Cutis

Pyogenic granuloma (PG) is a common vascular hyperplasia of the skin and mucous membranes that occurs in children and young adults.1-3 It is usually found on the face, trunk, and limbs. There are also subcutaneous4 and intravenous5,6 variants. PG is often solitary, but multiple satellite lesions may occur.7

PG was identified over a century ago and has been associated with minor trauma, chronic irritation, hormonal factors, and viral infections. To date, however, no significant causative relationships have been verified. The etiologic hypotheses have led to a number of terms used to describe PG that suggest a causative agent; these terms include botryomycosis hominis,8 granuloma telangiectodes,9 and granuloma pediculatum.10 The term pyogenic granuloma was adopted in 1925 because it was considered descriptive of the underlying process.10 Recently, the term lobular capillary hemangioma has been suggested because of the histologic appearance of the lesions.11

Epidemiology PG is common in children and young adults. In children, the mean age of onset is 6.7 years; 42% of cases occur by 5 years of age, 12% occur before 1 year of age, and 1.1% are present at birth.2 Cutaneous PG has no gender predisposition and accounts for 0.5% of all skin nodules in children.12 The incidence of oral mucosal nodules peaks in the second or third decade of life13; oral mucosal nodules occur in a 2:1 female-male ratio and are associated with pregnancy and oral contraceptive use.13 Multiple PGs usually occur in young adults but have been reported in children.13,14

Etiology and Pathogenesis The etiology of PG is unknown, but because PG regresses when potential initiating stimuli are removed, it qualifies as a vascular hyperplasia.3 Possible predisposing factors include trauma, chronic irritation, increased levels of female sex hormones, infections, viral oncogenes, and microscopic arteriovenous anastamoses.

As many as 50% of individuals with PG have a history of local trauma.10,15,16 Further, multiple PGs often develop following surgical manipulation of primary nodules.7 It has been postulated that excessive production of an angiogenic factor following trauma may be responsible for the vascular hyperplasia.17-19 However, some studies report little association between trauma and PG.2

Female sex hormones also may play a role in the pathogenesis of PG. Oral mucosal nodules occur at an increased frequency in pregnant women and in women who use oral contraceptives.13,20-22 This increased occurrence is thought to be due to an imbalance between angiogenesis enhancers and inhibitors.23 A recent study demonstrated that female sex hormones enhance the expression of angiogenic factors, including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin 1β.21 A decreased rate of endothelial cell apoptosis also was seen. Recurrence of an excised nodule is not uncommon during pregnancy, and conversely, lesions tend to resolve after childbirth.20,22,24 There is no relationship between sex hormones and cutaneous PG.

Bacterial infection is another suspected cause of PG, yet no etiologic agents have been found. Bartonella infection may manifest as a spectrum of lesions, ranging from solitary PG to widespread bacillary angiomatosis.25,26 There was a statistically significant association between PG and seropositivity for Bartonella.26 Gram-positive bacilli have also been observed on microscopic examination of PG tissue samples.25

Viral oncogenes might lead to sudden and uncoordinated growth of the dermal papillae, resulting in PG. It is hypothesized that viral infection leads to disregulation of gene repression in papillary fibroblasts.27 PG nodules may have a propensity to develop at sites of microscopic arteriovenous anastomoses.28 Consistent with this idea is the observation that the frequency of PG and the density of cutaneous vascularity is greatest in the head and neck, followed by the trunk and limbs (with vascularity greater in the upper limbs than in the lower).2,29 In addition, PGs have occurred within a nevus flammeus (port-wine stain), a type of vascular malformation.30-33 

Clinical Features Commonly recognized variants of PG include cutaneous, oral mucosal (granuloma gravidarum), satellite, subcutaneous, intravenous, and congenital types. Cutaneous PG often arises as a painless, red, and crusted or ulcerated papule on the skin surface (Figure). The mean diameter of a cutaneous PG is 6.5 mm.2 The lesion develops over weeks, and growth typically stabilizes over several months.2,11,15 Eventually, it shrinks to become a fibrotic "angioma."2 Some nodules spontaneously infarct and involute. Solitary cutaneous PGs are commonly located on the head and neck (62.5%), trunk (19.7%), or limbs (17.9%), with the upper limbs involved more often than the lower.2,13

Oral mucosal nodules account for up to 70% of PGs in women.13 These lesions may develop on the gingiva, lips, or buccal mucosa.13,23 Lesions often arise during the second or third trimester of pregnancy or with the use of oral contraceptives.13,20-23 PG on the oral mucosa has a higher rate of recurrence than cutaneous PG if excised during pregnancy and often resolves spontaneously after childbirth. Mucosal PG also has been reported on the tongue,34 in the larynx,35 and on the glans penis.16,36

Satellite PGs are rare, usually occurring after treatment or manipulation of a solitary nodule.7,25,37 Spontaneous occurrence is rare.7,38 Satellite lesions are smooth, red, sessile papules that range in diameter from 1 to 10 mm. Unlike solitary PGs, satellite PGs most commonly appear on the trunk.7,39

Subcutaneous PGs also are uncommon and appear as nonspecific subcutaneous nodules.4,11,40 Because the clinical appearance of this tumor is quite different from that of cutaneous PG, subcutaneous PG is often difficult to diagnose based on clinical features. It is sometimes mistaken for a hemangioma or an epidermal cyst. Biopsy results readily distinguish it from granulation tissue or from other vascular entities.

Intravenous PGs may appear as subcutaneous nodules with nonspecific features, most commonly developing on the upper limb.6,41 Intravenous PG also may be evident as a red-brown polyp.41 Clinical diagnosis of intravenous PG can be difficult, as it can be mistaken for an organizing thrombus.

Congenital PG is an uncommon disseminated variant.2,42 Multiple lesions, similar in appearance to the cutaneous form, are present at birth. The condition appears to follow a benign course, with spontaneous resolution over 6 to 12 months.

Differential Diagnosis The differential diagnosis of PG should include amelanotic melanoma,43 angiosarcoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma,44 hemangioma, bacillary angiomatosis,45-47 metastatic visceral malignancies,48 and granulation tissue. A case of hepatocellular metastases to the gingiva mimicking PG also has been reported.49 

Histology Early PG is histologically identical to granulation tissue, appearing as highly vascularized connective tissue with capillaries and venules in an edematous matrix.2,3 As the lesion matures, a fibromyxoid stroma separates the lesions into lobules containing aggregates of capillaries and venules with plump endothelial cells.3 By this point, the edema has resolved. The epidermis exhibits inward growth at the lesion base, forming a so-called epidermal collarette and causing slight pedunculation. Extensive fibrosis signifies the final stage of regression.

Treatment and Prognosis Various treatment modalities have been used to remove PG. Effective means include excision, shave excision, laser surgery, sclerotherapy, electrodesiccation, curettage, ligation, or a combination of methods.

Excision with linear closure offers the lowest recurrence rate and allows histologic examination of a tissue sample. Closure, however, leaves a linear scar.50 Shave excision followed by argon laser photocoagulation is an effective therapeutic alternative that minimizes scar formation while preserving the ability to confirm the diagnosis with histologic examination.50

More conservative methods such as 585-nm flashlamp-pumped pulsed-dye laser surgery are beneficial but require multiple treatments and can only be used for small lesions.51 A 100% cure rate was observed with ethanolamine oleate sclerotherapy on both large and small lesions.52 Recurrence rate with shave excision plus cauterization or cauterization alone has been reported to be 43.5%.2 None of these tissue-preserving methods allows histologic examination. The lack of histologic confirmation should not pose a problem for experienced dermatologists or in clinically obvious cases. However, in one series, 18% of PGs were incorrectly diagnosed.50

Surgical debulking of cutaneous lesions followed by cauterization with silver nitrate has been advocated as an effective yet inexpensive treatment. Follow-up should occur weekly, with repeat cauterization as needed. This regimen results in an 85% resolution rate in an average of 1.6 treatments.53

Peduncular PGs may be ligated at the base using absorbable suture.54 The tumor is lifted with forceps and ligated at the base with tight suture knots. The tumor will become necrotic and fall off over several days. The procedure is atraumatic and inexpensive and requires no anesthesia or special equipment. Persistence or recurrence can be treated with excision or laser surgery. However, the procedure does not allow histologic examination. 

Conclusion

PG is an acquired vascular neoplasm of considerable interest.55-60 Its friability often produces an enhanced level of clinical concern. PG needs to be distinguished from Kaposi sarcoma, melanoma, and metastatic carcinoma, as well as an important systemic bacterial infection, bacillary angiomatosis. 

