Xia Y

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients.