Nodular lymphangitis: Report of a case with presentation of a diagnostic paradigm
- Author(s): Giordano, Cerrene Nicole;
- Kalb, Robert E;
- Brass, Corstiaan;
- Lin, Lin;
- Helm, Thomas N
- et al.
Published Web Locationhttps://doi.org/10.5070/D342f9h4sk
Nodular lymphangitis: Report of a case with presentation of a diagnostic paradigmUniversity at Buffalo School of Medicine and Biomedical Sciences
Cerrene Nicole Giordano BS, Robert E Kalb MD, Corstiaan Brass MD, Lin Lin MD PhD, Thomas N Helm MD
Dermatology Online Journal 16 (9): 1
A 54-year-old man with asthma, mitral valve prolapse, and a back injury developed erythematous nodules that progressed along the lymphatic drainage of his right arm. Skin biopsy revealed granulomatous inflammation with microabscess formation. Culture confirmed Mycobacterium marinum infection. The patient was treated with clarithromycin, ethambutol, rifampin, and topical silver sulfadiazine. Oral doxycycline hyclate was later added because of slow healing. Mycobacterium marinum is one of a group of infectious agents that can cause nodular lymphangitis. Sporotrichoid lesions most commonly develop after cutaneous inoculation with Sporothrix schenckii, Leishmania species, Nocardia species, and Mycobacterium marinum. A thorough clinical history and physical examination can narrow the differential diagnosis by eliciting information about the etiologic setting, incubation time, clinical appearance of the lesions, and presence or absence of systemic involvement for each of the causative organisms. Skin biopsy and microbiological tissue cultures are essential for diagnostic confirmation. The differential diagnosis and a suggested diagnostic paradigm will be reviewed.
Nodular lymphangitis describes a characteristic clinical presentation in which erythematous papules and nodules are located along the site of lymphatic drainage. Clinical clues, history, and a focused diagnostic workup can usually lead to a rapid and accurate diagnosis. We report a case and discuss the diagnostic workup and differential diagnosis.
2. Clinical presentation
A 54-year-old man presented with a nodule on the right hand. He had noted injury to the right third finger while retrieving something from a drawer near his sink. A splinter entered the skin and he developed erythema over the next five days near his injury. He developed nodules over the following two weeks. The nodules extended up his wrist and forearm. The nodules were erythematous and tender. Trochlear lymphadenopathy was noted without any other accompanying adenopathy. His past history was remarkable for mitral valve prolapse and asthma as well as disability caused by a prior back injury. He was formerly employed as a therapist at a psychiatric center. His hobbies included collecting coins and studying dogs and tropical plants. He owned a fish aquarium. He had no known allergies.
|Figure 1||Figure 2|
|Figure 1. Nodular and erythematous lesions on the right hand and arm following the lymphatic drainage|
Figure 2. Lymphocytes, histiocytes, and giant cells (H&E, x20)
Physical examination revealed erythema and nodular areas on the dorsum of the third finger. Nodules appeared in a linear fashion along the forearm and lymphatic channels (Figure 1). Radiological studies demonstrated mild osteoarthritis but were otherwise noncontributory.
A skin biopsy was obtained and revealed granulomatous inflammation with microabscess formation (Figure 2). An acid-fast stain performed by the Richard-Allen Chromaview technique was noncontributory. The preliminary culture revealed acid-fast bacilli. Fungal culture was negative. The results of the initial culture directed the differential diagnosis toward Mycobacterium species, more specifically, either Mycobacterium marinum or Mycobacterium avium-intracellulare complex (MAC) because both are found in the local water systems. Given the extent of the patient’s disease, we were concerned about the immunological status of the patient. Therefore, MAC was deemed more likely a cause than M. marinum. The treatment regimen was therefore aggressive and was directed against the initial presumption of MAC. Treatment consisted of combination antibiotic therapy including clarithromycin (500 mg, one tablet every 12 hours), ethambutol (400 mg, 3 tablets daily), and rifampin (300 mg, 2 capsules daily), as well as topical silver sulfadiazine (Silvadene® cream) applied twice daily to the affected area . The final culture result revealed Mycobacterium marinum. Given the slow healing response, oral doxycycline hyclate (100 mg, twice per day) was added to the regime after 2½ months of treatment with the above medications. Doxycycline was discontinued after only three days of treatment because of intractable nausea and vomiting, presumably caused by the drug. The patient has continued the original regimen for 6 months during which time the nodules cleared. He will be finished in 1 more month, resulting in a total treatment time of 7 months. The patient will follow up every 3 months for 1 year to determine a cure.
