Cutis

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.

Acquired reactive perforating collagenosis (ARPC), first described in 1967 by Mehregan et al,1 is a rare perforating disease of the skin characterized by hyperkeratotic papules with transepidermal elimination of degenerated material, including collagen and elastic fibers, that present clinically as umbilicated papules with a central adherent keratotic plug.1-3 ARPC occurs more commonly in patients with diabetes mellitus and has been reported in 5% to 10% of patients undergoing hemodialysis.2 Mucormycosis, caused by the molds of the class Zygomycetes and order Mucorales, generally occurs as an opportunistic infection. It presents most frequently in patients with diabetes mellitus, in patients with leukemia receiving chemotherapy, and in those on sustained immunosuppressive therapy.4-7 Although most commonly found in the rhinocerebral form, mucormycosis also can present in a systemic or cutaneous form that frequently invades sites of impaired skin integrity.8,9 We report a patient with ARPC who developed extensive cutaneous mucormycosis with secondary spread to the brain, lumbar spine, and breast. 

CASE REPORT

Over a 4-month period, a 61-year-old white woman with type 2 diabetes mellitus and end-stage renal disease requiring hemodialysis 3 times weekly developed multiple skin papules followed by night sweats and a 25-lb weight loss. The patient initially presented to the dermatology department at the Lahey Clinic Medical Center in Burlington, Massachusetts, complaining of severe pruritus and several small skin lesions that resembled warts (Figure 1). When the lesions enlarged, she was able to extract the core by the "root," yielding a gelatinous exudate. The histopathology of the lesion was consistent with ARPC (Figure 2).

Having achieved no relief from topical antipruritics over the subsequent month, the patient returned to the dermatology department. By that time, she had developed large necrotic plaques (approximately 8–12 cm in diameter) on her right lateral thigh (Figure 3) and smaller lesions on her anterolateral tibiofibular areas bilaterally. The infectious disease department was consulted, and the patient was admitted to the hospital for a wedge biopsy, diagnosis, and therapy.

On physical examination, the patient was a pale, elderly, afebrile, normotensive obese woman in no apparent distress. Her cardiopulmonary examination results were normal. The dialysis catheter site in her left anterior chest was not indurated or erythematous, though a left breast mass inferior to the dialysis port was noted. Examination of her skin revealed multiple ulcerated, umbilicated red-brown papules ranging from 4 to 8 mm, a few of which had a retained adherent keratotic plug. Most lesions had an area of central necrosis and were surrounded by an erythematous ring. Some exhibited a linear presentation (Köbner phenomenon). The two 8- to 12-cm necrotic ulcerations on the patient's right lateral thigh were acutely tender, were surrounded by a 3- to 4-mm erythematous border, and appeared to extend into the subcutaneous tissue. Initial laboratory results included a leukocyte count of 7.6x103μL (75% neutrophils, 14% lymphocytes, 5% monocytes, 5% eosinophils), a serum urea nitrogen concentration of 58 mg/dL, and a creatinine level of 7.9 mg/dL. Transaminases, bilirubin, and alkaline phosphatase levels were within reference range. Blood cultures, both peripheral and from the dialysis catheter port, grew coagulase-negative staphylococci. The dialysis catheter was removed and had more than 100 colonies of coagulase-negative staphylococci; fungal plate culture results were negative. Pathologic examination of the biopsy of the gangrenous plaque on the right thigh revealed ischemic necrosis of the epidermis, dermis, and subcutis, with hyphal forms throughout the biopsy and within thrombosed vessel walls (Figure 4). Cultures grew mucormycosis, genus Rhizopus.

Plain films of the patient's femur and tibia demonstrated no bony destruction. Computed tomography of the chest and abdomen revealed a compression fracture with a probable vertebral lesion and possible paraspinal abscess at the fourth lumbar vertebra. Magnetic resonance imaging of the central nervous system displayed focal areas of subacute hemorrhage that were consistent with a possible infectious process. Additional focal areas of abnormal enhancement were found within the right centrum semiovale and in the leptomeningeal space, suggestive of infection, infarct, or tumor. Results of the cerebral spinal fluid examination were unremarkable. Treatment with lipophilic amphotericin B at 10 to 15 mg/kg per day and vancomycin were initiated; however, the patient's central nervous system disease and cutaneous lesions continued to progress. The small mass noted in her left breast on initial presentation rapidly increased to the size of a tennis ball. The infection in the thighs and tibiofibular areas were so extensive that surgical resection was not performed. The patient died of progressive disease after 3 weeks of hospitalization; permission for postmortem examination was not granted.
Comment