Pyogenic granuloma (PG) is a common vascular hyperplasia of the skin and mucous membranes that occurs in children and young adults.1-3 It is usually found on the face, trunk, and limbs. There are also subcutaneous4 and intravenous5,6 variants. PG is often solitary, but multiple satellite lesions may occur.7

PG was identified over a century ago and has been associated with minor trauma, chronic irritation, hormonal factors, and viral infections. To date, however, no significant causative relationships have been verified. The etiologic hypotheses have led to a number of terms used to describe PG that suggest a causative agent; these terms include botryomycosis hominis,8 granuloma telangiectodes,9 and granuloma pediculatum.10 The term pyogenic granuloma was adopted in 1925 because it was considered descriptive of the underlying process.10 Recently, the term lobular capillary hemangioma has been suggested because of the histologic appearance of the lesions.11

Epidemiology PG is common in children and young adults. In children, the mean age of onset is 6.7 years; 42% of cases occur by 5 years of age, 12% occur before 1 year of age, and 1.1% are present at birth.2 Cutaneous PG has no gender predisposition and accounts for 0.5% of all skin nodules in children.12 The incidence of oral mucosal nodules peaks in the second or third decade of life13; oral mucosal nodules occur in a 2:1 female-male ratio and are associated with pregnancy and oral contraceptive use.13 Multiple PGs usually occur in young adults but have been reported in children.13,14

Etiology and Pathogenesis The etiology of PG is unknown, but because PG regresses when potential initiating stimuli are removed, it qualifies as a vascular hyperplasia.3 Possible predisposing factors include trauma, chronic irritation, increased levels of female sex hormones, infections, viral oncogenes, and microscopic arteriovenous anastamoses.

As many as 50% of individuals with PG have a history of local trauma.10,15,16 Further, multiple PGs often develop following surgical manipulation of primary nodules.7 It has been postulated that excessive production of an angiogenic factor following trauma may be responsible for the vascular hyperplasia.17-19 However, some studies report little association between trauma and PG.2

Female sex hormones also may play a role in the pathogenesis of PG. Oral mucosal nodules occur at an increased frequency in pregnant women and in women who use oral contraceptives.13,20-22 This increased occurrence is thought to be due to an imbalance between angiogenesis enhancers and inhibitors.23 A recent study demonstrated that female sex hormones enhance the expression of angiogenic factors, including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin 1β.21 A decreased rate of endothelial cell apoptosis also was seen. Recurrence of an excised nodule is not uncommon during pregnancy, and conversely, lesions tend to resolve after childbirth.20,22,24 There is no relationship between sex hormones and cutaneous PG.

Bacterial infection is another suspected cause of PG, yet no etiologic agents have been found. Bartonella infection may manifest as a spectrum of lesions, ranging from solitary PG to widespread bacillary angiomatosis.25,26 There was a statistically significant association between PG and seropositivity for Bartonella.26 Gram-positive bacilli have also been observed on microscopic examination of PG tissue samples.25

Viral oncogenes might lead to sudden and uncoordinated growth of the dermal papillae, resulting in PG. It is hypothesized that viral infection leads to disregulation of gene repression in papillary fibroblasts.27 PG nodules may have a propensity to develop at sites of microscopic arteriovenous anastomoses.28 Consistent with this idea is the observation that the frequency of PG and the density of cutaneous vascularity is greatest in the head and neck, followed by the trunk and limbs (with vascularity greater in the upper limbs than in the lower).2,29 In addition, PGs have occurred within a nevus flammeus (port-wine stain), a type of vascular malformation.30-33 

Clinical Features Commonly recognized variants of PG include cutaneous, oral mucosal (granuloma gravidarum), satellite, subcutaneous, intravenous, and congenital types. Cutaneous PG often arises as a painless, red, and crusted or ulcerated papule on the skin surface (Figure). The mean diameter of a cutaneous PG is 6.5 mm.2 The lesion develops over weeks, and growth typically stabilizes over several months.2,11,15 Eventually, it shrinks to become a fibrotic "angioma."2 Some nodules spontaneously infarct and involute. Solitary cutaneous PGs are commonly located on the head and neck (62.5%), trunk (19.7%), or limbs (17.9%), with the upper limbs involved more often than the lower.2,13

