 3), and was negative for the other antibodies used. Most of the infiltrating plasma cells were positively stained with anti-AX antibody, and some were stained with anti-A/c. Case 2 A 40-year-old woman, a daughter of the patient in case 1, had a subcutaneous nodule on her philtrum (the depression above the upper lip and below the nasal septum), which had been noticed for 3 months before presentation. The lesion was neither painful nor pruritic. The nodule gradually increased in size. She had suffered from Raynaud phenomenon for several years before she visited our hospital in March, 1988. The cutaneous examination revealed afirmsubcutaneous nodule measuring 1 cm in diameter on her philtrum. The overlying skin was normal. Her general condition appeared to be good. The normal or negative laboratory findings included a complete blood cell count, as well as the results of urinalysis, serum protein electrophoresis, and fluorescent antinuclear antibody test. No M-protein was detected in the serum. Roentgenographic examination of the skull demonstrated no punched-out lesions. Biopsy of the bone marrow showed no abnormal or neoplastic plasma cells. There was no amyloid deposit in hiopsy specimens from the stomach and rectum. Histologically, the nodule on the philtrum consisted of hyaline-like amorphous masses in the middle and lower dermis, which encased the blood vessels and epidermal appendages (Fig. 4). At the periphery of the masses, a small number of lymphocytes and plasma cells was observed. The overlying epidermis was normal. The amorphous material was positively stained with Congo red, and the staining was September 1991, Vol. 30, No. 9
No. 9
Primary Localized Amyloidosis • Hashimoto et al.
633
Figure 3. Plasma cells and amyloid surrounding the blood vessels are stained with anti-X light chain amyloid antibody (ABC method, original magnification X2OO).
Figure 1. Larynx of case 1. Heavy deposits of faintly eosinophiiic amorphous materials are seen in the submucosal tissue (H&E, X4O).
resistant to potassium permanganate treatment. Immunohistocbemical studies revealed tbat the amyloid material was stained only with anti-amyloid antibody of the X light chain, as in case 1 (Fig. 5).
Discussion Familial primary localized amyloidosis is an extremely rare disease, but several familial occurrences have been reported in endocrine, senile, cutaneous, and corneal
Figure 2. Amyloid deposition around the blood vessels and dense plasma cell infiltration (Congo-red, original magnification X2OO).
amyloidosis.' The nature of amyloid fibrils has been biochemically and immunohistochemically characterized in the first two types of amyloidosis.^ Unfortunately, however, the immunohistochemical characteristics of amyloid fibrils still remain to be clarified in the remaining two types.*"* To our knowledge, this is the first report of familial localized amyloidosis of immunoglobulin light chain origin. The mother (case 1) had deposits of amyloid in the larynx, which later involved the lower respiratory tract. The larynx is the most frequently affected site in primary localized amyloidosis'''^; amyloid deposits extend to the bronchi in some cases.* In this patient the amyloid material and plasma cells infiltrating the lesion were positively stained with anti-amyloid antiserum of the X light chain. These findings suggest that precursor light chains were locally produced by the plasma cells.'-"
Figure 4. Cutaneous nodule of case 2. Hyaline-like amorphous masses are seen in the entire dermis (H&E, original magnification XlOO).
634
International Journal of Dermatology • September 1991
Vol. 30
volved systemically,'*'" and because familial occurrence of primary systemic amyloidosis has been reported.'* References
Figure 5. Massive amyloid stained with anti-X light chain amyloid antibody (ABC method, x40).
The daughter (case 2) had a nodule on the philtrum without systemic involvement of amyloidosis. Primary localized cutaneous amyloidosis can be classified into three types: macular, lichenoid, and tumefactive types.'^ In the first two types, the amyloid protein is derived from epidermal keratin.'^ On the other hand, amyloid deposits are stained with anti-AL antiserum in the tumefactive or nodular type,''''' of which this case was an example. Our patients must be carefully followed up, because some cases once diagnosed as primary localized amyloidosis of light chain origin later proved to be in-
1. Thomas PK. Genetic factors in amyloidosis. J Med Genet. 1975;12:317-326. 2. Fujihara S, Balow JE, Costa JC, et al. Identification and classification of amyloid in formalin-fixed, paraffin-embedded tissue sections by the unlabeled immunoperoxidase method. Lab Invest. 1980;43:35S-365. 3. Cohen AS, Shirahama T, Sipe JD, et al. Amyloid proteins, precursors, mediator, and enhancer. Lab Invest. 1983;48:l-4. 4. Vasily DB, Bhatia SG, Uhlin SR. Familial primary cutaneous amyloidosis. Arch Dermatol. 1978; 114:1173-1176. 5. Newton JA, Jagjivan A, Bhogal B, et al. Familial primary cutaneous amyloidosis. BrJ Dermatol. 1985;112:201-208. 6. Stock EL, Kielar RA. Primary familial amyloidosis of the cornea. Am J Ophthalmol. 1976;82:266-27I. 7. Jepsen O, Nielsen K. Primary localized amyloid tumours of the upper respiratory tract. Acta Med Scand. I955;l51:312-328. 8. McAlpine JC, Fuller AP. Localized laryngeal amyloidosis: A report of a case with a review of the literature. J Laryngol Otol. 1964;78:296-314. 9. Nagata H, Yoshihara T, Nomoto M, et al. Light and electron microscopic studies of localized laryngeal amyloidosis. Arch Otorhinolaryngol. 1987;244:180-184. 10. Hui AN, Koss MN, Hochholzer L, et al. Amyloidosis presenting in the lower respiratory tract. Arcb Pathol Lab Med. 1986;110:212-218. 11. Glenner GG. Amyloid deposits and amyloidosis: The /3-fibrilloses. N Engl J Med. I980;302:1333-1343. 12. Ratz JL, Bailin PL. Cutaneous amyloidosis. J Am Acad Dermatol. 1981;4:21-26. 13. Lever WF, Schaumberg-Lever G. Histopathology of the Skin. Philadelphia: JB Lippincott, 1989:452-457. 14. Northcutt AD, Vanover MJ. Nodular cutaneous amyloidosis involving the vulva. Arch Dermatol. I985;121:518-521. 15. Kitajima Y, Seno J, Aoki S, et al. Nodular primary cutaneous amyloidosis. Arch Dermatol. 1986; 122:1425-1430. 16. Brownstein MH, Helwig EB. The cutaneous amyloidosis. Arch Dermatol. 1970;102:8-19. 17. Franklin EC. Amyloid and amyloidosis of the skin. J Invest Dermatol. 1976;67:451-456. 18. Gerts MA, Garton JP, Kyle RA. Primary amyloidosis (AL) in families. Am J Hematol. 1986;22:193-198.
Alleged Phthirophagy The idea tbat the Greeks were acquainted with the custom of eating lice seems to rest on very fragile grounds. Herodotus 4.109 mentions a tribe in the middle Volga who eat the phtheir, but in this context the word could mean 'fir-cone' and this is how most scholars bave taken it. Such an interpretation is by no means refuted by a iater passage of Herodotus (4.168) which recounts how women of the Adyrmacbidae in Libya, when they catch lice on themseives, bite them before throwing them away. Lice-eating has been reported in Scythia, for instance, and also among the Budini, the Hottentots (as described by P. Kolben, The Present State of the Cape of Good Hope (London 1738) 2.179), American Indians and fhose of the Amazon (A. R. Wallace, Transactions of the Ent. Soc. London 2 (1852/3) 244); also monkeys—accidentally, in the course of grooming. See in general Busvine pp. 86ff. who iists other alleged instances but cautiously concludes that what is actually involved is the disposing of the lice by cracking them between the teeth, a practice 'by no means uncommon among primitive peoples (which) when observed by divers imaginative travellers . . . gave rise to stories of the use of lice as food.'—Davies M, Kathirithamby J. Greek Insects. New York: Oxford, 1986:172.