This patient presented with 2 unusual illnesses, ARPC and cutaneous mucormycosis, which may have had a cause-and-effect relationship. Both of these diseases are more likely to occur in patients with diabetes mellitus and end-stage renal disease. A comprehensive MEDLINE search of the literature published from 1969 to 2001 did not reveal an association of ARPC with mucormycosis. Perforating collagenosis may present in 2 forms, an inherited autosomal-recessive form and a sporadic acquired form that may be associated with systemic diseases. As in our patient, most patients with ARPC also have diabetes or renal failure. In addition, the disease has been reported in 5% to 10% of all patients undergoing hemodialysis.2,10 ARPC lesions have been speculated to develop from the chronic rubbing that occurs secondary to the xerotic pruritus of renal disease. The constant rubbing results in an epithelial hyperplasia, follicular hyperkeratosis, or prurigolike lesions.2 Diabetic vasculopathy also has been projected as a predisposing factor for ARPC.3 Histologically, ARPC presents as altered dermal collagen bundles eliminated through the epidermis. Varying clinical and histologic findings are considered to be due to different stages of disease. Cutaneous mucormycosis is a rare, acute, subacute, or chronic infection with only 116 cases listed in the English literature as of 2000. The mycelium of the Mucorales pathogen is composed of nonseptate coenocytic hyphae, which have a special affinity for blood vessels.11 Cutaneous lesions initially present as erythematous papules or pustules but may rapidly evolve into necrotic ulcerations because the pathologic process of this angiophilic pathogen often involves early invasion of blood vessels, vascular occlusion, infarction, and ischemia.7,12 The broad nonseptate hyphae of Mucor are seen invading the vascular endothelium. Mucor fungi may cross fascial planes with little regard for tissue barriers by using proteases, lipases, and mycotoxins that may cause further infarction and tissue necrosis. Although ubiquitous in the environment, particularly soil, Mucor, like other opportunistic saprophytes, almost never causes disease unless the patient also has underlying immunosuppression, neutropenia, or burns and there is direct cutaneous inoculation of the organism or spores at a site of trauma or impaired skin integrity.4,12 More than 85% of those diagnosed with cutaneous mucormycosis have had trauma or a break to the skin integrity.9 Our patient's mucormycosis was distributed in the areas of her ARPC lesions, which could be reached and traumatized by the patient. Secondary hematogenous spread to her brain, lumbar spine, and breast most likely occurred. Another site of disseminated infection may have been the dialysis catheter, despite the negative culture results. Cutaneous mucormycosis tends to present most frequently (31%) in the lower extremities. Of those patients who contract the disease, 20% also have diabetes, and 5% have renal failure. Mortality rates for patients diagnosed with cutaneous mucormycosis exceed 25% and are even higher if there is secondary dissemination.12 Cutaneous lesions may be the first sign of disseminated mucormycosis.13 Infection does not start through a cutaneous portal; rather, it usually arises from the inhalation of spores, followed by local infection and hematogenous spread.14 Evidence of cerebral infarction on a computed tomography scan can be due to vascular invasion by fungi with resultant thromboses. Treatment strategies generally require intravenous amphotericin B therapy coupled with surgical excision and extensive debridement of the skin lesions.7,15 Correction of underlying predisposing medical conditions whenever possible is also helpful. Current oral azole antifungal agents and caspofungin generally are not useful in treating mucormycosis.5 The differential diagnoses of skin lesions resembling those of cutaneous mucormycosis include calciphylaxis, coagulopathic disease such as cryoglobulinemia, and the large vessel vasculitides such as polyarteritis, granulomatous vasculitides, and lymphoproliferative granulomatosis.


CONCLUSION

To our knowledge, cutaneous mucormycosis has not been previously reported in the setting of ARPC. Because ARPC is common in patients with diabetes and end-stage renal disease, physicians should be alerted to the possibility and potential complications of fungal, mycobacterial, or bacterial opportunistic superinfection of these skin lesions and the necessity of appropriate diagnostic tests and early management and therapy.
 

Acquired reactive perforating collagenosis (ARPC), first described in 1967 by Mehregan et al,1 is a rare perforating disease of the skin characterized by hyperkeratotic papules with transepidermal elimination of degenerated material, including collagen and elastic fibers, that present clinically as umbilicated papules with a central adherent keratotic plug.1-3 ARPC occurs more commonly in patients with diabetes mellitus and has been reported in 5% to 10% of patients undergoing hemodialysis.2 Mucormycosis, caused by the molds of the class Zygomycetes and order Mucorales, generally occurs as an opportunistic infection. It presents most frequently in patients with diabetes mellitus, in patients with leukemia receiving chemotherapy, and in those on sustained immunosuppressive therapy.4-7 Although most commonly found in the rhinocerebral form, mucormycosis also can present in a systemic or cutaneous form that frequently invades sites of impaired skin integrity.8,9 We report a patient with ARPC who developed extensive cutaneous mucormycosis with secondary spread to the brain, lumbar spine, and breast. 

CASE REPORT

Over a 4-month period, a 61-year-old white woman with type 2 diabetes mellitus and end-stage renal disease requiring hemodialysis 3 times weekly developed multiple skin papules followed by night sweats and a 25-lb weight loss. The patient initially presented to the dermatology department at the Lahey Clinic Medical Center in Burlington, Massachusetts, complaining of severe pruritus and several small skin lesions that resembled warts (Figure 1). When the lesions enlarged, she was able to extract the core by the "root," yielding a gelatinous exudate. The histopathology of the lesion was consistent with ARPC (Figure 2).

Having achieved no relief from topical antipruritics over the subsequent month, the patient returned to the dermatology department. By that time, she had developed large necrotic plaques (approximately 8–12 cm in diameter) on her right lateral thigh (Figure 3) and smaller lesions on her anterolateral tibiofibular areas bilaterally. The infectious disease department was consulted, and the patient was admitted to the hospital for a wedge biopsy, diagnosis, and therapy.

On physical examination, the patient was a pale, elderly, afebrile, normotensive obese woman in no apparent distress. Her cardiopulmonary examination results were normal. The dialysis catheter site in her left anterior chest was not indurated or erythematous, though a left breast mass inferior to the dialysis port was noted. Examination of her skin revealed multiple ulcerated, umbilicated red-brown papules ranging from 4 to 8 mm, a few of which had a retained adherent keratotic plug. Most lesions had an area of central necrosis and were surrounded by an erythematous ring. Some exhibited a linear presentation (Köbner phenomenon). The two 8- to 12-cm necrotic ulcerations on the patient's right lateral thigh were acutely tender, were surrounded by a 3- to 4-mm erythematous border, and appeared to extend into the subcutaneous tissue. Initial laboratory results included a leukocyte count of 7.6x103μL (75% neutrophils, 14% lymphocytes, 5% monocytes, 5% eosinophils), a serum urea nitrogen concentration of 58 mg/dL, and a creatinine level of 7.9 mg/dL. Transaminases, bilirubin, and alkaline phosphatase levels were within reference range. Blood cultures, both peripheral and from the dialysis catheter port, grew coagulase-negative staphylococci. The dialysis catheter was removed and had more than 100 colonies of coagulase-negative staphylococci; fungal plate culture results were negative. Pathologic examination of the biopsy of the gangrenous plaque on the right thigh revealed ischemic necrosis of the epidermis, dermis, and subcutis, with hyphal forms throughout the biopsy and within thrombosed vessel walls (Figure 4). Cultures grew mucormycosis, genus Rhizopus.