Oral mucosal nodules account for up to 70% of PGs in women.13 These lesions may develop on the gingiva, lips, or buccal mucosa.13,23 Lesions often arise during the second or third trimester of pregnancy or with the use of oral contraceptives.13,20-23 PG on the oral mucosa has a higher rate of recurrence than cutaneous PG if excised during pregnancy and often resolves spontaneously after childbirth. Mucosal PG also has been reported on the tongue,34 in the larynx,35 and on the glans penis.16,36

Satellite PGs are rare, usually occurring after treatment or manipulation of a solitary nodule.7,25,37 Spontaneous occurrence is rare.7,38 Satellite lesions are smooth, red, sessile papules that range in diameter from 1 to 10 mm. Unlike solitary PGs, satellite PGs most commonly appear on the trunk.7,39

Subcutaneous PGs also are uncommon and appear as nonspecific subcutaneous nodules.4,11,40 Because the clinical appearance of this tumor is quite different from that of cutaneous PG, subcutaneous PG is often difficult to diagnose based on clinical features. It is sometimes mistaken for a hemangioma or an epidermal cyst. Biopsy results readily distinguish it from granulation tissue or from other vascular entities.

Intravenous PGs may appear as subcutaneous nodules with nonspecific features, most commonly developing on the upper limb.6,41 Intravenous PG also may be evident as a red-brown polyp.41 Clinical diagnosis of intravenous PG can be difficult, as it can be mistaken for an organizing thrombus.

Congenital PG is an uncommon disseminated variant.2,42 Multiple lesions, similar in appearance to the cutaneous form, are present at birth. The condition appears to follow a benign course, with spontaneous resolution over 6 to 12 months.

Differential Diagnosis The differential diagnosis of PG should include amelanotic melanoma,43 angiosarcoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma,44 hemangioma, bacillary angiomatosis,45-47 metastatic visceral malignancies,48 and granulation tissue. A case of hepatocellular metastases to the gingiva mimicking PG also has been reported.49 

Histology Early PG is histologically identical to granulation tissue, appearing as highly vascularized connective tissue with capillaries and venules in an edematous matrix.2,3 As the lesion matures, a fibromyxoid stroma separates the lesions into lobules containing aggregates of capillaries and venules with plump endothelial cells.3 By this point, the edema has resolved. The epidermis exhibits inward growth at the lesion base, forming a so-called epidermal collarette and causing slight pedunculation. Extensive fibrosis signifies the final stage of regression.

Treatment and Prognosis Various treatment modalities have been used to remove PG. Effective means include excision, shave excision, laser surgery, sclerotherapy, electrodesiccation, curettage, ligation, or a combination of methods.

Excision with linear closure offers the lowest recurrence rate and allows histologic examination of a tissue sample. Closure, however, leaves a linear scar.50 Shave excision followed by argon laser photocoagulation is an effective therapeutic alternative that minimizes scar formation while preserving the ability to confirm the diagnosis with histologic examination.50

More conservative methods such as 585-nm flashlamp-pumped pulsed-dye laser surgery are beneficial but require multiple treatments and can only be used for small lesions.51 A 100% cure rate was observed with ethanolamine oleate sclerotherapy on both large and small lesions.52 Recurrence rate with shave excision plus cauterization or cauterization alone has been reported to be 43.5%.2 None of these tissue-preserving methods allows histologic examination. The lack of histologic confirmation should not pose a problem for experienced dermatologists or in clinically obvious cases. However, in one series, 18% of PGs were incorrectly diagnosed.50

Surgical debulking of cutaneous lesions followed by cauterization with silver nitrate has been advocated as an effective yet inexpensive treatment. Follow-up should occur weekly, with repeat cauterization as needed. This regimen results in an 85% resolution rate in an average of 1.6 treatments.53

Peduncular PGs may be ligated at the base using absorbable suture.54 The tumor is lifted with forceps and ligated at the base with tight suture knots. The tumor will become necrotic and fall off over several days. The procedure is atraumatic and inexpensive and requires no anesthesia or special equipment. Persistence or recurrence can be treated with excision or laser surgery. However, the procedure does not allow histologic examination. 

Conclusion

PG is an acquired vascular neoplasm of considerable interest.55-60 Its friability often produces an enhanced level of clinical concern. PG needs to be distinguished from Kaposi sarcoma, melanoma, and metastatic carcinoma, as well as an important systemic bacterial infection, bacillary angiomatosis. 

