British journal of Dermatology (1992) 127.
CORRESPONDENCE
Widespread foUiculitis induced by human granulocytecolony-stimulating factor therapy SiK. Colony-Stimulating factors (CSFs) are glycoproteins produced by recombinant DNA techniques. They include granulocyte CSF (G-CSF) which primarily stimulates the production and function of neutrophils and to a lesser extent monocytes. iind granulocyte-inacrophage CSF (GM-CSF) which increases the production of neutrophils. monocytes and eosinophils.' CSFs have mainly been used in the amelioration of chemotherapy-induced neutropenia. although they have also been used in the treatment of non-malignant neutropenias.- aplastic anaemia, acquired immune deficiency syndrome, myeiodysplasia. and to aid recovery following bone marrow transplantation.' There have been four previous reports of skin manifestations with this therapy—two cases of leucocytoclastic vasculitis.'"^ a case of bullous pyoderma gangrenosum.'' and worsening of pre-existing cutaneous vasculitis in a patient with hairy-cell leukaemia/ We report a patient with myelodysplasia who developed a recurrent foUiculitis with C-CSF therapy. A f>4-year-oid Creek man was referred in April 1991 for treatment of myelodysplasia which had been diagnosed in 1989. At presentation he had a right middle zone lobar pneumonia, oropharyngeal candidiasis. cardiac failure and gastrointestinal bleeding. He was anaemic (haemoglobin 4- J g/dl|. thrombocytopenic (platelets lOx W/l} and leucopenic (total white cellcount l ' 4 x 1 OVI: neutrophils \-0x lOVD.He was treated with repeated blood and platelet transfusions. intravenous cefotaxime and frusemide, and oral erythromycin. tiuconazoie and amphotericin B suspension. His condition improved on the above treatment, and subcutaneous G-CSF therapy was started at a dose of JOO fig/ day. This was initially well tolerated, with no side-eflects. and resulted in a good granulocyte response. Six weeks after starting G-CSF. whilst on 300 /ig twice a week, he developed recurrent painful pustular lesions on the face, arms and upper trunk. New lesions appeared within 24 h of each G-CSF injection and lasted 1-2 weeks. On examination there were
1. Erytbematous papules and pustules over upper trunk.
Figure 2. Mixed inflammatory inliltraie around hair Iblliclc.
numerous 2-4-mm-diameter foilicular erythematous papules and pustules scattered over the face, scalp, upper chest and arms (Fig. 1). The total white cell count was 19-8 x lOVI, neutrophils 17-1 x 1071. and platelets 160x I OVI. A skin biopsy showed a mixed inflammatory infiltrate around the hair follicles and eccrine glands (Fig. 2). This consisted principally of lymphocytes and histiocytes with a few neutrophils and eosinophils. PAS. Gram, and Ziehl-Neelsen stains were all negative. Culture of a swab from a pustule produced a scanty growth of coagulase-negative Staphiilucoctiis iiurnis. The G-CSF was slowly reduced to JOO //g once a month which maintains an adequate neutrophil count, and he has had no further episodes of infection. However, he continues to develop new crops of skin lesions within 24 h of each GCSF injection, which resolve before tbe next montbly injection. There have been four previous reports of rashes associated with G-CSF therapy. Wodzinski et al.'' and Welte ft a!.^ reported leucocytoclastic vasculitis developing in patients with chronic idiopathic neutropenia on 0-CSF when the neutrophil count was greater than 1 •() x lOVl- The vasculitis resolved on cessation of tbe G-CSF. Ross et al.'' reported a SO-year-old woman with small-cell lung cancer wbo was treated with chemotherapy and G-CSF. She developed vesiculopustular lesions on the hands, the histology of which showed a dermal infiltrate of mature neutrophils. and oedema. A diagnosis of bullous pyoderma gangrenosum was made and the rasb resolved witb topical corticosteroid treatment after stopping tbe G-CSF. Claspy et «/.' described a patient with hairy-cell leukaemia complicated by neutropenia and a histologically confirmed leucocytoclastic vasculitis. After 1 week of G-CSF therapy there was increased size and tenderness of the skin lesions with associated fever. Sweet s syndrome was diagnosed, although a repeat skin biopsy was not performed. The lesions persisted for 2 weeks after the G-CSF was stopped, and then improved. Drug-induced foUiculitis is a well recognized but poorly understood phenomenon. It has been reported witb the use of a number of drugs including tetracydine.*^ rifampicin.*" phenytoin'" and halogens." A foUiculitis has not been previously
194
British Journal of Dermatology (1992) 127.