Plain films of the patient's femur and tibia demonstrated no bony destruction. Computed tomography of the chest and abdomen revealed a compression fracture with a probable vertebral lesion and possible paraspinal abscess at the fourth lumbar vertebra. Magnetic resonance imaging of the central nervous system displayed focal areas of subacute hemorrhage that were consistent with a possible infectious process. Additional focal areas of abnormal enhancement were found within the right centrum semiovale and in the leptomeningeal space, suggestive of infection, infarct, or tumor. Results of the cerebral spinal fluid examination were unremarkable. Treatment with lipophilic amphotericin B at 10 to 15 mg/kg per day and vancomycin were initiated; however, the patient's central nervous system disease and cutaneous lesions continued to progress. The small mass noted in her left breast on initial presentation rapidly increased to the size of a tennis ball. The infection in the thighs and tibiofibular areas were so extensive that surgical resection was not performed. The patient died of progressive disease after 3 weeks of hospitalization; permission for postmortem examination was not granted.
Comment

This patient presented with 2 unusual illnesses, ARPC and cutaneous mucormycosis, which may have had a cause-and-effect relationship. Both of these diseases are more likely to occur in patients with diabetes mellitus and end-stage renal disease. A comprehensive MEDLINE search of the literature published from 1969 to 2001 did not reveal an association of ARPC with mucormycosis. Perforating collagenosis may present in 2 forms, an inherited autosomal-recessive form and a sporadic acquired form that may be associated with systemic diseases. As in our patient, most patients with ARPC also have diabetes or renal failure. In addition, the disease has been reported in 5% to 10% of all patients undergoing hemodialysis.2,10 ARPC lesions have been speculated to develop from the chronic rubbing that occurs secondary to the xerotic pruritus of renal disease. The constant rubbing results in an epithelial hyperplasia, follicular hyperkeratosis, or prurigolike lesions.2 Diabetic vasculopathy also has been projected as a predisposing factor for ARPC.3 Histologically, ARPC presents as altered dermal collagen bundles eliminated through the epidermis. Varying clinical and histologic findings are considered to be due to different stages of disease. Cutaneous mucormycosis is a rare, acute, subacute, or chronic infection with only 116 cases listed in the English literature as of 2000. The mycelium of the Mucorales pathogen is composed of nonseptate coenocytic hyphae, which have a special affinity for blood vessels.11 Cutaneous lesions initially present as erythematous papules or pustules but may rapidly evolve into necrotic ulcerations because the pathologic process of this angiophilic pathogen often involves early invasion of blood vessels, vascular occlusion, infarction, and ischemia.7,12 The broad nonseptate hyphae of Mucor are seen invading the vascular endothelium. Mucor fungi may cross fascial planes with little regard for tissue barriers by using proteases, lipases, and mycotoxins that may cause further infarction and tissue necrosis. Although ubiquitous in the environment, particularly soil, Mucor, like other opportunistic saprophytes, almost never causes disease unless the patient also has underlying immunosuppression, neutropenia, or burns and there is direct cutaneous inoculation of the organism or spores at a site of trauma or impaired skin integrity.4,12 More than 85% of those diagnosed with cutaneous mucormycosis have had trauma or a break to the skin integrity.9 Our patient's mucormycosis was distributed in the areas of her ARPC lesions, which could be reached and traumatized by the patient. Secondary hematogenous spread to her brain, lumbar spine, and breast most likely occurred. Another site of disseminated infection may have been the dialysis catheter, despite the negative culture results. Cutaneous mucormycosis tends to present most frequently (31%) in the lower extremities. Of those patients who contract the disease, 20% also have diabetes, and 5% have renal failure. Mortality rates for patients diagnosed with cutaneous mucormycosis exceed 25% and are even higher if there is secondary dissemination.12 Cutaneous lesions may be the first sign of disseminated mucormycosis.13 Infection does not start through a cutaneous portal; rather, it usually arises from the inhalation of spores, followed by local infection and hematogenous spread.14 Evidence of cerebral infarction on a computed tomography scan can be due to vascular invasion by fungi with resultant thromboses. Treatment strategies generally require intravenous amphotericin B therapy coupled with surgical excision and extensive debridement of the skin lesions.7,15 Correction of underlying predisposing medical conditions whenever possible is also helpful. Current oral azole antifungal agents and caspofungin generally are not useful in treating mucormycosis.5 The differential diagnoses of skin lesions resembling those of cutaneous mucormycosis include calciphylaxis, coagulopathic disease such as cryoglobulinemia, and the large vessel vasculitides such as polyarteritis, granulomatous vasculitides, and lymphoproliferative granulomatosis.


CONCLUSION

To our knowledge, cutaneous mucormycosis has not been previously reported in the setting of ARPC. Because ARPC is common in patients with diabetes and end-stage renal disease, physicians should be alerted to the possibility and potential complications of fungal, mycobacterial, or bacterial opportunistic superinfection of these skin lesions and the necessity of appropriate diagnostic tests and early management and therapy.
 

Acquired reactive perforating collagenosis (ARPC), first described in 1967 by Mehregan et al,1 is a rare perforating disease of the skin characterized by hyperkeratotic papules with transepidermal elimination of degenerated material, including collagen and elastic fibers, that present clinically as umbilicated papules with a central adherent keratotic plug.1-3 ARPC occurs more commonly in patients with diabetes mellitus and has been reported in 5% to 10% of patients undergoing hemodialysis.2 Mucormycosis, caused by the molds of the class Zygomycetes and order Mucorales, generally occurs as an opportunistic infection. It presents most frequently in patients with diabetes mellitus, in patients with leukemia receiving chemotherapy, and in those on sustained immunosuppressive therapy.4-7 Although most commonly found in the rhinocerebral form, mucormycosis also can present in a systemic or cutaneous form that frequently invades sites of impaired skin integrity.8,9 We report a patient with ARPC who developed extensive cutaneous mucormycosis with secondary spread to the brain, lumbar spine, and breast. 