Pyogenic granuloma (PG) is a common vascular hyperplasia of the skin and mucous membranes that occurs in children and young adults.1-3 It is usually found on the face, trunk, and limbs. There are also subcutaneous4 and intravenous5,6 variants. PG is often solitary, but multiple satellite lesions may occur.7

PG was identified over a century ago and has been associated with minor trauma, chronic irritation, hormonal factors, and viral infections. To date, however, no significant causative relationships have been verified. The etiologic hypotheses have led to a number of terms used to describe PG that suggest a causative agent; these terms include botryomycosis hominis,8 granuloma telangiectodes,9 and granuloma pediculatum.10 The term pyogenic granuloma was adopted in 1925 because it was considered descriptive of the underlying process.10 Recently, the term lobular capillary hemangioma has been suggested because of the histologic appearance of the lesions.11

Epidemiology PG is common in children and young adults. In children, the mean age of onset is 6.7 years; 42% of cases occur by 5 years of age, 12% occur before 1 year of age, and 1.1% are present at birth.2 Cutaneous PG has no gender predisposition and accounts for 0.5% of all skin nodules in children.12 The incidence of oral mucosal nodules peaks in the second or third decade of life13; oral mucosal nodules occur in a 2:1 female-male ratio and are associated with pregnancy and oral contraceptive use.13 Multiple PGs usually occur in young adults but have been reported in children.13,14

Etiology and Pathogenesis The etiology of PG is unknown, but because PG regresses when potential initiating stimuli are removed, it qualifies as a vascular hyperplasia.3 Possible predisposing factors include trauma, chronic irritation, increased levels of female sex hormones, infections, viral oncogenes, and microscopic arteriovenous anastamoses.

As many as 50% of individuals with PG have a history of local trauma.10,15,16 Further, multiple PGs often develop following surgical manipulation of primary nodules.7 It has been postulated that excessive production of an angiogenic factor following trauma may be responsible for the vascular hyperplasia.17-19 However, some studies report little association between trauma and PG.2

Female sex hormones also may play a role in the pathogenesis of PG. Oral mucosal nodules occur at an increased frequency in pregnant women and in women who use oral contraceptives.13,20-22 This increased occurrence is thought to be due to an imbalance between angiogenesis enhancers and inhibitors.23 A recent study demonstrated that female sex hormones enhance the expression of angiogenic factors, including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin 1β.21 A decreased rate of endothelial cell apoptosis also was seen. Recurrence of an excised nodule is not uncommon during pregnancy, and conversely, lesions tend to resolve after childbirth.20,22,24 There is no relationship between sex hormones and cutaneous PG.

Bacterial infection is another suspected cause of PG, yet no etiologic agents have been found. Bartonella infection may manifest as a spectrum of lesions, ranging from solitary PG to widespread bacillary angiomatosis.25,26 There was a statistically significant association between PG and seropositivity for Bartonella.26 Gram-positive bacilli have also been observed on microscopic examination of PG tissue samples.25

Viral oncogenes might lead to sudden and uncoordinated growth of the dermal papillae, resulting in PG. It is hypothesized that viral infection leads to disregulation of gene repression in papillary fibroblasts.27 PG nodules may have a propensity to develop at sites of microscopic arteriovenous anastomoses.28 Consistent with this idea is the observation that the frequency of PG and the density of cutaneous vascularity is greatest in the head and neck, followed by the trunk and limbs (with vascularity greater in the upper limbs than in the lower).2,29 In addition, PGs have occurred within a nevus flammeus (port-wine stain), a type of vascular malformation.30-33 

Clinical Features Commonly recognized variants of PG include cutaneous, oral mucosal (granuloma gravidarum), satellite, subcutaneous, intravenous, and congenital types. Cutaneous PG often arises as a painless, red, and crusted or ulcerated papule on the skin surface (Figure). The mean diameter of a cutaneous PG is 6.5 mm.2 The lesion develops over weeks, and growth typically stabilizes over several months.2,11,15 Eventually, it shrinks to become a fibrotic "angioma."2 Some nodules spontaneously infarct and involute. Solitary cutaneous PGs are commonly located on the head and neck (62.5%), trunk (19.7%), or limbs (17.9%), with the upper limbs involved more often than the lower.2,13

Oral mucosal nodules account for up to 70% of PGs in women.13 These lesions may develop on the gingiva, lips, or buccal mucosa.13,23 Lesions often arise during the second or third trimester of pregnancy or with the use of oral contraceptives.13,20-23 PG on the oral mucosa has a higher rate of recurrence than cutaneous PG if excised during pregnancy and often resolves spontaneously after childbirth. Mucosal PG also has been reported on the tongue,34 in the larynx,35 and on the glans penis.16,36

