The Clinical Picture

The patient says she has had intense sunlight exposure during her life, due to agricultural work.

Q: What is the most likely diagnosis?

• Basal cell carcinoma
• Cutaneous leishmaniasis
• Squamous cell carcinoma
• Viral wart
• Pyoderma gangrenosum

A: Squamous cell carcinoma is the most likely diagnosis. It is the second most common form of skin cancer (after basal cell carcinoma) that arises on the sun-exposed skin of elderly individuals.

Basal cell carcinoma usually presents as a slow-growing, pearly nodule with telangiectasias over the surface, but without a keratotic component. Cutaneous leishmaniasis is caused by a protozoan and is transmitted by the bite of a sandfly. It presents as a crusted papule or ulcer at the site of the bite, only rarely presenting as a cutaneous horn. Viral warts may present as horns (filiform warts), but the horn is slender and is usually around the lips, eyelids, or nares. Although warts can occur at any age, they are more frequently seen among school-aged children, and they peak between ages 12 and 16. Pyoderma gangrenosum is considered a reactive dermatosis sometimes secondary to a systemic disease such as inflammatory bowel disease. It usually presents as a small, red papule or pustule that progresses to a larger ulcerative lesion.

SQUAMOUS CELL CARCINOMA: CAUSES, RISK FACTORS

Exposure to ultraviolet radiation is the most common cause of squamous cell carcinoma. Other risk factors include exposure to ionizing radiation, human papilloma virus, thermal injury, burns, immunosuppression, exposure to chemical carcinogens, and diseases such as xeroderma pigmentosum, oculocutaneous albinism, and junctional epidermolysis bullosa.^1,2 Organ transplantation is another significant risk factor, and cutaneous squamous cell carcinoma is the most common malignancy in renal transplant recipients.³

People born in areas that receive high amounts of ultraviolet radiation from the sun have a risk of squamous cell carcinoma three times higher than people who move to those areas in adulthood.¹ Occupational exposure to ultraviolet radiation is also implicated in this type of cancer.

CLINICAL APPEARANCE

Clinically, squamous cell carcinoma of the skin may manifest as a variety of primary morphologies with or without associated symptoms. The characteristic invasive squamous cell carcinoma is a raised, firm, pink or flesh-colored keratotic papule or plaque arising on sun-exposed skin. Approximately 70% of all squamous cell carcinomas occur on the head and neck, with an additional 15% found on the upper extremities. Surface changes may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Squamous cell carcinoma can also present as an eczematous patch that does not resolve with emollient or topical steroids. Less commonly, it may manifest as a pink cutaneous nodule with no overlying surface changes. Often, the patient has a background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses.

MAKING THE DIAGNOSIS

Skin biopsy usually confirms the clinical diagnosis. Histologic examination shows neoplastic proliferation of atypical keratinocytes extending into the dermis, with large hyperchromatic and pleomorphic nuclei.

Imaging is not routinely indicated for diagnosing cutaneous squamous cell carcinoma. However, radiologic imaging should be obtained in patients with regional lymphadenopathy or neurologic symptoms suggestive of perineural involvement.

Other lesions found at the base of a cutaneous horn include actinic keratosis, keratoacanthoma, basal cell carcinoma, and benign lesions such as seborrheic keratosis and verruca vulgaris.^4,5

MANAGEMENT

Most cutaneous squamous cell carcinomas are easily treated, and the rate of cure is high. Treatment options include topical chemotherapy, cryosurgery, electrodesiccation and curettage, surgical excision, Mohs micrographic surgery, radiotherapy, and photodynamic therapy. Fractionated radiation treatment may be preferred for patients who are unable to tolerate surgery or who have inoperable tumors, and it may provide favorable functional and cosmetic results.¹

Photodynamic therapy and topical chemotherapy with imiquimod are currently not recommended for invasive squamous cell carcinoma.

Low-risk tumors are usually cured with surgical therapy. However, patients who develop one squamous cell carcinoma have a 40% risk of developing additional squamous cell carcinomas within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of this cancer should be evaluated with a complete skin examination every 6 to 12 months.

OUR PATIENT’S TREATMENT

Our patient underwent total surgical excision of the lesion with a safety margin of 0.5 cm. Histologic results confirmed the diagnosis of squamous cell carcinoma with tumor-free margins. No clinical relapse was observed after 1 year of follow-up.

The patient says she has had intense sunlight exposure during her life, due to agricultural work.

Q: What is the most likely diagnosis?

• Basal cell carcinoma
• Cutaneous leishmaniasis
• Squamous cell carcinoma
• Viral wart
• Pyoderma gangrenosum

A: Squamous cell carcinoma is the most likely diagnosis. It is the second most common form of skin cancer (after basal cell carcinoma) that arises on the sun-exposed skin of elderly individuals.

Basal cell carcinoma usually presents as a slow-growing, pearly nodule with telangiectasias over the surface, but without a keratotic component. Cutaneous leishmaniasis is caused by a protozoan and is transmitted by the bite of a sandfly. It presents as a crusted papule or ulcer at the site of the bite, only rarely presenting as a cutaneous horn. Viral warts may present as horns (filiform warts), but the horn is slender and is usually around the lips, eyelids, or nares. Although warts can occur at any age, they are more frequently seen among school-aged children, and they peak between ages 12 and 16. Pyoderma gangrenosum is considered a reactive dermatosis sometimes secondary to a systemic disease such as inflammatory bowel disease. It usually presents as a small, red papule or pustule that progresses to a larger ulcerative lesion.

SQUAMOUS CELL CARCINOMA: CAUSES, RISK FACTORS

Exposure to ultraviolet radiation is the most common cause of squamous cell carcinoma. Other risk factors include exposure to ionizing radiation, human papilloma virus, thermal injury, burns, immunosuppression, exposure to chemical carcinogens, and diseases such as xeroderma pigmentosum, oculocutaneous albinism, and junctional epidermolysis bullosa.^1,2 Organ transplantation is another significant risk factor, and cutaneous squamous cell carcinoma is the most common malignancy in renal transplant recipients.³

People born in areas that receive high amounts of ultraviolet radiation from the sun have a risk of squamous cell carcinoma three times higher than people who move to those areas in adulthood.¹ Occupational exposure to ultraviolet radiation is also implicated in this type of cancer.

CLINICAL APPEARANCE

Clinically, squamous cell carcinoma of the skin may manifest as a variety of primary morphologies with or without associated symptoms. The characteristic invasive squamous cell carcinoma is a raised, firm, pink or flesh-colored keratotic papule or plaque arising on sun-exposed skin. Approximately 70% of all squamous cell carcinomas occur on the head and neck, with an additional 15% found on the upper extremities. Surface changes may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Squamous cell carcinoma can also present as an eczematous patch that does not resolve with emollient or topical steroids. Less commonly, it may manifest as a pink cutaneous nodule with no overlying surface changes. Often, the patient has a background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses.

MAKING THE DIAGNOSIS

Skin biopsy usually confirms the clinical diagnosis. Histologic examination shows neoplastic proliferation of atypical keratinocytes extending into the dermis, with large hyperchromatic and pleomorphic nuclei.

Imaging is not routinely indicated for diagnosing cutaneous squamous cell carcinoma. However, radiologic imaging should be obtained in patients with regional lymphadenopathy or neurologic symptoms suggestive of perineural involvement.