CORRESPONDENCE
reported in association with G-CSF therapy. The histology of our case showed a mixed inflammatory infiltrate around the hair follicles consisting principally of lymphocytes and histiocytes. with occasional neutrophils and eosinophils. Our patient is unusually sensitive to G-CSF and requires only monthly subcutaneous injections to maintain an adequate neutrophil count. The development of new skin lesions always occurs within 24 h of (5-CSF therapy, thus strongly implicating it in the pathogenesis ofthe rash. Department of Dermatology and *Haematolociy.
The Hoyal Free Hospital and Siiiool of Medicine, Pond Street. HampsteadNW3 2QG. U.K.
L.S.OSTLERE D.HARRIS
*H.G.PRENTICE M.H.A.RUSTIN
References 1 Wakeiicid PE. James WD. Samlaska CP, Meltzer MS. Colonystimulating factors. / Am Aaid Dermatol 1990; 23: 9OJ-12. 2 Morstyn G. The impact of colony stimulating factors on cancer chemotherapy. Br I Haermtol 1990: 75: JOJ-7, 3 Weisbart RH, Gasson IC Golde DW. Colony-stimulating factors and host defence. Anu Intern Med I 989: 110: 297-J03, 4 W'eite K. Zcidlcr C, Reiter A et ai Differential effects of granulocytt.'macrophagc colony-stimulating factor and granulocytc colcmystimulating factor in children with severe congenital neutropenia. Blood 1990: 75: 1056-63. 5 Wodzinski MA, Hampton KK, Reilly JT. Differential effect of G-CSF and GM-CSF in acquired chronic neutropenia. Brj Haematol 1991; 77: 249-50. IS Ross HJ, Moy LA. Kaplan R. Figlin RA. Biillous pyodtrma gangrenosum after granulocyte colony-stimulating factor treatment. Ctimer 1991; 68: 441-3. 7 Glaspy |A. Baldwin CC. Robertson PA et al. Therapy for neutropenia in hairy cell leukaemia with recombinant human granulocyte colony-stimulating factor. Ann Int Med 1988: 109: 789-95. 8 Bean SF. Acneiform eruption from tetracycline. Br j DernmtoJ 1971:85; 585-6. 9 \'wokolo IJ. Acneiform lesions in combined rifampicin treatment in Africans (letter). Br Med I 1974; 3: 473. 10 Jenkins RB, Ratner AC. Diphenylhydantoin and acne (lellerl, ;\' End I Med 1972; 287: 148. 11 Hitch JM. Acneform eruptions induced by drugs and chemicals.