Nodular lymphangitis describes the spread, along dermal and subcutaneous lymphatic channels, of superficial cutaneous lesions from a primary inoculation site. The presence of nodular lymphangitis suggests a limited differential diagnosis, including cutaneous inoculation with Mycobacterium marinum, Sporothrix schenckii, Leishmania braziliensis, and Nocardia brasiliensis [2, 3, 4, 5]. A history of travel can frequently provide a clue to the specific cause of infection. For example, Leishmania is native to the tropics and subtropics . The causative organisms for these conditions typically vary in incubation time from a few weeks to a few months. The presence of ulceration, suppuration, and drainage will typically vary between causative species. A detailed history, accompanied by familiarity with the clinical presentation of nodular lymphangitis, allows for the appropriate diagnostic tests and laboratory studies to be initiated so that directed treatment can commence.
This review will focus on the four main causes of nodular lymphangitis in the United States. Although these organisms are taxonomically diverse, they share common features. Each of these infections is typically found in immunocompetent hosts . As a result, the majority begin from a previous episode of trauma, regardless of the extent of injury. Systemic complaints are infrequent in nodular lymphangitis [2, 3]. Infections tend to congregate around regional lymphatics without deep penetration or spread to distant areas. Exceptions may occur in immunocompromised hosts with local invasion and diffuse spreading [7, 8, 9]. Appropriate histology and tissue cultures can establish a diagnosis in most patients [2, 3, 10].
3a. Mycobacterium marinum
There are reports that various nontuberculous Mycobacteria species may cause lymphocutaneous infection. However, of these, M. marinum is the species most commonly associated with nodular lymphangitis [2, 3, 4, 5, 8]. Mycobacterium marinum infections generally follow local trauma and subsequent exposure to an aqueous environment. Fish-handlers and fish tank hobbyists are at the highest risk of developing infection, although there are documented outbreaks from swimming pools, lakes, and oceans [2, 3, 5, 11]. Primary inoculation typically develops as tender nodules or pustules most common on the upper extremity, often 2-3 weeks after the initial trauma. The papules commonly ulcerate, suppurate, and frequently spread along proximal lymphatics. The lesions are often painless and enlarge slowly. Adjacent adenopathy is generally absent unless secondary bacterial infection is present and systemic symptoms are rare [3, 5]. Less often, deep infections such as tenosynovitis, osteomyelitis, arthritis, and bursitis may occur . The number of lesions, extent of cutaneous involvement, and presence of internal or systemic involvement depends on the immunological status of the patient . As expected, immunocompromised patients tend to have a more severe presentation and course of illness. Because mycobacteria fail to grow on routine bacterial cultures, a high index of clinical suspicion is necessary to make the diagnosis . The clinical picture, preferential location, and history of trauma with subsequent aquatic exposure are useful in this regard .
Appropriate culture of the tissue requires weeks of incubation at 32°C with organism-specific media [3, 9]. Histology reveals granulomatous inflammation without caseation . Tissue histology is also useful as these organisms can be identified with classic acid-fast stains [4, 9]. Several different types of stains for acid-fast organisms may increase the likelihood of detecting organisms on routine histology. However, absence of organisms on histology does not rule out the diagnosis of M. marinum. The PCR technique, if available, can lead to a diagnosis in days . Treatment in each individual case must be established by susceptibility tests because of the rarity of the infection and the scarcity of clinical evidence [4, 5, 9]. Clarithromycin is currently regarded as the single best agent, although equal success has been achieved using minocycline and amikacin. Doxycycline, trimethoprim-sulfamethoxazole, and the combination of rifampin and ethambutol can be effective but encounter different degrees of resistance [2, 3, 4, 5, 9, 12]. Monotherapy is typically used for mild cutaneous disease without complication . Combination therapy is necessary for more significant cutaneous infections and/or disseminated disease. The typical duration of therapy is continued for 2-3 months beyond symptom resolution. Surgical treatment (from mild debridement to limb amputation) may be required if deep structures are involved [12, 13].