Other lesions found at the base of a cutaneous horn include actinic keratosis, keratoacanthoma, basal cell carcinoma, and benign lesions such as seborrheic keratosis and verruca vulgaris.^4,5

MANAGEMENT

Most cutaneous squamous cell carcinomas are easily treated, and the rate of cure is high. Treatment options include topical chemotherapy, cryosurgery, electrodesiccation and curettage, surgical excision, Mohs micrographic surgery, radiotherapy, and photodynamic therapy. Fractionated radiation treatment may be preferred for patients who are unable to tolerate surgery or who have inoperable tumors, and it may provide favorable functional and cosmetic results.¹

Photodynamic therapy and topical chemotherapy with imiquimod are currently not recommended for invasive squamous cell carcinoma.

Low-risk tumors are usually cured with surgical therapy. However, patients who develop one squamous cell carcinoma have a 40% risk of developing additional squamous cell carcinomas within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of this cancer should be evaluated with a complete skin examination every 6 to 12 months.

OUR PATIENT’S TREATMENT

Our patient underwent total surgical excision of the lesion with a safety margin of 0.5 cm. Histologic results confirmed the diagnosis of squamous cell carcinoma with tumor-free margins. No clinical relapse was observed after 1 year of follow-up.

The patient says she has had intense sunlight exposure during her life, due to agricultural work.

Q: What is the most likely diagnosis?

• Basal cell carcinoma
• Cutaneous leishmaniasis
• Squamous cell carcinoma
• Viral wart
• Pyoderma gangrenosum

A: Squamous cell carcinoma is the most likely diagnosis. It is the second most common form of skin cancer (after basal cell carcinoma) that arises on the sun-exposed skin of elderly individuals.

Basal cell carcinoma usually presents as a slow-growing, pearly nodule with telangiectasias over the surface, but without a keratotic component. Cutaneous leishmaniasis is caused by a protozoan and is transmitted by the bite of a sandfly. It presents as a crusted papule or ulcer at the site of the bite, only rarely presenting as a cutaneous horn. Viral warts may present as horns (filiform warts), but the horn is slender and is usually around the lips, eyelids, or nares. Although warts can occur at any age, they are more frequently seen among school-aged children, and they peak between ages 12 and 16. Pyoderma gangrenosum is considered a reactive dermatosis sometimes secondary to a systemic disease such as inflammatory bowel disease. It usually presents as a small, red papule or pustule that progresses to a larger ulcerative lesion.

SQUAMOUS CELL CARCINOMA: CAUSES, RISK FACTORS

Exposure to ultraviolet radiation is the most common cause of squamous cell carcinoma. Other risk factors include exposure to ionizing radiation, human papilloma virus, thermal injury, burns, immunosuppression, exposure to chemical carcinogens, and diseases such as xeroderma pigmentosum, oculocutaneous albinism, and junctional epidermolysis bullosa.^1,2 Organ transplantation is another significant risk factor, and cutaneous squamous cell carcinoma is the most common malignancy in renal transplant recipients.³

People born in areas that receive high amounts of ultraviolet radiation from the sun have a risk of squamous cell carcinoma three times higher than people who move to those areas in adulthood.¹ Occupational exposure to ultraviolet radiation is also implicated in this type of cancer.

CLINICAL APPEARANCE

Clinically, squamous cell carcinoma of the skin may manifest as a variety of primary morphologies with or without associated symptoms. The characteristic invasive squamous cell carcinoma is a raised, firm, pink or flesh-colored keratotic papule or plaque arising on sun-exposed skin. Approximately 70% of all squamous cell carcinomas occur on the head and neck, with an additional 15% found on the upper extremities. Surface changes may include scaling, ulceration, crusting, or the presence of a cutaneous horn. Squamous cell carcinoma can also present as an eczematous patch that does not resolve with emollient or topical steroids. Less commonly, it may manifest as a pink cutaneous nodule with no overlying surface changes. Often, the patient has a background of severely sun-damaged skin, including solar elastosis, mottled dyspigmentation, telangiectasia, and multiple actinic keratoses.

MAKING THE DIAGNOSIS

Skin biopsy usually confirms the clinical diagnosis. Histologic examination shows neoplastic proliferation of atypical keratinocytes extending into the dermis, with large hyperchromatic and pleomorphic nuclei.

Imaging is not routinely indicated for diagnosing cutaneous squamous cell carcinoma. However, radiologic imaging should be obtained in patients with regional lymphadenopathy or neurologic symptoms suggestive of perineural involvement.

Other lesions found at the base of a cutaneous horn include actinic keratosis, keratoacanthoma, basal cell carcinoma, and benign lesions such as seborrheic keratosis and verruca vulgaris.^4,5

MANAGEMENT

Most cutaneous squamous cell carcinomas are easily treated, and the rate of cure is high. Treatment options include topical chemotherapy, cryosurgery, electrodesiccation and curettage, surgical excision, Mohs micrographic surgery, radiotherapy, and photodynamic therapy. Fractionated radiation treatment may be preferred for patients who are unable to tolerate surgery or who have inoperable tumors, and it may provide favorable functional and cosmetic results.¹

Photodynamic therapy and topical chemotherapy with imiquimod are currently not recommended for invasive squamous cell carcinoma.

Low-risk tumors are usually cured with surgical therapy. However, patients who develop one squamous cell carcinoma have a 40% risk of developing additional squamous cell carcinomas within the next 2 years. This risk is likely even greater as more time elapses. Thus, patients with a history of this cancer should be evaluated with a complete skin examination every 6 to 12 months.

OUR PATIENT’S TREATMENT

Our patient underwent total surgical excision of the lesion with a safety margin of 0.5 cm. Histologic results confirmed the diagnosis of squamous cell carcinoma with tumor-free margins. No clinical relapse was observed after 1 year of follow-up.

A 44-year-old man is referred for evaluation of asymptomatic swelling of the lower lip that has persisted for 10 months. He has been treated unsuccessfully with oral antihistamines for suspected chronic angioedema. He has no other symptoms and appears to be well otherwise. He has no history of applied irritants or local trauma, and his medical history is unremarkable.

Results of the laboratory evaluation, including serum angiotensin-converting enzyme level, are normal. Patch tests to detect contact sensitivity to food additives are negative. Biopsy of the affected lip reveals dense infiltrate of the submucosal connective tissue with focal nonnecrotizing granulomas. Imaging and endoscopic studies show no evidence of sarcoidosis or Crohn disease.

Q: Given what we know so far, which of the following is the most likely diagnosis of the persistent lip swelling?

• Melkersson-Rosenthal syndrome
• Amyloidosis
• Quincke edema
• Cheilitis granulomatosa
• Cutaneous tuberculosis

A: From what we know so far, the correct answer is cheilitis granulomatosa. While this rare condition may be a feature of Melkersson-Rosenthal syndrome and amyloidosis, at this point in the evaluation these have not been confirmed. Quincke edema (ie, angioedema) is unlikely, given the ineffectiveness of previous treatment with oral antihistamines. Cutaneous tuberculosis usually presents as “lupus vulgaris,” which is characterized by solitary, small, sharply marginated, red-brown papules of gelatinous consistency (“apple-jelly nodules”), mainly on the head and neck.

Cheilitis granulomatosa is a rare inflammatory disorder¹ that primarily affects young adults. Its key feature is recurrent or persistent painless swelling of one or both lips. It may occur without other signs of disease, but it is also a manifestation of Melkersson-Rosenthal syndrome and it may be a presenting symptom of Crohn disease or, rarely, sarcoidosis.² The term “orofacial granulomatosis” was introduced to encompass the broad spectrum of nonnecrotizing granulomatous inflammation in the orofacial region, including cheilitis granulomatosa, the complete Melkersson-Rosenthal syndrome, sarcoidosis, Crohn disease, and infectious disorders such as tuberculosis.¹

The cause of cheilitis granulomatosa is unknown. Specific T-cell clonality has been identified in several patients with orofacial granulomatosis, suggesting a delayed hypersensitivity response. Moreover, the HLA haplotypes HLA-A2 and HLA-A11 have been found in 25% of patients with orofacial granulomatosis, suggesting a viral etiology. A genetic predisposition may exist in Melkersson- Rosenthal syndrome: siblings have been affected, and otherwise unaffected relatives may have a fissured tongue (lingua plicata).