lAMA 1967:200:879-80. Familial multiple pilomatrixomas SIR. We report a mother and daughter suffering from multiple pilomatrixomas. The occurrence of familial pilomatrixomas is very rare, and as most reported cases involve multiple lesions, a genetic basis must be considered. Case I. A 64-year-old woman gave a history of having developed three nodular lesions in early childhood. A lesion on the right temple was excised in 1946. and she was told it was a pilomatrixoma (histology not available). The other lesions, on theright and left upper arms, were asymptomatic and were not treated. On examination in August 1991 the two remaining
lesions were hard, angular nodules, located in the subcutaneous tissue, and covered by normal skin. They measured 1 cm in diameter. Physical examination was otherwise normal. The nodule on the right arm was excised, and histology showed typical features of a pilomatrixoma. with prominent calcification. Case 2. The 31-year-old daughter of Case I has. to date. developed a total of eight lesions, of which five have been removed. The first lesion developed on the nape ofthe neck at the age of 5. Successive lesions then appeared on the left arm, lateral half of the left eyebrow, left leg. left thigb. left popliteal fossa and two on the right upper arm. over a period of2 7 years. Clinically a spectrum of presentation was evident. Most ofthe lesions were subcutaneous with normal overlying skin, and all were hard on palpation. However, the popliteal fossa lesion was eruptive (an exophytic nodule which arose within J weeks), and the lower leg and one right upper arm lesion had both discharged yellowish viscous material in the past. Both these lesions were very painful when discharging. Five lesions were removed because they were painful and tender to palpation. Histologically they were typical pilomatrixomas. with calcification and even frank ossification in the thigh lesion. Neither patient showed any stigmata of myotonic dystrophy, and there was no family history of colonic polyposis. There were no osteomas on skull X-ray, and flexible sigmoidoscopy to the transverse colon was normal. Pilomatrixoma-like changes have been found in the epidermal cysts of Gardners syndrome' and pilomatrixomas can occur in patients with myotonic dystrophy. In the latter disorder they are often multiple and familial.-^ Kruptivc and perforating forms of pilomatrixoma have been described. Eruptive lesions develop rapidly and are usually exophytic, like the popliteal fossa lesion of Case 2. Only seven cases of perforating pilomatrixoma have been reported in the English literature' and they represent a form of transepidermal elimination. The history in Case 2 suggested that two of her lesions had perforated. Moehlenbeck found one pilomatrixoma for every 824 surgical specimens.'* In a statistical study of 1569 cases of pilomatrixoma he estimated the incidence of multiple tumours as 3 • 5%. Familial pilomatrixoma in otherwise healthy patients is extremely rare, with only five previous reports in the world literature.'^ ** Rarer still is the occurrence of familial multiple pilomatrixomas, and multiple lesions were present in only two of the reported families. In these two families each aHected member had multiple pilomatrixomas. In two other families one member had multiple pilomatrixomas. Moehlenbeck^ felt that familial occurrence should be considered as an accidental event, in view of the extreme rarity of cases. However, including our cases, there are now six reported families, in three of which multiple lesions have occurred in successive generations, and in two others multiple lesions occurred in members of one generation. A genetic basis should therefore be considered. This seems more plausible if one considers the comparatively high incidence of multiple familial pilomatrixomas in myotonic dystrophy as representing tbe full expression
CORRESPONDENCE
Widespread foUiculitis induced by human granulocytecolony-stimulating factor therapy SiK. Colony-Stimulating factors (CSFs) are glycoproteins produced by recombinant DNA techniques. They include granulocyte CSF (G-CSF) which primarily stimulates the production and function of neutrophils and to a lesser extent monocytes. iind granulocyte-inacrophage CSF (GM-CSF) which increases the production of neutrophils. monocytes and eosinophils.' CSFs have mainly been used in the amelioration of chemotherapy-induced neutropenia. although they have also been used in the treatment of non-malignant neutropenias.- aplastic anaemia, acquired immune deficiency syndrome, myeiodysplasia. and to aid recovery following bone marrow transplantation.' There have been four previous reports of skin manifestations with this therapy—two cases of leucocytoclastic vasculitis.'"^ a case of bullous pyoderma gangrenosum.'' and worsening of pre-existing cutaneous vasculitis in a patient with hairy-cell leukaemia/ We report a patient with myelodysplasia who developed a recurrent foUiculitis with C-CSF therapy. A f>4-year-oid Creek man was referred in April 1991 for treatment of myelodysplasia which had been diagnosed in 1989. At presentation he had a right middle zone lobar pneumonia, oropharyngeal candidiasis. cardiac failure and gastrointestinal bleeding. He was anaemic (haemoglobin 4- J g/dl|. thrombocytopenic (platelets lOx W/l} and leucopenic (total white cellcount l ' 4 x 1 OVI: neutrophils \-0x lOVD.He was treated with repeated blood and platelet transfusions. intravenous cefotaxime and frusemide, and oral erythromycin. tiuconazoie and amphotericin B suspension. His condition improved on the above treatment, and subcutaneous G-CSF therapy was started at a dose of JOO fig/ day. This was initially well tolerated, with no side-eflects. and resulted in a good granulocyte response. Six weeks after starting G-CSF. whilst on 300 /ig twice a week, he developed recurrent painful pustular lesions on the face, arms and upper trunk. New lesions appeared within 24 h of each G-CSF injection and lasted 1-2 weeks. On examination there were
1. Erytbematous papules and pustules over upper trunk.
Figure 2. Mixed inflammatory inliltraie around hair Iblliclc.