CASE REPORT

Over a 4-month period, a 61-year-old white woman with type 2 diabetes mellitus and end-stage renal disease requiring hemodialysis 3 times weekly developed multiple skin papules followed by night sweats and a 25-lb weight loss. The patient initially presented to the dermatology department at the Lahey Clinic Medical Center in Burlington, Massachusetts, complaining of severe pruritus and several small skin lesions that resembled warts (Figure 1). When the lesions enlarged, she was able to extract the core by the "root," yielding a gelatinous exudate. The histopathology of the lesion was consistent with ARPC (Figure 2).

Having achieved no relief from topical antipruritics over the subsequent month, the patient returned to the dermatology department. By that time, she had developed large necrotic plaques (approximately 8–12 cm in diameter) on her right lateral thigh (Figure 3) and smaller lesions on her anterolateral tibiofibular areas bilaterally. The infectious disease department was consulted, and the patient was admitted to the hospital for a wedge biopsy, diagnosis, and therapy.

On physical examination, the patient was a pale, elderly, afebrile, normotensive obese woman in no apparent distress. Her cardiopulmonary examination results were normal. The dialysis catheter site in her left anterior chest was not indurated or erythematous, though a left breast mass inferior to the dialysis port was noted. Examination of her skin revealed multiple ulcerated, umbilicated red-brown papules ranging from 4 to 8 mm, a few of which had a retained adherent keratotic plug. Most lesions had an area of central necrosis and were surrounded by an erythematous ring. Some exhibited a linear presentation (Köbner phenomenon). The two 8- to 12-cm necrotic ulcerations on the patient's right lateral thigh were acutely tender, were surrounded by a 3- to 4-mm erythematous border, and appeared to extend into the subcutaneous tissue. Initial laboratory results included a leukocyte count of 7.6x103μL (75% neutrophils, 14% lymphocytes, 5% monocytes, 5% eosinophils), a serum urea nitrogen concentration of 58 mg/dL, and a creatinine level of 7.9 mg/dL. Transaminases, bilirubin, and alkaline phosphatase levels were within reference range. Blood cultures, both peripheral and from the dialysis catheter port, grew coagulase-negative staphylococci. The dialysis catheter was removed and had more than 100 colonies of coagulase-negative staphylococci; fungal plate culture results were negative. Pathologic examination of the biopsy of the gangrenous plaque on the right thigh revealed ischemic necrosis of the epidermis, dermis, and subcutis, with hyphal forms throughout the biopsy and within thrombosed vessel walls (Figure 4). Cultures grew mucormycosis, genus Rhizopus.

Plain films of the patient's femur and tibia demonstrated no bony destruction. Computed tomography of the chest and abdomen revealed a compression fracture with a probable vertebral lesion and possible paraspinal abscess at the fourth lumbar vertebra. Magnetic resonance imaging of the central nervous system displayed focal areas of subacute hemorrhage that were consistent with a possible infectious process. Additional focal areas of abnormal enhancement were found within the right centrum semiovale and in the leptomeningeal space, suggestive of infection, infarct, or tumor. Results of the cerebral spinal fluid examination were unremarkable. Treatment with lipophilic amphotericin B at 10 to 15 mg/kg per day and vancomycin were initiated; however, the patient's central nervous system disease and cutaneous lesions continued to progress. The small mass noted in her left breast on initial presentation rapidly increased to the size of a tennis ball. The infection in the thighs and tibiofibular areas were so extensive that surgical resection was not performed. The patient died of progressive disease after 3 weeks of hospitalization; permission for postmortem examination was not granted.
Comment

This patient presented with 2 unusual illnesses, ARPC and cutaneous mucormycosis, which may have had a cause-and-effect relationship. Both of these diseases are more likely to occur in patients with diabetes mellitus and end-stage renal disease. A comprehensive MEDLINE search of the literature published from 1969 to 2001 did not reveal an association of ARPC with mucormycosis. Perforating collagenosis may present in 2 forms, an inherited autosomal-recessive form and a sporadic acquired form that may be associated with systemic diseases. As in our patient, most patients with ARPC also have diabetes or renal failure. In addition, the disease has been reported in 5% to 10% of all patients undergoing hemodialysis.2,10 ARPC lesions have been speculated to develop from the chronic rubbing that occurs secondary to the xerotic pruritus of renal disease. The constant rubbing results in an epithelial hyperplasia, follicular hyperkeratosis, or prurigolike lesions.2 Diabetic vasculopathy also has been projected as a predisposing factor for ARPC.3 Histologically, ARPC presents as altered dermal collagen bundles eliminated through the epidermis. Varying clinical and histologic findings are considered to be due to different stages of disease. Cutaneous mucormycosis is a rare, acute, subacute, or chronic infection with only 116 cases listed in the English literature as of 2000. The mycelium of the Mucorales pathogen is composed of nonseptate coenocytic hyphae, which have a special affinity for blood vessels.11 Cutaneous lesions initially present as erythematous papules or pustules but may rapidly evolve into necrotic ulcerations because the pathologic process of this angiophilic pathogen often involves early invasion of blood vessels, vascular occlusion, infarction, and ischemia.7,12 The broad nonseptate hyphae of Mucor are seen invading the vascular endothelium. Mucor fungi may cross fascial planes with little regard for tissue barriers by using proteases, lipases, and mycotoxins that may cause further infarction and tissue necrosis. Although ubiquitous in the environment, particularly soil, Mucor, like other opportunistic saprophytes, almost never causes disease unless the patient also has underlying immunosuppression, neutropenia, or burns and there is direct cutaneous inoculation of the organism or spores at a site of trauma or impaired skin integrity.4,12 More than 85% of those diagnosed with cutaneous mucormycosis have had trauma or a break to the skin integrity.9 Our patient's mucormycosis was distributed in the areas of her ARPC lesions, which could be reached and traumatized by the patient. Secondary hematogenous spread to her brain, lumbar spine, and breast most likely occurred. Another site of disseminated infection may have been the dialysis catheter, despite the negative culture results. Cutaneous mucormycosis tends to present most frequently (31%) in the lower extremities. Of those patients who contract the disease, 20% also have diabetes, and 5% have renal failure. Mortality rates for patients diagnosed with cutaneous mucormycosis exceed 25% and are even higher if there is secondary dissemination.12 Cutaneous lesions may be the first sign of disseminated mucormycosis.13 Infection does not start through a cutaneous portal; rather, it usually arises from the inhalation of spores, followed by local infection and hematogenous spread.14 Evidence of cerebral infarction on a computed tomography scan can be due to vascular invasion by fungi with resultant thromboses. Treatment strategies generally require intravenous amphotericin B therapy coupled with surgical excision and extensive debridement of the skin lesions.7,15 Correction of underlying predisposing medical conditions whenever possible is also helpful. Current oral azole antifungal agents and caspofungin generally are not useful in treating mucormycosis.5 The differential diagnoses of skin lesions resembling those of cutaneous mucormycosis include calciphylaxis, coagulopathic disease such as cryoglobulinemia, and the large vessel vasculitides such as polyarteritis, granulomatous vasculitides, and lymphoproliferative granulomatosis.


CONCLUSION

To our knowledge, cutaneous mucormycosis has not been previously reported in the setting of ARPC. Because ARPC is common in patients with diabetes and end-stage renal disease, physicians should be alerted to the possibility and potential complications of fungal, mycobacterial, or bacterial opportunistic superinfection of these skin lesions and the necessity of appropriate diagnostic tests and early management and therapy.
 

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

Adapalene (Differin®) is a naphthoic-acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris.1-4 Adapalene, in both gel and cream formulations, at the marketed and approved concentration of 0.1%, is better tolerated than most tretinoin formulations, including tretinoin microsphere gel 0.1% (Retin-A Micro®) and tretinoin cream 0.025% (Avita®).5-10 The cumulative irritancy assay (patch test) is designed to assess the irritation potential of topically applied materials. Irritation results obtained from this type of assay are due to direct damage to the epidermal cells, and no immunologic (allergic) mechanism is involved. Results of this standard assay are widely accepted to be indicators of irritation. This study compared the irritation potential of adapalene gel and solution with several retinoid and retinoidlike products containing either tazarotene or tretinoin.back to top

METHODS This cumulative irritancy study was conducted as a single-center, randomized, controlled, investigator/evaluator, double-blind, intraindividual comparison involving healthy subjects meeting specific inclusion-exclusion criteria. The cumulative irritancy assay, a 21-day patch test, was designed to assess the irritation potential of topically applied dermatologic materials under stressful conditions (ie, occlusion).11 A total of 42 subjects (6 males and 36 females) ranging in age from 22.9 to 74.8 years were enrolled and evaluated. All subjects received adapalene gel 0.1%, adapalene solution 0.1%, tazarotene gel 0.1%, tazarotene gel 0.05%, tretinoin microsphere gel 0.1%, tretinoin cream 0.025%, tretinoin gel 0.025%, and white petrolatum (negative control). Approximately 0.2 g of each of the 7 test products and negative control was applied to 8 sites on the upper area of the back according to a predefined randomization list. Application was made under occlusive conditions for 24 hours (4 times per week) and 72 hours (once weekly) for 3 weeks. At each study visit, skin reactions (erythema scores±other local reactions) were assessed by the same trained board-certified physician evaluator during the study, 15 to 30 minutes after removal of the product, using the grading scale for erythema (Table 1).

Statistical Methodology Sample Size, Design, and Randomization—A standard sample size for this type of cumulative irritancy clinical study is 25 subjects. To account for the multiplicity of comparisons, planned enrollment was estimated at 48 subjects. Enrollment was completed at 42 subjects, with the consent of the sponsor. On initiation, each of the 8 products was applied to one of the zones (Z1–Z8) according to the predefined randomization schedule. This randomization schedule was generated by the RANUNI routine of SAS using 8x8 Latin squares. Statistically Analyzed Variables—For evaluating the cutaneous tolerance, a cumulative irritancy index (CII) was calculated for each treatment and for each subject, as follows: CII=sum of irritation score/number of readings. The following conventions were applied for the CII calculation: baseline (day 1) score was excluded from the calculation. When the irritation reaction was rated 3 for any site, the product application was discontinued for the incriminated sites, and a score of 3 was assigned to the remaining readings (last observation carried forward). When a subject missed a scheduled visit, the scores of the sites from the next visit were assigned to the previously missed visit. Individual CII scores were averaged across subjects to obtain an MCII score for each treatment. MCII scores were submitted to an analysis of variance with effects for subject, zone, and formulation. To adjust for multiple comparisons, MCII score was compared, and formulations were classified using the Tukey multiple comparisons test performed at the 1% and 5% significance levels. According to MCII values, each test product could be classified into the irritation classes (Table 2).

results Of the 42 subjects enrolled, 38 subjects (90.5%) completed the study. Demographic data are presented in Table 3. Results are summarized in Table 4 and Figure 1. Figure 2 shows a clinical photograph of typical irritation observed during the study.