Melkersson-Rosenthal syndrome, a rare condition, is characterized by a classic triad of recurrent swelling of the lips or face (or both), fissured tongue, and relapsing peripheral facial nerve paralysis. It is an unusual cause of facial swelling that can be confused with angioedema.³ This syndrome can be ruled out in this patient because he has only one of the three classic signs. Contact antigens are sometimes implicated.

DIFFERENTIAL DIAGNOSIS OF CHEILITIS GRANULOMATOSA

The differential diagnosis of cheilitis granulomatosa is extensive and includes amyloidosis, cheilitis glandularis, sarcoidosis, Crohn disease, actinic cheilitis, neoplasms, and infections, such as tuberculosis, syphilis, and leprosy.¹

As many as 11% of patients with Crohn disease may develop mucocutaneous lesions. Oral lesions of Crohn disease include apthae, cobblestoning of the buccal mucosa, swelling of one or both lips (soft or rubbery), vertical clefts of the lips, or hypertrophic gingivitis. Only 5% of patients with Crohn disease ever develop cheilitis granulomatosa, though most cases occur in children.

Ultimately, the diagnosis of cheilitis granulomatosa is made by correlating the patient’s history and clinical features, usually supported by histopathologic findings of nonnecrotic granulomas extending into the deep dermis, composed of histiocytes and giant cells and associated with a lymphomonocytic infiltrate.

TREATMENT

Treatment of cheilitis granulomatosa is difficult because the cause is unknown and the rate of recurrence is high. Response to treatment is often late and unpredictable. Corticosteroids, clofazimine (Lamprene), and surgical intervention such as cheiloplasty have been described as treatment options. Other treatment options include thalidomide (Thalomid), sulfasalazine (Sulfazine), erythromycin, azathioprine (Imuran), and cyclosporine (Sandimmune). Infliximab (Remicade) has been recently reported as a new alternative treatment, in particular for Melkersson-Rosenthal syndrome.⁴

In our patient, twice-monthly injections of 1 mL of triamcinolone acetonide 10 mg/mL into the affected lip brought acceptable improvement at 3 months. The patient is on maintenance treatment with twice-monthly triamcinolone injections and has had no relapses after 2 years.

A 44-year-old man is referred for evaluation of asymptomatic swelling of the lower lip that has persisted for 10 months. He has been treated unsuccessfully with oral antihistamines for suspected chronic angioedema. He has no other symptoms and appears to be well otherwise. He has no history of applied irritants or local trauma, and his medical history is unremarkable.

Results of the laboratory evaluation, including serum angiotensin-converting enzyme level, are normal. Patch tests to detect contact sensitivity to food additives are negative. Biopsy of the affected lip reveals dense infiltrate of the submucosal connective tissue with focal nonnecrotizing granulomas. Imaging and endoscopic studies show no evidence of sarcoidosis or Crohn disease.

Q: Given what we know so far, which of the following is the most likely diagnosis of the persistent lip swelling?

• Melkersson-Rosenthal syndrome
• Amyloidosis
• Quincke edema
• Cheilitis granulomatosa
• Cutaneous tuberculosis

A: From what we know so far, the correct answer is cheilitis granulomatosa. While this rare condition may be a feature of Melkersson-Rosenthal syndrome and amyloidosis, at this point in the evaluation these have not been confirmed. Quincke edema (ie, angioedema) is unlikely, given the ineffectiveness of previous treatment with oral antihistamines. Cutaneous tuberculosis usually presents as “lupus vulgaris,” which is characterized by solitary, small, sharply marginated, red-brown papules of gelatinous consistency (“apple-jelly nodules”), mainly on the head and neck.

Cheilitis granulomatosa is a rare inflammatory disorder¹ that primarily affects young adults. Its key feature is recurrent or persistent painless swelling of one or both lips. It may occur without other signs of disease, but it is also a manifestation of Melkersson-Rosenthal syndrome and it may be a presenting symptom of Crohn disease or, rarely, sarcoidosis.² The term “orofacial granulomatosis” was introduced to encompass the broad spectrum of nonnecrotizing granulomatous inflammation in the orofacial region, including cheilitis granulomatosa, the complete Melkersson-Rosenthal syndrome, sarcoidosis, Crohn disease, and infectious disorders such as tuberculosis.¹

The cause of cheilitis granulomatosa is unknown. Specific T-cell clonality has been identified in several patients with orofacial granulomatosis, suggesting a delayed hypersensitivity response. Moreover, the HLA haplotypes HLA-A2 and HLA-A11 have been found in 25% of patients with orofacial granulomatosis, suggesting a viral etiology. A genetic predisposition may exist in Melkersson- Rosenthal syndrome: siblings have been affected, and otherwise unaffected relatives may have a fissured tongue (lingua plicata).

Melkersson-Rosenthal syndrome, a rare condition, is characterized by a classic triad of recurrent swelling of the lips or face (or both), fissured tongue, and relapsing peripheral facial nerve paralysis. It is an unusual cause of facial swelling that can be confused with angioedema.³ This syndrome can be ruled out in this patient because he has only one of the three classic signs. Contact antigens are sometimes implicated.

DIFFERENTIAL DIAGNOSIS OF CHEILITIS GRANULOMATOSA

The differential diagnosis of cheilitis granulomatosa is extensive and includes amyloidosis, cheilitis glandularis, sarcoidosis, Crohn disease, actinic cheilitis, neoplasms, and infections, such as tuberculosis, syphilis, and leprosy.¹

As many as 11% of patients with Crohn disease may develop mucocutaneous lesions. Oral lesions of Crohn disease include apthae, cobblestoning of the buccal mucosa, swelling of one or both lips (soft or rubbery), vertical clefts of the lips, or hypertrophic gingivitis. Only 5% of patients with Crohn disease ever develop cheilitis granulomatosa, though most cases occur in children.

Ultimately, the diagnosis of cheilitis granulomatosa is made by correlating the patient’s history and clinical features, usually supported by histopathologic findings of nonnecrotic granulomas extending into the deep dermis, composed of histiocytes and giant cells and associated with a lymphomonocytic infiltrate.

TREATMENT

Treatment of cheilitis granulomatosa is difficult because the cause is unknown and the rate of recurrence is high. Response to treatment is often late and unpredictable. Corticosteroids, clofazimine (Lamprene), and surgical intervention such as cheiloplasty have been described as treatment options. Other treatment options include thalidomide (Thalomid), sulfasalazine (Sulfazine), erythromycin, azathioprine (Imuran), and cyclosporine (Sandimmune). Infliximab (Remicade) has been recently reported as a new alternative treatment, in particular for Melkersson-Rosenthal syndrome.⁴

In our patient, twice-monthly injections of 1 mL of triamcinolone acetonide 10 mg/mL into the affected lip brought acceptable improvement at 3 months. The patient is on maintenance treatment with twice-monthly triamcinolone injections and has had no relapses after 2 years.

A 44-year-old man is referred for evaluation of asymptomatic swelling of the lower lip that has persisted for 10 months. He has been treated unsuccessfully with oral antihistamines for suspected chronic angioedema. He has no other symptoms and appears to be well otherwise. He has no history of applied irritants or local trauma, and his medical history is unremarkable.

Results of the laboratory evaluation, including serum angiotensin-converting enzyme level, are normal. Patch tests to detect contact sensitivity to food additives are negative. Biopsy of the affected lip reveals dense infiltrate of the submucosal connective tissue with focal nonnecrotizing granulomas. Imaging and endoscopic studies show no evidence of sarcoidosis or Crohn disease.

Q: Given what we know so far, which of the following is the most likely diagnosis of the persistent lip swelling?

• Melkersson-Rosenthal syndrome
• Amyloidosis
• Quincke edema
• Cheilitis granulomatosa
• Cutaneous tuberculosis

A: From what we know so far, the correct answer is cheilitis granulomatosa. While this rare condition may be a feature of Melkersson-Rosenthal syndrome and amyloidosis, at this point in the evaluation these have not been confirmed. Quincke edema (ie, angioedema) is unlikely, given the ineffectiveness of previous treatment with oral antihistamines. Cutaneous tuberculosis usually presents as “lupus vulgaris,” which is characterized by solitary, small, sharply marginated, red-brown papules of gelatinous consistency (“apple-jelly nodules”), mainly on the head and neck.

Cheilitis granulomatosa is a rare inflammatory disorder¹ that primarily affects young adults. Its key feature is recurrent or persistent painless swelling of one or both lips. It may occur without other signs of disease, but it is also a manifestation of Melkersson-Rosenthal syndrome and it may be a presenting symptom of Crohn disease or, rarely, sarcoidosis.² The term “orofacial granulomatosis” was introduced to encompass the broad spectrum of nonnecrotizing granulomatous inflammation in the orofacial region, including cheilitis granulomatosa, the complete Melkersson-Rosenthal syndrome, sarcoidosis, Crohn disease, and infectious disorders such as tuberculosis.¹

The cause of cheilitis granulomatosa is unknown. Specific T-cell clonality has been identified in several patients with orofacial granulomatosis, suggesting a delayed hypersensitivity response. Moreover, the HLA haplotypes HLA-A2 and HLA-A11 have been found in 25% of patients with orofacial granulomatosis, suggesting a viral etiology. A genetic predisposition may exist in Melkersson- Rosenthal syndrome: siblings have been affected, and otherwise unaffected relatives may have a fissured tongue (lingua plicata).

Melkersson-Rosenthal syndrome, a rare condition, is characterized by a classic triad of recurrent swelling of the lips or face (or both), fissured tongue, and relapsing peripheral facial nerve paralysis. It is an unusual cause of facial swelling that can be confused with angioedema.³ This syndrome can be ruled out in this patient because he has only one of the three classic signs. Contact antigens are sometimes implicated.

DIFFERENTIAL DIAGNOSIS OF CHEILITIS GRANULOMATOSA

The differential diagnosis of cheilitis granulomatosa is extensive and includes amyloidosis, cheilitis glandularis, sarcoidosis, Crohn disease, actinic cheilitis, neoplasms, and infections, such as tuberculosis, syphilis, and leprosy.¹

As many as 11% of patients with Crohn disease may develop mucocutaneous lesions. Oral lesions of Crohn disease include apthae, cobblestoning of the buccal mucosa, swelling of one or both lips (soft or rubbery), vertical clefts of the lips, or hypertrophic gingivitis. Only 5% of patients with Crohn disease ever develop cheilitis granulomatosa, though most cases occur in children.

Ultimately, the diagnosis of cheilitis granulomatosa is made by correlating the patient’s history and clinical features, usually supported by histopathologic findings of nonnecrotic granulomas extending into the deep dermis, composed of histiocytes and giant cells and associated with a lymphomonocytic infiltrate.

TREATMENT

Treatment of cheilitis granulomatosa is difficult because the cause is unknown and the rate of recurrence is high. Response to treatment is often late and unpredictable. Corticosteroids, clofazimine (Lamprene), and surgical intervention such as cheiloplasty have been described as treatment options. Other treatment options include thalidomide (Thalomid), sulfasalazine (Sulfazine), erythromycin, azathioprine (Imuran), and cyclosporine (Sandimmune). Infliximab (Remicade) has been recently reported as a new alternative treatment, in particular for Melkersson-Rosenthal syndrome.⁴

In our patient, twice-monthly injections of 1 mL of triamcinolone acetonide 10 mg/mL into the affected lip brought acceptable improvement at 3 months. The patient is on maintenance treatment with twice-monthly triamcinolone injections and has had no relapses after 2 years.

A 71-year-old man presents for evaluation of an asymptomatic black discoloration of the tongue that he noticed several days earlier. The tongue does not itch or hurt, and the patient is otherwise well, although he is concerned about potential malignancy.

He has a history of hypertension, hyperuricemia, and type 2 diabetes treated with oral glucose-lowering drugs, and he has had no recent changes in his medications. He drinks coffee and uses tobacco. His oral hygiene is poor, with intense halitosis.

Q: What is the most likely diagnosis?

• Oral leukoplakia
• Epidermoid carcinoma of the tongue
• Malignant melanoma of the tongue
• Mucosal candidiasis
• Black hairy tongue

A: Black hairy tongue is correct. A simple treatment consisting of brushing the tongue daily with a soft toothbrush enhanced by previous application of 30% urea is recommended to the patient, and the discoloration resolves completely within 4 weeks. He is educated on correct oral hygiene and discontinues smoking, with no clinical relapses after 2 years of follow-up.

THE CAUSES AND THE COURSE

Black hairy tongue, also known as lingua villosa nigra, is a painless, benign disorder caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. The hairy appearance is due to elongation of keratinized filiform papillae, which may have different colors, varying from white to yellowish brown to black depending on extrinsic factors (eg, tobacco, coffee, tea, food) and intrinsic factors (ie, chromogenic organisms in normal flora).¹

The exact pathogenesis is unclear. Precipitating factors include poor oral hygiene, use of the antipsychotic drug olanzapine¹ (Zyprexa) or a broad-spectrum antibiotic such as erythromycin,² and therapeutic radiation of the head and the neck. Tobacco use and drinking coffee and tea are also contributory factors. Neurologic conditions such as trigeminal neuropathy may be associated. ³ Manabe et al⁴ applied a panel of antikeratin probes, showing that defective desquamation of the cells in the central column of filiform papillae resulted in the formation of highly elongated, cornified spines or “hairs”—the hallmark of lingua villosa nigra.

PRESENTATION AND DIAGNOSIS

Black hairy tongue is usually asymptomatic. However, symptoms such as altered (metallic) taste, nausea, or halitosis may be noted. Most patients with hairy tongue drink coffee or tea, often in addition to tobacco use.

The diagnosis is based on filiform papillae that are elongated more than 3 mm on the dorsal surface of the tongue. Cultures may be taken to rule out a superimposed oral candidiasis or other suspected oral infection.

MANAGEMENT

Although frightening to the patient, black hairy tongue is completely harmless. In most cases, treatment does not require drugs. If fungal overgrowth is present, a topical antifungal can be used when the condition is symptomatic.

Empirical approaches such as brushing or scraping the tongue, improving oral hygiene, and eliminating potential offending factors (eg, tobacco, candies, strong mouthwashes, antibiotics) is usually sufficient to resolve the lesions.⁵

In our experience, educating the patient about proper oral hygiene (including discontinuing smoking) and encouraging routine tongue brushing are the best preventive and therapeutic measures.

A 71-year-old man presents for evaluation of an asymptomatic black discoloration of the tongue that he noticed several days earlier. The tongue does not itch or hurt, and the patient is otherwise well, although he is concerned about potential malignancy.

He has a history of hypertension, hyperuricemia, and type 2 diabetes treated with oral glucose-lowering drugs, and he has had no recent changes in his medications. He drinks coffee and uses tobacco. His oral hygiene is poor, with intense halitosis.

Q: What is the most likely diagnosis?