numerous 2-4-mm-diameter foilicular erythematous papules and pustules scattered over the face, scalp, upper chest and arms (Fig. 1). The total white cell count was 19-8 x lOVI, neutrophils 17-1 x 1071. and platelets 160x I OVI. A skin biopsy showed a mixed inflammatory infiltrate around the hair follicles and eccrine glands (Fig. 2). This consisted principally of lymphocytes and histiocytes with a few neutrophils and eosinophils. PAS. Gram, and Ziehl-Neelsen stains were all negative. Culture of a swab from a pustule produced a scanty growth of coagulase-negative Staphiilucoctiis iiurnis. The G-CSF was slowly reduced to JOO //g once a month which maintains an adequate neutrophil count, and he has had no further episodes of infection. However, he continues to develop new crops of skin lesions within 24 h of each GCSF injection, which resolve before tbe next montbly injection. There have been four previous reports of rashes associated with G-CSF therapy. Wodzinski et al.'' and Welte ft a!.^ reported leucocytoclastic vasculitis developing in patients with chronic idiopathic neutropenia on 0-CSF when the neutrophil count was greater than 1 •() x lOVl- The vasculitis resolved on cessation of tbe G-CSF. Ross et al.'' reported a SO-year-old woman with small-cell lung cancer wbo was treated with chemotherapy and G-CSF. She developed vesiculopustular lesions on the hands, the histology of which showed a dermal infiltrate of mature neutrophils. and oedema. A diagnosis of bullous pyoderma gangrenosum was made and the rasb resolved witb topical corticosteroid treatment after stopping tbe G-CSF. Claspy et «/.' described a patient with hairy-cell leukaemia complicated by neutropenia and a histologically confirmed leucocytoclastic vasculitis. After 1 week of G-CSF therapy there was increased size and tenderness of the skin lesions with associated fever. Sweet s syndrome was diagnosed, although a repeat skin biopsy was not performed. The lesions persisted for 2 weeks after the G-CSF was stopped, and then improved. Drug-induced foUiculitis is a well recognized but poorly understood phenomenon. It has been reported witb the use of a number of drugs including tetracydine.*^ rifampicin.*" phenytoin'" and halogens." A foUiculitis has not been previously
194
British Journal of Dermatology (1992) 127.
CORRESPONDENCE
reported in association with G-CSF therapy. The histology of our case showed a mixed inflammatory infiltrate around the hair follicles consisting principally of lymphocytes and histiocytes. with occasional neutrophils and eosinophils. Our patient is unusually sensitive to G-CSF and requires only monthly subcutaneous injections to maintain an adequate neutrophil count. The development of new skin lesions always occurs within 24 h of (5-CSF therapy, thus strongly implicating it in the pathogenesis ofthe rash. Department of Dermatology and *Haematolociy.
The Hoyal Free Hospital and Siiiool of Medicine, Pond Street. HampsteadNW3 2QG. U.K.
L.S.OSTLERE D.HARRIS
*H.G.PRENTICE M.H.A.RUSTIN
References 1 Wakeiicid PE. James WD. Samlaska CP, Meltzer MS. Colonystimulating factors. / Am Aaid Dermatol 1990; 23: 9OJ-12. 2 Morstyn G. The impact of colony stimulating factors on cancer chemotherapy. Br I Haermtol 1990: 75: JOJ-7, 3 Weisbart RH, Gasson IC Golde DW. Colony-stimulating factors and host defence. Anu Intern Med I 989: 110: 297-J03, 4 W'eite K. Zcidlcr C, Reiter A et ai Differential effects of granulocytt.'macrophagc colony-stimulating factor and granulocytc colcmystimulating factor in children with severe congenital neutropenia. Blood 1990: 75: 1056-63. 5 Wodzinski MA, Hampton KK, Reilly JT. Differential effect of G-CSF and GM-CSF in acquired chronic neutropenia. Brj Haematol 1991; 77: 249-50. IS Ross HJ, Moy LA. Kaplan R. Figlin RA. Biillous pyodtrma gangrenosum after granulocyte colony-stimulating factor treatment. Ctimer 1991; 68: 441-3. 7 Glaspy |A. Baldwin CC. Robertson PA et al. Therapy for neutropenia in hairy cell leukaemia with recombinant human granulocyte colony-stimulating factor. Ann Int Med 1988: 109: 789-95. 8 Bean SF. Acneiform eruption from tetracycline. Br j DernmtoJ 1971:85; 585-6. 9 \'wokolo IJ. Acneiform lesions in combined rifampicin treatment in Africans (letter). Br Med I 1974; 3: 473. 10 Jenkins RB, Ratner AC. Diphenylhydantoin and acne (lellerl, ;\' End I Med 1972; 287: 148. 11 Hitch JM. Acneform eruptions induced by drugs and chemicals.