It is said that in dermatology, residents spend 3 years learning diagnoses and a lifetime learning treatment. The lengthy differential diagnosis that residents are required to provide when assessing dermatology patients at ground rounds is less useful in private practice than an exhaustive knowledge of therapeutics. No one has more thoroughly and intensively written about treatment and therapeutics than Drs. Walter B. and E. Dorinda Shelley. Their contributions to dermatology in the form of a dermatologic diary in Cutis® and in their first magnum opus—Advanced Dermatologic Therapy are substantive and unique. I recall during my time in residency when Michael Fisher, MD (Professor and Head, Division of Dermatology, Albert Einstein College of Medicine), would ask a resident after the differential was laid out, “How would the Shelleys treat this patient?” The original edition of Advanced Dermatologic Therapy was published in 1987 and quickly became a standard reference. It was more than a compendium of abstracts; it was a work along the lines of Aristotle’s heuristics—a logical categorization of disease treatment accompanied by scholarly glosses. Since 1987, much has happened in dermatologic therapeutics. Powerful immunosuppressive drugs, as well as novel topical therapies, have become available. The developments in the treatment of dermatologic diseases between 1987 and 2001 have been distilled by the Shelleys into a new book—Advanced Dermatologic Therapy II. The Shelleys have been pillars of Cutis for 30 years, as editors and writers. Advanced Dermatologic Therapy II can be seen as a companion volume to Wolverton’s Comprehensive Dermatologic Drug Therapy. Wolverton organizes medications by type and cites treatments, while the Shelleys explicate diseases by citing treatments. Numerous pearls pepper the text. For example, it is noted that: seborrheic dermatitis is worsened by cigarette smoke; the treatment of anetoderma should include a search of streptococcal infection; those with angioedema should have their dental prostheses checked; vitamins and tetracycline rinses can ameliorate aphthous stomatitis; and antiplatelet therapy aids the treatment of atrophie blanche. The Shelleys have assembled information that transcends any simple categorization of this book as a collection of abstracts; rather, it is a thorough approach to treating patients with both common and uncommon diseases. Of special note are the anecdotes and stories regarding patients and their treatment. The humanism that animates these stories is unique in the dermatology literature. The Shelleys never let us forget that it is the improvement of the lives of patients that is the foundation of our efforts as physicians. Textbooks often elide the human and the mutable; the Shelleys bring these things to the fore. Advanced Dermatologic Therapy II is a welcome and deserving successor to Advanced Dermatological Therapy. It is a worthwhile, if not essential, addition to the libraries of dermatologists who wish to help and serve their patients. The Shelleys’ contribution is great; their new book will ensure that their efforts last. I, for one, await Advanced Dermatologic Therapy III, a text that will no doubt capture the immediate past and that which is yet to come.

It is said that in dermatology, residents spend 3 years learning diagnoses and a lifetime learning treatment. The lengthy differential diagnosis that residents are required to provide when assessing dermatology patients at ground rounds is less useful in private practice than an exhaustive knowledge of therapeutics. No one has more thoroughly and intensively written about treatment and therapeutics than Drs. Walter B. and E. Dorinda Shelley. Their contributions to dermatology in the form of a dermatologic diary in Cutis® and in their first magnum opus—Advanced Dermatologic Therapy are substantive and unique. I recall during my time in residency when Michael Fisher, MD (Professor and Head, Division of Dermatology, Albert Einstein College of Medicine), would ask a resident after the differential was laid out, “How would the Shelleys treat this patient?” The original edition of Advanced Dermatologic Therapy was published in 1987 and quickly became a standard reference. It was more than a compendium of abstracts; it was a work along the lines of Aristotle’s heuristics—a logical categorization of disease treatment accompanied by scholarly glosses. Since 1987, much has happened in dermatologic therapeutics. Powerful immunosuppressive drugs, as well as novel topical therapies, have become available. The developments in the treatment of dermatologic diseases between 1987 and 2001 have been distilled by the Shelleys into a new book—Advanced Dermatologic Therapy II. The Shelleys have been pillars of Cutis for 30 years, as editors and writers. Advanced Dermatologic Therapy II can be seen as a companion volume to Wolverton’s Comprehensive Dermatologic Drug Therapy. Wolverton organizes medications by type and cites treatments, while the Shelleys explicate diseases by citing treatments. Numerous pearls pepper the text. For example, it is noted that: seborrheic dermatitis is worsened by cigarette smoke; the treatment of anetoderma should include a search of streptococcal infection; those with angioedema should have their dental prostheses checked; vitamins and tetracycline rinses can ameliorate aphthous stomatitis; and antiplatelet therapy aids the treatment of atrophie blanche. The Shelleys have assembled information that transcends any simple categorization of this book as a collection of abstracts; rather, it is a thorough approach to treating patients with both common and uncommon diseases. Of special note are the anecdotes and stories regarding patients and their treatment. The humanism that animates these stories is unique in the dermatology literature. The Shelleys never let us forget that it is the improvement of the lives of patients that is the foundation of our efforts as physicians. Textbooks often elide the human and the mutable; the Shelleys bring these things to the fore. Advanced Dermatologic Therapy II is a welcome and deserving successor to Advanced Dermatological Therapy. It is a worthwhile, if not essential, addition to the libraries of dermatologists who wish to help and serve their patients. The Shelleys’ contribution is great; their new book will ensure that their efforts last. I, for one, await Advanced Dermatologic Therapy III, a text that will no doubt capture the immediate past and that which is yet to come.

It is said that in dermatology, residents spend 3 years learning diagnoses and a lifetime learning treatment. The lengthy differential diagnosis that residents are required to provide when assessing dermatology patients at ground rounds is less useful in private practice than an exhaustive knowledge of therapeutics. No one has more thoroughly and intensively written about treatment and therapeutics than Drs. Walter B. and E. Dorinda Shelley. Their contributions to dermatology in the form of a dermatologic diary in Cutis® and in their first magnum opus—Advanced Dermatologic Therapy are substantive and unique. I recall during my time in residency when Michael Fisher, MD (Professor and Head, Division of Dermatology, Albert Einstein College of Medicine), would ask a resident after the differential was laid out, “How would the Shelleys treat this patient?” The original edition of Advanced Dermatologic Therapy was published in 1987 and quickly became a standard reference. It was more than a compendium of abstracts; it was a work along the lines of Aristotle’s heuristics—a logical categorization of disease treatment accompanied by scholarly glosses. Since 1987, much has happened in dermatologic therapeutics. Powerful immunosuppressive drugs, as well as novel topical therapies, have become available. The developments in the treatment of dermatologic diseases between 1987 and 2001 have been distilled by the Shelleys into a new book—Advanced Dermatologic Therapy II. The Shelleys have been pillars of Cutis for 30 years, as editors and writers. Advanced Dermatologic Therapy II can be seen as a companion volume to Wolverton’s Comprehensive Dermatologic Drug Therapy. Wolverton organizes medications by type and cites treatments, while the Shelleys explicate diseases by citing treatments. Numerous pearls pepper the text. For example, it is noted that: seborrheic dermatitis is worsened by cigarette smoke; the treatment of anetoderma should include a search of streptococcal infection; those with angioedema should have their dental prostheses checked; vitamins and tetracycline rinses can ameliorate aphthous stomatitis; and antiplatelet therapy aids the treatment of atrophie blanche. The Shelleys have assembled information that transcends any simple categorization of this book as a collection of abstracts; rather, it is a thorough approach to treating patients with both common and uncommon diseases. Of special note are the anecdotes and stories regarding patients and their treatment. The humanism that animates these stories is unique in the dermatology literature. The Shelleys never let us forget that it is the improvement of the lives of patients that is the foundation of our efforts as physicians. Textbooks often elide the human and the mutable; the Shelleys bring these things to the fore. Advanced Dermatologic Therapy II is a welcome and deserving successor to Advanced Dermatological Therapy. It is a worthwhile, if not essential, addition to the libraries of dermatologists who wish to help and serve their patients. The Shelleys’ contribution is great; their new book will ensure that their efforts last. I, for one, await Advanced Dermatologic Therapy III, a text that will no doubt capture the immediate past and that which is yet to come.