• Oral leukoplakia
• Epidermoid carcinoma of the tongue
• Malignant melanoma of the tongue
• Mucosal candidiasis
• Black hairy tongue

A: Black hairy tongue is correct. A simple treatment consisting of brushing the tongue daily with a soft toothbrush enhanced by previous application of 30% urea is recommended to the patient, and the discoloration resolves completely within 4 weeks. He is educated on correct oral hygiene and discontinues smoking, with no clinical relapses after 2 years of follow-up.

THE CAUSES AND THE COURSE

Black hairy tongue, also known as lingua villosa nigra, is a painless, benign disorder caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. The hairy appearance is due to elongation of keratinized filiform papillae, which may have different colors, varying from white to yellowish brown to black depending on extrinsic factors (eg, tobacco, coffee, tea, food) and intrinsic factors (ie, chromogenic organisms in normal flora).¹

The exact pathogenesis is unclear. Precipitating factors include poor oral hygiene, use of the antipsychotic drug olanzapine¹ (Zyprexa) or a broad-spectrum antibiotic such as erythromycin,² and therapeutic radiation of the head and the neck. Tobacco use and drinking coffee and tea are also contributory factors. Neurologic conditions such as trigeminal neuropathy may be associated. ³ Manabe et al⁴ applied a panel of antikeratin probes, showing that defective desquamation of the cells in the central column of filiform papillae resulted in the formation of highly elongated, cornified spines or “hairs”—the hallmark of lingua villosa nigra.

PRESENTATION AND DIAGNOSIS

Black hairy tongue is usually asymptomatic. However, symptoms such as altered (metallic) taste, nausea, or halitosis may be noted. Most patients with hairy tongue drink coffee or tea, often in addition to tobacco use.

The diagnosis is based on filiform papillae that are elongated more than 3 mm on the dorsal surface of the tongue. Cultures may be taken to rule out a superimposed oral candidiasis or other suspected oral infection.

MANAGEMENT

Although frightening to the patient, black hairy tongue is completely harmless. In most cases, treatment does not require drugs. If fungal overgrowth is present, a topical antifungal can be used when the condition is symptomatic.

Empirical approaches such as brushing or scraping the tongue, improving oral hygiene, and eliminating potential offending factors (eg, tobacco, candies, strong mouthwashes, antibiotics) is usually sufficient to resolve the lesions.⁵

In our experience, educating the patient about proper oral hygiene (including discontinuing smoking) and encouraging routine tongue brushing are the best preventive and therapeutic measures.

A 71-year-old man presents for evaluation of an asymptomatic black discoloration of the tongue that he noticed several days earlier. The tongue does not itch or hurt, and the patient is otherwise well, although he is concerned about potential malignancy.

He has a history of hypertension, hyperuricemia, and type 2 diabetes treated with oral glucose-lowering drugs, and he has had no recent changes in his medications. He drinks coffee and uses tobacco. His oral hygiene is poor, with intense halitosis.

Q: What is the most likely diagnosis?

• Oral leukoplakia
• Epidermoid carcinoma of the tongue
• Malignant melanoma of the tongue
• Mucosal candidiasis
• Black hairy tongue

A: Black hairy tongue is correct. A simple treatment consisting of brushing the tongue daily with a soft toothbrush enhanced by previous application of 30% urea is recommended to the patient, and the discoloration resolves completely within 4 weeks. He is educated on correct oral hygiene and discontinues smoking, with no clinical relapses after 2 years of follow-up.

THE CAUSES AND THE COURSE

Black hairy tongue, also known as lingua villosa nigra, is a painless, benign disorder caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. The hairy appearance is due to elongation of keratinized filiform papillae, which may have different colors, varying from white to yellowish brown to black depending on extrinsic factors (eg, tobacco, coffee, tea, food) and intrinsic factors (ie, chromogenic organisms in normal flora).¹

The exact pathogenesis is unclear. Precipitating factors include poor oral hygiene, use of the antipsychotic drug olanzapine¹ (Zyprexa) or a broad-spectrum antibiotic such as erythromycin,² and therapeutic radiation of the head and the neck. Tobacco use and drinking coffee and tea are also contributory factors. Neurologic conditions such as trigeminal neuropathy may be associated. ³ Manabe et al⁴ applied a panel of antikeratin probes, showing that defective desquamation of the cells in the central column of filiform papillae resulted in the formation of highly elongated, cornified spines or “hairs”—the hallmark of lingua villosa nigra.

PRESENTATION AND DIAGNOSIS

Black hairy tongue is usually asymptomatic. However, symptoms such as altered (metallic) taste, nausea, or halitosis may be noted. Most patients with hairy tongue drink coffee or tea, often in addition to tobacco use.

The diagnosis is based on filiform papillae that are elongated more than 3 mm on the dorsal surface of the tongue. Cultures may be taken to rule out a superimposed oral candidiasis or other suspected oral infection.

MANAGEMENT

Although frightening to the patient, black hairy tongue is completely harmless. In most cases, treatment does not require drugs. If fungal overgrowth is present, a topical antifungal can be used when the condition is symptomatic.

Empirical approaches such as brushing or scraping the tongue, improving oral hygiene, and eliminating potential offending factors (eg, tobacco, candies, strong mouthwashes, antibiotics) is usually sufficient to resolve the lesions.⁵

In our experience, educating the patient about proper oral hygiene (including discontinuing smoking) and encouraging routine tongue brushing are the best preventive and therapeutic measures.

(Photo courtesy of Dr. Michelle Bennett)

Q: Which is the best diagnosis?

• Seborrheic keratosis
• Pigmented basal cell carcinoma
• Congenital nevus
• Lentigo maligna melanoma
• Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.¹ Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.²

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.^3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,⁵ but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

(Photo courtesy of Dr. Michelle Bennett)

Q: Which is the best diagnosis?

• Seborrheic keratosis
• Pigmented basal cell carcinoma
• Congenital nevus
• Lentigo maligna melanoma
• Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.¹ Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.²

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.^3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,⁵ but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

(Photo courtesy of Dr. Michelle Bennett)

Q: Which is the best diagnosis?

• Seborrheic keratosis
• Pigmented basal cell carcinoma
• Congenital nevus
• Lentigo maligna melanoma
• Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.¹ Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.²

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.^3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,⁵ but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

A 51-year-old diabetic man presents with a 1-year history of episodic pain, swelling, and stiffness in some of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of his fingers. During these episodes, he has significant morning stiffness. He says he has no other joint problems or back pain. A review of systems is otherwise unremarkable.

WHAT IS THE MOST LIKELY DIAGNOSIS?

• Gouty tophi
• Rheumatoid nodulosis
• Calcinosis cutis
• Tuberous xanthomas

GOUTY TOPHI: OUR INITIAL IMPRESSION

RHEUMATOID NODULOSIS: THE TRUE DIAGNOSIS

The patient’s nodules kept growing, and new ones kept developing, causing significant impairment of hand function. Hence, some of the larger nodules were surgically removed. The resected specimens revealed a yellow nodular cut surface on sectioning. Histopathologic analysis revealed multiple necrobiotic nodules, consistent with rheumatoid nodulosis. Urate crystals were not seen on histology, although crystals can be dissolved in some tissue preparations, and gouty tophi provoke pathologically a granulomatous inflammatory reaction. However, unlike what is expected with gouty tophi, material aspirated from the nodules did not reveal monosodium urate crystals on polarized light microscopy. A repeat rheumatoid factor test 2 years after his initial presentation became positive at 57 IU/ mL (normal < 20 IU/mL).

Comment. Rheumatoid nodules are one of the most common extra-articular manifestations of rheumatoid arthritis, seen in 20% to 25% of cases, and they are usually associated with seropositivity for rheumatoid factor and with more aggressive disease.¹ Rheumatoid nodulosis, on the other hand, usually runs a more benign clinical course.² It was first described in 1949,³ and the diagnostic criteria were developed in 1988 by Couret et al.⁴ Patients develop nontender subcutaneous rheumatoid nodules, usually around areas of repeated microtrauma.² Often there is a history of attacks of palindromic rheumatism, characterized by recurrent, self-limited episodes of monoarthritis or polyarthritis without an alternative explanation, as in this patient. However, systemic manifestations of rheumatoid arthritis and radiologic evidence of joint damage are often not seen. Rheumatoid factor positivity is also not a requirement. Over time, some patients progress to full-blown rheumatoid arthritis. Methotrexate use has been associated with accelerated rheumatoid nodulosis in some rheumatoid arthritis patients.²

Rheumatoid nodulosis can be progressive and difficult to treat. Hydroxychloroquine has induced complete resolution in some cases.⁵ Surgical removal of the nodules may be considered if they limit joint motion.⁶ A placebo-controlled, double-blind trial of intralesional corticosteroid injection has demonstrated efficacy in reducing nodule size.⁷

In our patient, treatment with hydroxychloroquine, sulfasalazine, and methotrexate did not relieve the joint pain, nor did these drugs stop the nodules from growing. He was started on the tumor necrosis factor antagonist etanercept (Enbrel), which significantly helped the joint pain, but the nodules continued to progress relentlessly. Some of the larger nodules were later injected with triamcinolone (Kenalog), which led to significant shrinkage in nodule size.

THE OTHER DIAGNOSTIC CHOICES

The other two choices are unlikely.

Calcinosis cutis results from the cutaneous deposition of insoluble compounds of calcium (hydroxyapatite or amorphous calcium phosphate), due to local or systemic factors, or both. This can be the result either of ectopic calcification in normal tissue in the setting of hypercalcemia or hyperphosphatemia, or of dystrophic calcification in damaged tissue. They appear as multiple, firm, whitish dermal papules, plaques, nodules, or subcutaneous nodules, which can sometimes ulcerate. They are radio-opaque. On biopsy, dermal deposits of calcium are seen, with or without a surrounding foreign-body giant-cell reaction. Calcium deposition may be confirmed on Von Kossa and alizarin red stains.

Tuberous xanthomas are firm, painless, red-yellow nodules that usually develop in pressure areas such as the extensor surfaces of the knees, the elbows, and the buttocks. They can be associated with familial dysbetalipoproteinemia, familial hypercholesterolemia, and even some of the secondary dyslipidemias. Histologic study shows accumulations of vacuolated lipid-laden macrophages (foamy histiocytes) and sometimes multinucleated histiocytes (Touton giant cells). The lipid droplets are dissolved during routine histologic processing, but lipid stains on frozen sections can be useful.

A 51-year-old diabetic man presents with a 1-year history of episodic pain, swelling, and stiffness in some of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of his fingers. During these episodes, he has significant morning stiffness. He says he has no other joint problems or back pain. A review of systems is otherwise unremarkable.

WHAT IS THE MOST LIKELY DIAGNOSIS?

• Gouty tophi
• Rheumatoid nodulosis
• Calcinosis cutis
• Tuberous xanthomas

GOUTY TOPHI: OUR INITIAL IMPRESSION

RHEUMATOID NODULOSIS: THE TRUE DIAGNOSIS

The patient’s nodules kept growing, and new ones kept developing, causing significant impairment of hand function. Hence, some of the larger nodules were surgically removed. The resected specimens revealed a yellow nodular cut surface on sectioning. Histopathologic analysis revealed multiple necrobiotic nodules, consistent with rheumatoid nodulosis. Urate crystals were not seen on histology, although crystals can be dissolved in some tissue preparations, and gouty tophi provoke pathologically a granulomatous inflammatory reaction. However, unlike what is expected with gouty tophi, material aspirated from the nodules did not reveal monosodium urate crystals on polarized light microscopy. A repeat rheumatoid factor test 2 years after his initial presentation became positive at 57 IU/ mL (normal < 20 IU/mL).

Comment. Rheumatoid nodules are one of the most common extra-articular manifestations of rheumatoid arthritis, seen in 20% to 25% of cases, and they are usually associated with seropositivity for rheumatoid factor and with more aggressive disease.¹ Rheumatoid nodulosis, on the other hand, usually runs a more benign clinical course.² It was first described in 1949,³ and the diagnostic criteria were developed in 1988 by Couret et al.⁴ Patients develop nontender subcutaneous rheumatoid nodules, usually around areas of repeated microtrauma.² Often there is a history of attacks of palindromic rheumatism, characterized by recurrent, self-limited episodes of monoarthritis or polyarthritis without an alternative explanation, as in this patient. However, systemic manifestations of rheumatoid arthritis and radiologic evidence of joint damage are often not seen. Rheumatoid factor positivity is also not a requirement. Over time, some patients progress to full-blown rheumatoid arthritis. Methotrexate use has been associated with accelerated rheumatoid nodulosis in some rheumatoid arthritis patients.²

Rheumatoid nodulosis can be progressive and difficult to treat. Hydroxychloroquine has induced complete resolution in some cases.⁵ Surgical removal of the nodules may be considered if they limit joint motion.⁶ A placebo-controlled, double-blind trial of intralesional corticosteroid injection has demonstrated efficacy in reducing nodule size.⁷

In our patient, treatment with hydroxychloroquine, sulfasalazine, and methotrexate did not relieve the joint pain, nor did these drugs stop the nodules from growing. He was started on the tumor necrosis factor antagonist etanercept (Enbrel), which significantly helped the joint pain, but the nodules continued to progress relentlessly. Some of the larger nodules were later injected with triamcinolone (Kenalog), which led to significant shrinkage in nodule size.

THE OTHER DIAGNOSTIC CHOICES

The other two choices are unlikely.

Calcinosis cutis results from the cutaneous deposition of insoluble compounds of calcium (hydroxyapatite or amorphous calcium phosphate), due to local or systemic factors, or both. This can be the result either of ectopic calcification in normal tissue in the setting of hypercalcemia or hyperphosphatemia, or of dystrophic calcification in damaged tissue. They appear as multiple, firm, whitish dermal papules, plaques, nodules, or subcutaneous nodules, which can sometimes ulcerate. They are radio-opaque. On biopsy, dermal deposits of calcium are seen, with or without a surrounding foreign-body giant-cell reaction. Calcium deposition may be confirmed on Von Kossa and alizarin red stains.

Tuberous xanthomas are firm, painless, red-yellow nodules that usually develop in pressure areas such as the extensor surfaces of the knees, the elbows, and the buttocks. They can be associated with familial dysbetalipoproteinemia, familial hypercholesterolemia, and even some of the secondary dyslipidemias. Histologic study shows accumulations of vacuolated lipid-laden macrophages (foamy histiocytes) and sometimes multinucleated histiocytes (Touton giant cells). The lipid droplets are dissolved during routine histologic processing, but lipid stains on frozen sections can be useful.

A 51-year-old diabetic man presents with a 1-year history of episodic pain, swelling, and stiffness in some of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of his fingers. During these episodes, he has significant morning stiffness. He says he has no other joint problems or back pain. A review of systems is otherwise unremarkable.

WHAT IS THE MOST LIKELY DIAGNOSIS?

• Gouty tophi
• Rheumatoid nodulosis
• Calcinosis cutis
• Tuberous xanthomas

GOUTY TOPHI: OUR INITIAL IMPRESSION

RHEUMATOID NODULOSIS: THE TRUE DIAGNOSIS

The patient’s nodules kept growing, and new ones kept developing, causing significant impairment of hand function. Hence, some of the larger nodules were surgically removed. The resected specimens revealed a yellow nodular cut surface on sectioning. Histopathologic analysis revealed multiple necrobiotic nodules, consistent with rheumatoid nodulosis. Urate crystals were not seen on histology, although crystals can be dissolved in some tissue preparations, and gouty tophi provoke pathologically a granulomatous inflammatory reaction. However, unlike what is expected with gouty tophi, material aspirated from the nodules did not reveal monosodium urate crystals on polarized light microscopy. A repeat rheumatoid factor test 2 years after his initial presentation became positive at 57 IU/ mL (normal < 20 IU/mL).

Comment. Rheumatoid nodules are one of the most common extra-articular manifestations of rheumatoid arthritis, seen in 20% to 25% of cases, and they are usually associated with seropositivity for rheumatoid factor and with more aggressive disease.¹ Rheumatoid nodulosis, on the other hand, usually runs a more benign clinical course.² It was first described in 1949,³ and the diagnostic criteria were developed in 1988 by Couret et al.⁴ Patients develop nontender subcutaneous rheumatoid nodules, usually around areas of repeated microtrauma.² Often there is a history of attacks of palindromic rheumatism, characterized by recurrent, self-limited episodes of monoarthritis or polyarthritis without an alternative explanation, as in this patient. However, systemic manifestations of rheumatoid arthritis and radiologic evidence of joint damage are often not seen. Rheumatoid factor positivity is also not a requirement. Over time, some patients progress to full-blown rheumatoid arthritis. Methotrexate use has been associated with accelerated rheumatoid nodulosis in some rheumatoid arthritis patients.²

Rheumatoid nodulosis can be progressive and difficult to treat. Hydroxychloroquine has induced complete resolution in some cases.⁵ Surgical removal of the nodules may be considered if they limit joint motion.⁶ A placebo-controlled, double-blind trial of intralesional corticosteroid injection has demonstrated efficacy in reducing nodule size.⁷

In our patient, treatment with hydroxychloroquine, sulfasalazine, and methotrexate did not relieve the joint pain, nor did these drugs stop the nodules from growing. He was started on the tumor necrosis factor antagonist etanercept (Enbrel), which significantly helped the joint pain, but the nodules continued to progress relentlessly. Some of the larger nodules were later injected with triamcinolone (Kenalog), which led to significant shrinkage in nodule size.

THE OTHER DIAGNOSTIC CHOICES

The other two choices are unlikely.

Calcinosis cutis results from the cutaneous deposition of insoluble compounds of calcium (hydroxyapatite or amorphous calcium phosphate), due to local or systemic factors, or both. This can be the result either of ectopic calcification in normal tissue in the setting of hypercalcemia or hyperphosphatemia, or of dystrophic calcification in damaged tissue. They appear as multiple, firm, whitish dermal papules, plaques, nodules, or subcutaneous nodules, which can sometimes ulcerate. They are radio-opaque. On biopsy, dermal deposits of calcium are seen, with or without a surrounding foreign-body giant-cell reaction. Calcium deposition may be confirmed on Von Kossa and alizarin red stains.

Tuberous xanthomas are firm, painless, red-yellow nodules that usually develop in pressure areas such as the extensor surfaces of the knees, the elbows, and the buttocks. They can be associated with familial dysbetalipoproteinemia, familial hypercholesterolemia, and even some of the secondary dyslipidemias. Histologic study shows accumulations of vacuolated lipid-laden macrophages (foamy histiocytes) and sometimes multinucleated histiocytes (Touton giant cells). The lipid droplets are dissolved during routine histologic processing, but lipid stains on frozen sections can be useful.

A 30-year-old woman has a 6-month history of episodes of sudden loss of hair in well-demarcated, localized areas of her scalp. She is otherwise well and has had no pruritus or pain. She has had atopic dermatitis since childhood, occasionally treated with topical corticosteroids, and localized facial vitiligo for the past 8 years. She takes no systemic drugs. She has no family history of similar lesions.

Q: What is the most likely diagnosis?

• Telogen effluvium
• Syphilitic alopecia
• Alopecia areata
• Trichotillomania
• Androgenetic alopecia

A: The correct answer is alopecia areata, a disease characterized by recurrent episodes of sudden hair loss and nail changes such as trachyonychia. It can affect any hair-bearing area, but the scalp is the most common site (90% of cases).¹ The condition can range from a single patch of hair loss to complete loss of hair on the scalp (alopecia totalis) or the entire body (alopecia universalis).

The characteristic lesion is a round or oval, totally bald, smooth patch, which may have a mild peachy hue. A frequent feature is “exclamation-mark” hairs at the margin of the patch, appearing as broad distal hair shafts, narrow proximally. Active alopecia areata can be confirmed with a positive hair-pull test.

Nail involvement is common in alopecia areata, particularly in severe forms. Pitting is the most common finding, but other abnormalities such as trachyonychia have been reported.¹ Nail plate pitting tends to be more shallow and regularly spaced than in psori-atic nail pitting. Trachyonychia, also known as “twenty-nail dystrophy,” is the term used to describe nail plate roughness, pitting, and ridging, affecting 1 to 20 nails. It is associated with a number of skin conditions, including alopecia areata, psoriasis, lichen planus, atopic dermatitis, and ichthyosis vulgaris.⁴

AN AUTOIMMUNE DISEASE

The precise cause of this common disorder has not been elucidated, but substantial evidence suggests that it is an organ-specific autoimmune disease that targets hair follicles.^1–3

The current hypothesis is that the hair follicle is a site of immune privilege. In alopecia areata, increased expression of major histocompatibility complex class I molecules and down-regulation of immunosuppressants allows the immune system to recognize the immune-privileged follicle antigens.² Several autoimmune diseases, such as thyroid disorders, vitiligo, pernicious anemia, diabetes mellitus, lupus erythematosus, myasthenia gravis, lichen planus, autoimmune polyendocrine syndrome type I, and celiac disease, have been reported in association with alopecia areata¹; thyroid disorders and vitiligo have the strongest relationship. Other diseases reported to be associated with alopecia areata at a higher rate than in the general population are atopic dermatitis and Down syndrome.¹

NO CURE, BUT TREATABLE

The choice of treatment depends on the patient’s age and the extent of alopecia activity.⁵ No cure or preventive treatment has been found, so treatments are directed toward halting disease activity.

Corticosteroids are currently the most popular form of treatment, and published reports support their efficacy.¹ Topical and intralesional steroids are usually the first-line treatment for localized disease. Systemic steroids are rarely used, except in cases with rapid progression.

Other treatments that have been used with some success include minoxidil (Rogaine), anthralin (Dritho-Scalp), contact sensitizers (dinitrochlorobenzene, diphenylcycloprope-none), PUVA (psoralen plus ultraviolet A light), and cyclosporine (Sandimmune).¹ If the alopecia is resistant to therapy, hair pros-theses can be recommended.

Indicators of poor prognosis (ie, hair that will not regrow completely) include atopy, the presence of other immune diseases, young age at onset, family history, nail dystrophy, extensive hair loss, and ophiasis (a continuous band of baldness involving the temporal and occipital margins).

Because current treatments may not bring results for 3 to 6 months, it is essential to reassure and inform the patient about the results that can be expected. Physicians should also inform patients of the chronic relapsing nature of alopecia areata and its unpredictable course. Although the condition does not threaten the patient’s general health and does not cause scarring, its psychological impact is significant. Support groups such as the National Alopecia Areata Foundation (www.naaf.org) can help.