lAMA 1967:200:879-80. Familial multiple pilomatrixomas SIR. We report a mother and daughter suffering from multiple pilomatrixomas. The occurrence of familial pilomatrixomas is very rare, and as most reported cases involve multiple lesions, a genetic basis must be considered. Case I. A 64-year-old woman gave a history of having developed three nodular lesions in early childhood. A lesion on the right temple was excised in 1946. and she was told it was a pilomatrixoma (histology not available). The other lesions, on theright and left upper arms, were asymptomatic and were not treated. On examination in August 1991 the two remaining
lesions were hard, angular nodules, located in the subcutaneous tissue, and covered by normal skin. They measured 1 cm in diameter. Physical examination was otherwise normal. The nodule on the right arm was excised, and histology showed typical features of a pilomatrixoma. with prominent calcification. Case 2. The 31-year-old daughter of Case I has. to date. developed a total of eight lesions, of which five have been removed. The first lesion developed on the nape ofthe neck at the age of 5. Successive lesions then appeared on the left arm, lateral half of the left eyebrow, left leg. left thigb. left popliteal fossa and two on the right upper arm. over a period of2 7 years. Clinically a spectrum of presentation was evident. Most ofthe lesions were subcutaneous with normal overlying skin, and all were hard on palpation. However, the popliteal fossa lesion was eruptive (an exophytic nodule which arose within J weeks), and the lower leg and one right upper arm lesion had both discharged yellowish viscous material in the past. Both these lesions were very painful when discharging. Five lesions were removed because they were painful and tender to palpation. Histologically they were typical pilomatrixomas. with calcification and even frank ossification in the thigh lesion. Neither patient showed any stigmata of myotonic dystrophy, and there was no family history of colonic polyposis. There were no osteomas on skull X-ray, and flexible sigmoidoscopy to the transverse colon was normal. Pilomatrixoma-like changes have been found in the epidermal cysts of Gardners syndrome' and pilomatrixomas can occur in patients with myotonic dystrophy. In the latter disorder they are often multiple and familial.-^ Kruptivc and perforating forms of pilomatrixoma have been described. Eruptive lesions develop rapidly and are usually exophytic, like the popliteal fossa lesion of Case 2. Only seven cases of perforating pilomatrixoma have been reported in the English literature' and they represent a form of transepidermal elimination. The history in Case 2 suggested that two of her lesions had perforated. Moehlenbeck found one pilomatrixoma for every 824 surgical specimens.'* In a statistical study of 1569 cases of pilomatrixoma he estimated the incidence of multiple tumours as 3 • 5%. Familial pilomatrixoma in otherwise healthy patients is extremely rare, with only five previous reports in the world literature.'^ ** Rarer still is the occurrence of familial multiple pilomatrixomas, and multiple lesions were present in only two of the reported families. In these two families each aHected member had multiple pilomatrixomas. In two other families one member had multiple pilomatrixomas. Moehlenbeck^ felt that familial occurrence should be considered as an accidental event, in view of the extreme rarity of cases. However, including our cases, there are now six reported families, in three of which multiple lesions have occurred in successive generations, and in two others multiple lesions occurred in members of one generation. A genetic basis should therefore be considered. This seems more plausible if one considers the comparatively high incidence of multiple familial pilomatrixomas in myotonic dystrophy as representing tbe full expression