3b. Sporothrix schenckii
Sporothrix schenckii is the most common cause of nodular lymphangitis in the United States, and “sporotrichoid” spread is sometimes used synonymously with nodular lymphangitis [2, 3, 10]. This dimorphic fungus typically has a worldwide distribution, but is concentrated in the tropics and subtropical regions [14, 15]. Most patients are healthy adults, less than 30 years of age, and present with lesions on the upper extremities or face. Traumatic inoculation of the fungus is most common, and typically occurs after exposure to wood or soil, although zoonotic transmission has been described [11, 15]. Farmers, gardeners, and forestry workers are therefore a target risk population for S. schenckii infection. The primary lesion usually present as a painless, erythematous, indurated papule, developing 7 to 30 days post-inoculation. It may be delayed up to 6 months. Progressive induration leads to the formation of a nodule with eventual ulceration [11, 14, 15]. The subsequent course usually consists of secondary lesions following the lymphatic drainage pattern ascending proximally. Regional lymphadenopathy is frequently found. Small quantities of serous fluid or purulent material may be discharged from lesions. A disseminated or systemic course is rare and is almost always the result of immunosuppression. Colonies normally appear after 3-5 days in culture but cultures should be held for at least 4 weeks.
Skin biopsy reveals microabscess formation with a surrounding granulomatous infiltrate. Organisms may be evident with the Periodic Acid Schiff stain or the Gomori Methanamine Silver stain. The finding of asteroid bodies, mycotic cells surrounded by radiated, eosinophilic elongations, is characteristic . Oral itraconazole for 3-6 months is the treatment of choice, although saturated solution of potassium iodide remains an effective, low-cost alternative.
3c. Leishmania species
Leishmaniasis is caused by the protozoa Leishmania, and is still a major world health problem that is increasing in incidence . Infection results from the bite of an infected female sandfly, with vector species differing between “Old World” and “New World” demographic areas. Old World cutaneous leishmaniasis is typically found in the Middle East and in large parts of tropical and subtropical Africa and Asia . New World leishmaniasis is mainly contracted in Brazil and Peru, but can occasionally be found in Central America and Mexico [2, 3, 6]. In the United States, cutaneous leishmaniasis is most commonly found in travelers returning from endemic regions. Infection develops 1-12 weeks after the sandfly bite. The primary lesion manifests as an erythematous papule, which enlarges into an ulcerating or verrucous lesion with an indurated margin and necrotic base. Lesions are often pruritic and not as painful as they appear . The lesions are may be covered with a dry exudate and remain painless unless a secondary bacterial infection occurs, which is commonly seen [3, 11, 17]. Nodular lymphangitis (sporotrichoid spread) of the primary lesion is common and most often occurs with the Leishmania braziliensis species from the New World. With this species in particular, mucocutaneous spread is another frequent manifestation and rapid treatment is desired to prevent this complication. Systemic symptoms are generally absent, although lymphadenopathy, fever, and hepatomegaly have been reported . The initial diagnosis is based strictly on the clinical picture and travel history of the patient. However, a skin biopsy should be obtained for routine histology and culture.
Histological examination with Giemsa stain reveals amastigotes. If facilities are available, polymerase chain reaction (PCR) may be used, but is uncommon in practice [11, 17]. Endemic countries report the use of delayed skin reaction tests such as the Montenegro or Leishman reaction to aid in diagnosis, although this is uncommon in the United States [16, 17].
No single optimal treatment has been discovered for cutaneous leishmaniasis but physical, topical, and systemic therapies have been utilized. New World disease tends to be more severe and long-lasting compared to Old World disease and requires a minimum 20 day treatment course of sodium stibogluconate, although untreated lesions may sometimes resolve, usually within 6 months [6, 11, 17]. Pentavalent antimony is particularly recommended for American cutaneous leishmaniasis because of the potential risk of mucocutaneous spread. Pentamidine, miltefosine, amphotericin B, and azole drugs are promising second-line therapies, as well as allopurinol in combination with pentavalent antimony [16, 17]. Topical aminoglycoside antibiotics, such as paromomycin, can also be used in combination with oral therapy. Non-drug treatment includes cauterization, excision, cryotherapy, heat therapy, and photodynamic therapy. Lesions caused by L. braziliensis often do not resolve without medical intervention. The pentavalent antimony derivatives, specifically sodium stibogluconate and meglumine antimoniate have proven beneficial with minimum treatment duration of 3 weeks [3, 11].
3d. Nocardia species
The Nocardia species are filamentous, gram-positive bacteria that primarily cause pulmonary and systemic disseminated disease [2, 3, 10, 18, 19]. Nocardia asteroides is the most frequent cause of systemic nocardiosis, especially in immunocompromised patients. It is estimated to account for almost 90 percent of the reported cases in the United States . Cutaneous nocardiosis, often associated with nodular lymphangitis, is primarily caused by N. brasiliensis (although it can be caused by N. asteroides as well). Whereas N. brasiliensis only accounts for about 7 percent of United States cases, it is a more frequent finding in immunocompetent, rather than immune-deficient, hosts . The primary means of inoculation in immunocompetent patients is via percutaneous trauma, often by a thorn, abrasion, animal scratch, or insect bite. Gardeners, farmers, and nursery employees are at a heightened risk for N. brasiliensis infection because this species is recovered from soil [10, 18, 19]. The primary lesion typically presents a few days to 6 weeks post-trauma as a single, erythematous subcutaneous nodule or abscess that may ulcerate [2, 3]. Purulent drainage and sinus formation may develop and additional lesions will develop along the proximal lymphatics in a sporotrichoid pattern . The upper and lower extremities are the most vulnerable sites because they are often exposed. Regional adenopathy and mild systemic symptoms, such as fever, are common .
Gram stain and cultures distinguish between causative organisms. Microscopically, the gram stain will reveal Gram-positive, fine, branching filamentous bacteria, suggestive of Nocardia , which are partially acid-fast. Sulfonamides, specifically trimethoprim-sulfamethoxazole, are the preferred treatment of choice [2, 3, 10, 18, 19]. A course of 1-4 months duration is typical and often accompanied by surgical debridement and drainage . Additional antimicrobial agents have been found efficacious, namely minocycline, tetracycline, amikacin, carbapenems, and quinolones [2, 3, 18].
3e. Mycobacterium avium-intracellulare complex
Mycobacterium avium-intracellulare complex (MAC) are other species of acid-fast, atypical mycobacteria with the potential for causing cutaneous infection with sporotrichoid spread. Cutaneous infections with MAC target immunocompromised patients, particularly those with AIDS, and tend to spare those with intact immune function . A previous history of trauma is usually lacking and patients present with multiple cutaneous and subcutaneous nodules . In these patients, systemic involvement is not unusual and the skin is typically infected as a result of hematogenous spread from a distant site, although localized skin infections have been reported [8, 9]. The lesions develop with ulceration and abcesses more frequently than M. marinum; soft tissue swelling, pustules, and sporotrichoid spread have also been observed [8, 9]. Diagnosis is similar to M. marinum, where a high index of clinical suspicion is necessary so the proper culture media can be implemented .
These organisms, along with other mycobacteria species, can be identified on histopathology by acid-fast stains. However, histological changes are not species-specific and the diagnosis of non-tuberculous mycobacteria relies mostly on culture results [5, 7]. Treatment consists primarily of antimicrobials. Recommended therapy consists of ethambutol and clarithromycin, although rifamycines, clofazimine, ciprofloxacin, and aminoglycosides are alternative therapies [1, 9, 13]. The optimum duration of therapy has not officially been established, but typically lasts for 6-12 months depending on the clinical response .
3f. Other species
Nodular lymphangitis has been reported with many different organisms. The frequency is typically related to the frequency of cutaneous infections with a particular organism and the likelihood that nodular lymphangitis will develop after a cutaneous infection . Rapidly growing atypical mycobacteria and Francisella tularensis are both possible causes. Less commonly, nodular lymphangitis can develop from infection with various pyogenic bacteria (including Staphylococcus and Streptococcus species) and various fungi other than Sporothrix (including Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum, and Cryptococcus neoformans) . The deep fungal infections mentioned are rare and typically manifest in medical professionals in close contact with these agents, such as pathologists or laboratory personnel after inoculation accidents.
Sporotrichoid spread (also known as nodular lymphangitis) describes a characteristic pattern of superficial cutaneous lesions that progress along the path of lymphatic drainage. Although the nature of causative organisms is diverse, with the appropriate exposure history the differential diagnosis is relatively limited. Knowing the etiologic setting, incubation time, clinical appearance of the lesions, and presence or absence of systemic involvement, can help establish a presumptive diagnosis. Biopsy and microbiological cultures of tissue can confirm the diagnosis in most patients.
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