A 30-year-old woman has a 6-month history of episodes of sudden loss of hair in well-demarcated, localized areas of her scalp. She is otherwise well and has had no pruritus or pain. She has had atopic dermatitis since childhood, occasionally treated with topical corticosteroids, and localized facial vitiligo for the past 8 years. She takes no systemic drugs. She has no family history of similar lesions.

Q: What is the most likely diagnosis?

• Telogen effluvium
• Syphilitic alopecia
• Alopecia areata
• Trichotillomania
• Androgenetic alopecia

A: The correct answer is alopecia areata, a disease characterized by recurrent episodes of sudden hair loss and nail changes such as trachyonychia. It can affect any hair-bearing area, but the scalp is the most common site (90% of cases).¹ The condition can range from a single patch of hair loss to complete loss of hair on the scalp (alopecia totalis) or the entire body (alopecia universalis).

The characteristic lesion is a round or oval, totally bald, smooth patch, which may have a mild peachy hue. A frequent feature is “exclamation-mark” hairs at the margin of the patch, appearing as broad distal hair shafts, narrow proximally. Active alopecia areata can be confirmed with a positive hair-pull test.

Nail involvement is common in alopecia areata, particularly in severe forms. Pitting is the most common finding, but other abnormalities such as trachyonychia have been reported.¹ Nail plate pitting tends to be more shallow and regularly spaced than in psori-atic nail pitting. Trachyonychia, also known as “twenty-nail dystrophy,” is the term used to describe nail plate roughness, pitting, and ridging, affecting 1 to 20 nails. It is associated with a number of skin conditions, including alopecia areata, psoriasis, lichen planus, atopic dermatitis, and ichthyosis vulgaris.⁴

AN AUTOIMMUNE DISEASE

The precise cause of this common disorder has not been elucidated, but substantial evidence suggests that it is an organ-specific autoimmune disease that targets hair follicles.^1–3

The current hypothesis is that the hair follicle is a site of immune privilege. In alopecia areata, increased expression of major histocompatibility complex class I molecules and down-regulation of immunosuppressants allows the immune system to recognize the immune-privileged follicle antigens.² Several autoimmune diseases, such as thyroid disorders, vitiligo, pernicious anemia, diabetes mellitus, lupus erythematosus, myasthenia gravis, lichen planus, autoimmune polyendocrine syndrome type I, and celiac disease, have been reported in association with alopecia areata¹; thyroid disorders and vitiligo have the strongest relationship. Other diseases reported to be associated with alopecia areata at a higher rate than in the general population are atopic dermatitis and Down syndrome.¹

NO CURE, BUT TREATABLE

The choice of treatment depends on the patient’s age and the extent of alopecia activity.⁵ No cure or preventive treatment has been found, so treatments are directed toward halting disease activity.

Corticosteroids are currently the most popular form of treatment, and published reports support their efficacy.¹ Topical and intralesional steroids are usually the first-line treatment for localized disease. Systemic steroids are rarely used, except in cases with rapid progression.

Other treatments that have been used with some success include minoxidil (Rogaine), anthralin (Dritho-Scalp), contact sensitizers (dinitrochlorobenzene, diphenylcycloprope-none), PUVA (psoralen plus ultraviolet A light), and cyclosporine (Sandimmune).¹ If the alopecia is resistant to therapy, hair pros-theses can be recommended.

Indicators of poor prognosis (ie, hair that will not regrow completely) include atopy, the presence of other immune diseases, young age at onset, family history, nail dystrophy, extensive hair loss, and ophiasis (a continuous band of baldness involving the temporal and occipital margins).

Because current treatments may not bring results for 3 to 6 months, it is essential to reassure and inform the patient about the results that can be expected. Physicians should also inform patients of the chronic relapsing nature of alopecia areata and its unpredictable course. Although the condition does not threaten the patient’s general health and does not cause scarring, its psychological impact is significant. Support groups such as the National Alopecia Areata Foundation (www.naaf.org) can help.

A 30-year-old woman has a 6-month history of episodes of sudden loss of hair in well-demarcated, localized areas of her scalp. She is otherwise well and has had no pruritus or pain. She has had atopic dermatitis since childhood, occasionally treated with topical corticosteroids, and localized facial vitiligo for the past 8 years. She takes no systemic drugs. She has no family history of similar lesions.

Q: What is the most likely diagnosis?

• Telogen effluvium
• Syphilitic alopecia
• Alopecia areata
• Trichotillomania
• Androgenetic alopecia

A: The correct answer is alopecia areata, a disease characterized by recurrent episodes of sudden hair loss and nail changes such as trachyonychia. It can affect any hair-bearing area, but the scalp is the most common site (90% of cases).¹ The condition can range from a single patch of hair loss to complete loss of hair on the scalp (alopecia totalis) or the entire body (alopecia universalis).

The characteristic lesion is a round or oval, totally bald, smooth patch, which may have a mild peachy hue. A frequent feature is “exclamation-mark” hairs at the margin of the patch, appearing as broad distal hair shafts, narrow proximally. Active alopecia areata can be confirmed with a positive hair-pull test.

Nail involvement is common in alopecia areata, particularly in severe forms. Pitting is the most common finding, but other abnormalities such as trachyonychia have been reported.¹ Nail plate pitting tends to be more shallow and regularly spaced than in psori-atic nail pitting. Trachyonychia, also known as “twenty-nail dystrophy,” is the term used to describe nail plate roughness, pitting, and ridging, affecting 1 to 20 nails. It is associated with a number of skin conditions, including alopecia areata, psoriasis, lichen planus, atopic dermatitis, and ichthyosis vulgaris.⁴

AN AUTOIMMUNE DISEASE

The precise cause of this common disorder has not been elucidated, but substantial evidence suggests that it is an organ-specific autoimmune disease that targets hair follicles.^1–3

The current hypothesis is that the hair follicle is a site of immune privilege. In alopecia areata, increased expression of major histocompatibility complex class I molecules and down-regulation of immunosuppressants allows the immune system to recognize the immune-privileged follicle antigens.² Several autoimmune diseases, such as thyroid disorders, vitiligo, pernicious anemia, diabetes mellitus, lupus erythematosus, myasthenia gravis, lichen planus, autoimmune polyendocrine syndrome type I, and celiac disease, have been reported in association with alopecia areata¹; thyroid disorders and vitiligo have the strongest relationship. Other diseases reported to be associated with alopecia areata at a higher rate than in the general population are atopic dermatitis and Down syndrome.¹

NO CURE, BUT TREATABLE

The choice of treatment depends on the patient’s age and the extent of alopecia activity.⁵ No cure or preventive treatment has been found, so treatments are directed toward halting disease activity.

Corticosteroids are currently the most popular form of treatment, and published reports support their efficacy.¹ Topical and intralesional steroids are usually the first-line treatment for localized disease. Systemic steroids are rarely used, except in cases with rapid progression.

Other treatments that have been used with some success include minoxidil (Rogaine), anthralin (Dritho-Scalp), contact sensitizers (dinitrochlorobenzene, diphenylcycloprope-none), PUVA (psoralen plus ultraviolet A light), and cyclosporine (Sandimmune).¹ If the alopecia is resistant to therapy, hair pros-theses can be recommended.

Indicators of poor prognosis (ie, hair that will not regrow completely) include atopy, the presence of other immune diseases, young age at onset, family history, nail dystrophy, extensive hair loss, and ophiasis (a continuous band of baldness involving the temporal and occipital margins).

Because current treatments may not bring results for 3 to 6 months, it is essential to reassure and inform the patient about the results that can be expected. Physicians should also inform patients of the chronic relapsing nature of alopecia areata and its unpredictable course. Although the condition does not threaten the patient’s general health and does not cause scarring, its psychological impact is significant. Support groups such as the National Alopecia Areata Foundation (www.naaf.org) can help.