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

The major fighting in Iraq is over, and the work of rebuilding has begun. What can we expect in the months ahead? America is deeply invested in the rebuilding of Iraq, and our presence there is likely to continue for some time. Over the ensuing months, servicemen will return home with maladies acquired overseas. The potential for continued unrest in the region makes it likely that western countries will continue to receive a stream of asylum seekers, as well as the medical conditions these individuals bring with them. Dermatologists at home will see and treat these exotic diseases, the burden of which may endure for some time. A study of Southeast Asian immigrants in Australia demonstrated that intestinal parasite infections were still common 12 years after immigration.1
Dermatologists will play a significant role in treating these patients, as dermatologic diseases are prevalent among those seeking asylum in western countries. A study of 1487 refugee children in the Canton of Zurich found that almost 10% had skin diseases.2 Among Vietnamese refugees arriving in Hong Kong, chronic bacterial skin infections and lice were common problems,3,4 and Southeast Asian refugees living in Tennessee have presented to their physicians with chronic bacterial infections, including leprosy and parasitic diseases.5
A series of articles that covers the health problems encountered during war and rebuilding is timely, and of value to Cutis® readers. Important topics to be covered include dermatologic diseases endemic to Iraq and Afghanistan, diseases common in refugee and immigrant populations, and the continuing threat of bioterrorism. These articles will focus on problems that we may encounter at home and abroad.
A review of the health problems of soldiers during the last Gulf War gives us a sense of some of the problems we should be prepared to treat. Fortunately, the rate of infection with exotic diseases during that conflict was quite low considering the magnitude of our presence in the region. Approximately 800,000 coalition troops were deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. The liberal use of insecticides and repellents played a major role in reducing the incidence of disease. The deployment of most ground troops in the open desert during the cooler winter period also was important in reducing the number of reported infections, because these conditions were unfavorable for the transmission of arthropod-borne diseases. In contrast to World War II, there were no reports of sand fly fever among coalition forces during the first Gulf War, and there were only 31 cases of leishmaniasis among the 697,000 US troops. Although the region contained suspected vectors of cutaneous leishmaniasis, sand fly fever, West Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever, the prevalence of infection was low during the months of the war and was confined mostly to leishmaniasis.6 In addition to cutaneous leishmaniasis, there were 12 cases of visceral leishmaniasis due to Leishmania tropica during the first Gulf War.7
Vector control efforts during a prolonged peace-keeping and rebuilding effort may be more complicated than during the war. We are likely to remain in Iraq during the change of seasons, and vector-borne disease may be a more significant problem. We also should remain alert for signs of bioterrorism.
In addition to treating returning servicemen, western physicians will play a major role in providing healthcare to those displaced by the conflict and to a nation plagued by more than a decade of war and degraded infrastructure. Before the first Gulf War, many of Iraq’s healthcare professionals were foreign nationals. War and a crumbling economy led to a mass exodus of healthcare professionals. Doctors’ salaries were reported to fall to about $30 a month, barely enough for subsistence.8 As the economy decayed and money was continually diverted to the Iraqi military, there was little available to spend on public health measures. American forces and international aid agencies are now faced with the task of rebuilding a nation destroyed by years of war and isolation. We will confront malnutrition, malaria, tuberculosis, leishmaniasis, and infestation.
Over the next few months, Cutis plans to publish a series of articles focusing on the role of the dermatologist during war, rebuilding, refugee crises, and humanitarian missions. (For the first article, see page 39 of this issue.) We also will feature editorials on the role of military medicine in our national response to bioterrorism and the continuing role of military residency training programs. We hope this series of special articles will be helpful to our readers, as we pull together a nation to help with the work ahead.

back to top

The major fighting in Iraq is over, and the work of rebuilding has begun. What can we expect in the months ahead? America is deeply invested in the rebuilding of Iraq, and our presence there is likely to continue for some time. Over the ensuing months, servicemen will return home with maladies acquired overseas. The potential for continued unrest in the region makes it likely that western countries will continue to receive a stream of asylum seekers, as well as the medical conditions these individuals bring with them. Dermatologists at home will see and treat these exotic diseases, the burden of which may endure for some time. A study of Southeast Asian immigrants in Australia demonstrated that intestinal parasite infections were still common 12 years after immigration.1
Dermatologists will play a significant role in treating these patients, as dermatologic diseases are prevalent among those seeking asylum in western countries. A study of 1487 refugee children in the Canton of Zurich found that almost 10% had skin diseases.2 Among Vietnamese refugees arriving in Hong Kong, chronic bacterial skin infections and lice were common problems,3,4 and Southeast Asian refugees living in Tennessee have presented to their physicians with chronic bacterial infections, including leprosy and parasitic diseases.5
A series of articles that covers the health problems encountered during war and rebuilding is timely, and of value to Cutis® readers. Important topics to be covered include dermatologic diseases endemic to Iraq and Afghanistan, diseases common in refugee and immigrant populations, and the continuing threat of bioterrorism. These articles will focus on problems that we may encounter at home and abroad.
A review of the health problems of soldiers during the last Gulf War gives us a sense of some of the problems we should be prepared to treat. Fortunately, the rate of infection with exotic diseases during that conflict was quite low considering the magnitude of our presence in the region. Approximately 800,000 coalition troops were deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. The liberal use of insecticides and repellents played a major role in reducing the incidence of disease. The deployment of most ground troops in the open desert during the cooler winter period also was important in reducing the number of reported infections, because these conditions were unfavorable for the transmission of arthropod-borne diseases. In contrast to World War II, there were no reports of sand fly fever among coalition forces during the first Gulf War, and there were only 31 cases of leishmaniasis among the 697,000 US troops. Although the region contained suspected vectors of cutaneous leishmaniasis, sand fly fever, West Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever, the prevalence of infection was low during the months of the war and was confined mostly to leishmaniasis.6 In addition to cutaneous leishmaniasis, there were 12 cases of visceral leishmaniasis due to Leishmania tropica during the first Gulf War.7
Vector control efforts during a prolonged peace-keeping and rebuilding effort may be more complicated than during the war. We are likely to remain in Iraq during the change of seasons, and vector-borne disease may be a more significant problem. We also should remain alert for signs of bioterrorism.
In addition to treating returning servicemen, western physicians will play a major role in providing healthcare to those displaced by the conflict and to a nation plagued by more than a decade of war and degraded infrastructure. Before the first Gulf War, many of Iraq’s healthcare professionals were foreign nationals. War and a crumbling economy led to a mass exodus of healthcare professionals. Doctors’ salaries were reported to fall to about $30 a month, barely enough for subsistence.8 As the economy decayed and money was continually diverted to the Iraqi military, there was little available to spend on public health measures. American forces and international aid agencies are now faced with the task of rebuilding a nation destroyed by years of war and isolation. We will confront malnutrition, malaria, tuberculosis, leishmaniasis, and infestation.
Over the next few months, Cutis plans to publish a series of articles focusing on the role of the dermatologist during war, rebuilding, refugee crises, and humanitarian missions. (For the first article, see page 39 of this issue.) We also will feature editorials on the role of military medicine in our national response to bioterrorism and the continuing role of military residency training programs. We hope this series of special articles will be helpful to our readers, as we pull together a nation to help with the work ahead.

back to top

The major fighting in Iraq is over, and the work of rebuilding has begun. What can we expect in the months ahead? America is deeply invested in the rebuilding of Iraq, and our presence there is likely to continue for some time. Over the ensuing months, servicemen will return home with maladies acquired overseas. The potential for continued unrest in the region makes it likely that western countries will continue to receive a stream of asylum seekers, as well as the medical conditions these individuals bring with them. Dermatologists at home will see and treat these exotic diseases, the burden of which may endure for some time. A study of Southeast Asian immigrants in Australia demonstrated that intestinal parasite infections were still common 12 years after immigration.1
Dermatologists will play a significant role in treating these patients, as dermatologic diseases are prevalent among those seeking asylum in western countries. A study of 1487 refugee children in the Canton of Zurich found that almost 10% had skin diseases.2 Among Vietnamese refugees arriving in Hong Kong, chronic bacterial skin infections and lice were common problems,3,4 and Southeast Asian refugees living in Tennessee have presented to their physicians with chronic bacterial infections, including leprosy and parasitic diseases.5
A series of articles that covers the health problems encountered during war and rebuilding is timely, and of value to Cutis® readers. Important topics to be covered include dermatologic diseases endemic to Iraq and Afghanistan, diseases common in refugee and immigrant populations, and the continuing threat of bioterrorism. These articles will focus on problems that we may encounter at home and abroad.
A review of the health problems of soldiers during the last Gulf War gives us a sense of some of the problems we should be prepared to treat. Fortunately, the rate of infection with exotic diseases during that conflict was quite low considering the magnitude of our presence in the region. Approximately 800,000 coalition troops were deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. The liberal use of insecticides and repellents played a major role in reducing the incidence of disease. The deployment of most ground troops in the open desert during the cooler winter period also was important in reducing the number of reported infections, because these conditions were unfavorable for the transmission of arthropod-borne diseases. In contrast to World War II, there were no reports of sand fly fever among coalition forces during the first Gulf War, and there were only 31 cases of leishmaniasis among the 697,000 US troops. Although the region contained suspected vectors of cutaneous leishmaniasis, sand fly fever, West Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever, the prevalence of infection was low during the months of the war and was confined mostly to leishmaniasis.6 In addition to cutaneous leishmaniasis, there were 12 cases of visceral leishmaniasis due to Leishmania tropica during the first Gulf War.7
Vector control efforts during a prolonged peace-keeping and rebuilding effort may be more complicated than during the war. We are likely to remain in Iraq during the change of seasons, and vector-borne disease may be a more significant problem. We also should remain alert for signs of bioterrorism.
In addition to treating returning servicemen, western physicians will play a major role in providing healthcare to those displaced by the conflict and to a nation plagued by more than a decade of war and degraded infrastructure. Before the first Gulf War, many of Iraq’s healthcare professionals were foreign nationals. War and a crumbling economy led to a mass exodus of healthcare professionals. Doctors’ salaries were reported to fall to about $30 a month, barely enough for subsistence.8 As the economy decayed and money was continually diverted to the Iraqi military, there was little available to spend on public health measures. American forces and international aid agencies are now faced with the task of rebuilding a nation destroyed by years of war and isolation. We will confront malnutrition, malaria, tuberculosis, leishmaniasis, and infestation.
Over the next few months, Cutis plans to publish a series of articles focusing on the role of the dermatologist during war, rebuilding, refugee crises, and humanitarian missions. (For the first article, see page 39 of this issue.) We also will feature editorials on the role of military medicine in our national response to bioterrorism and the continuing role of military residency training programs. We hope this series of special articles will be helpful to our readers, as we pull together a nation to help with the work ahead.

back to top