Satellite PGs are rare, usually occurring after treatment or manipulation of a solitary nodule.7,25,37 Spontaneous occurrence is rare.7,38 Satellite lesions are smooth, red, sessile papules that range in diameter from 1 to 10 mm. Unlike solitary PGs, satellite PGs most commonly appear on the trunk.7,39

Subcutaneous PGs also are uncommon and appear as nonspecific subcutaneous nodules.4,11,40 Because the clinical appearance of this tumor is quite different from that of cutaneous PG, subcutaneous PG is often difficult to diagnose based on clinical features. It is sometimes mistaken for a hemangioma or an epidermal cyst. Biopsy results readily distinguish it from granulation tissue or from other vascular entities.

Intravenous PGs may appear as subcutaneous nodules with nonspecific features, most commonly developing on the upper limb.6,41 Intravenous PG also may be evident as a red-brown polyp.41 Clinical diagnosis of intravenous PG can be difficult, as it can be mistaken for an organizing thrombus.

Congenital PG is an uncommon disseminated variant.2,42 Multiple lesions, similar in appearance to the cutaneous form, are present at birth. The condition appears to follow a benign course, with spontaneous resolution over 6 to 12 months.

Differential Diagnosis The differential diagnosis of PG should include amelanotic melanoma,43 angiosarcoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma,44 hemangioma, bacillary angiomatosis,45-47 metastatic visceral malignancies,48 and granulation tissue. A case of hepatocellular metastases to the gingiva mimicking PG also has been reported.49 

Histology Early PG is histologically identical to granulation tissue, appearing as highly vascularized connective tissue with capillaries and venules in an edematous matrix.2,3 As the lesion matures, a fibromyxoid stroma separates the lesions into lobules containing aggregates of capillaries and venules with plump endothelial cells.3 By this point, the edema has resolved. The epidermis exhibits inward growth at the lesion base, forming a so-called epidermal collarette and causing slight pedunculation. Extensive fibrosis signifies the final stage of regression.

Treatment and Prognosis Various treatment modalities have been used to remove PG. Effective means include excision, shave excision, laser surgery, sclerotherapy, electrodesiccation, curettage, ligation, or a combination of methods.

Excision with linear closure offers the lowest recurrence rate and allows histologic examination of a tissue sample. Closure, however, leaves a linear scar.50 Shave excision followed by argon laser photocoagulation is an effective therapeutic alternative that minimizes scar formation while preserving the ability to confirm the diagnosis with histologic examination.50

More conservative methods such as 585-nm flashlamp-pumped pulsed-dye laser surgery are beneficial but require multiple treatments and can only be used for small lesions.51 A 100% cure rate was observed with ethanolamine oleate sclerotherapy on both large and small lesions.52 Recurrence rate with shave excision plus cauterization or cauterization alone has been reported to be 43.5%.2 None of these tissue-preserving methods allows histologic examination. The lack of histologic confirmation should not pose a problem for experienced dermatologists or in clinically obvious cases. However, in one series, 18% of PGs were incorrectly diagnosed.50

Surgical debulking of cutaneous lesions followed by cauterization with silver nitrate has been advocated as an effective yet inexpensive treatment. Follow-up should occur weekly, with repeat cauterization as needed. This regimen results in an 85% resolution rate in an average of 1.6 treatments.53

Peduncular PGs may be ligated at the base using absorbable suture.54 The tumor is lifted with forceps and ligated at the base with tight suture knots. The tumor will become necrotic and fall off over several days. The procedure is atraumatic and inexpensive and requires no anesthesia or special equipment. Persistence or recurrence can be treated with excision or laser surgery. However, the procedure does not allow histologic examination. 

Conclusion

PG is an acquired vascular neoplasm of considerable interest.55-60 Its friability often produces an enhanced level of clinical concern. PG needs to be distinguished from Kaposi sarcoma, melanoma, and metastatic carcinoma, as well as an important systemic bacterial infection, bacillary angiomatosis. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

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Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

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Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

Please refer to the PDF to view the table

Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

Please refer to the PDF to view the table

Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

Please refer to the PDF to view the table

Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

Please refer to the PDF to view the table

Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse.