Case 8 -

Mycobacterium, not Tuberculosis Kim M. Hiatt

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Clinical History: An 80 year old man returns to the dermatologist for the third time for evaluation asymptomatic enlarging papules (3 total) on his left upper arm. The papules have been present for several months and previous biopsies of these papules showed cutaneous lymphoid hyperplasia. Recently, an erythematous indurated plaque developed at the site. A repeat biopsy was performed. Case 8 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 8 - Figure 1 A dense dermal infiltrate with a vaguely nodular pattern is appreciated in this low power image. There is perifollicular and periadnexal involvement by this infiltrate. Case 8 - Figure 2 The mixed lympho-histiocytic nature of the infiltrate is noted at this higher power. Immunohistochemical staining reveals the cells with small hyperchromatic nuclei as well as some of the larger cells with open chromatin to be lymphocytes. There is mixed CD4+ and CD8+ expression in these lymphocytes. All these features support the reactive nature of the infiltrate. Case 8 - Figure 3 This higher power image confirms the heterogeneous population in this dermal infiltrate to be predominantly lymphocytes, histiocytes and plasma cells, along with plump endothelial cells. These features further support the reactive nature of this infiltrate. Histologic Features: The biopsy showed a dense dermal infiltrate with a vaguely nodular pattern. There is perifollicular and perivascular involvement. Higher power reveals this infiltrate to have mixed morphologies, all mononuclear. There are some cells with small hyperchromatic nuclei and larger cells with open chromatin pattern. Nuclear irregularities and prominent nucleoli are noted in a portion of the large cell population. Immunohistochemical staining reveals most of this infiltrate, both small and large cells, to be lymphocytic with a mixed CD4+ and CD8+ expression profile. Some large cells are CD3- and have the morphology of tissue histiocytes. These features are all supportive of a reactive process. Further special stains reveal numerous acid fast bacilli. An additional biopsy for culture and sensitivity showed numerous acid fast bacilli on stain, but no growth. Diagnosis: Mycobacterium, not tuberculosis. Further testing was not done for speciation. Clinical Course: Based on the lack of growth, the primary care physician was concerned for mycobacterium leprosum. The patient denied any risk factors for m. leprosum or m. marinum. The patient was put on clarithromycin, p.o. for 3 months. After 2 months of therapy, the patient is nearly clear of lesions. Discussion: A mixed inflammatory infiltrate, i.e. CD4+ and CD8+ lymphocytes and histiocytes is strong evidence for an infectious process. Neither special stains for microorganisms nor cultures were done on the previous biopsies. The most common mycobacteria to cause cutaneous disease are M. tuberculosis, M. leprae, M. ulcerans M. marinum, M. avium-intracellulare, M. chelonei, M. kansaii, M. abscessus and M. fortuitum. Of those, M. leprae is not able to be cultured. Of the other mycobacteria to infect skin and soft tissue, prevalence rates vary. However, in one study on upper extremity mycobacterial infections, most cutaneous lesions were, not surprisingly, caused by M. marinum, followed by M. ulcerans. In this case the patient denied any risk factors for M. leprosum. Transmission is via nasal or oral droplets from a contagious person, inoculated through broken skin or nasal mucosa. In Arkansas, where this patient resides, spread in through the 9-banded armadillo, a natural reservoir, or through an immigrant population from the Marshall Islands where leprosy is endemic. The incubation period of M.leprosum varies from months to years, with an average of 5 yr. The organism is hardy and may remain viable for up to 7 days in dried secretions. The histologic pattern and the presence of organisms on tissue sections is dependant on the patient's immune status as indicated in the table below. Histologic pattern Type of granuloma Presence of lymphocytes Presence of organisms Cell mediated immune status Tuberculoid (TT) Tuberculoid, non caseating yes Very rare intact Borderline tuberculoid (BT) With foreign body giant cells Borderline (BB) Poorly formed Borderline Lepromatous (BL) Poorly formed Lepromatous leprosy (LL) Numerous macrophages Rare numerous depressed indeterminate no Many around vessels, nerves, pattern Differential Diagnosis: Granulomatous rosacea presents on the face and in addition to the dermal granulomas, has a lymphocytic and histiocytic infiltrate in a perivascular and perifollicular pattern. Plasma cells and multinucleate cells are also present. Acute folliculitis and telangectatic vessels would also be present. Granulomatous arthropod bite reaction will classically have a mixed inflammatory infiltrate with numerous eosinophils. accompanying the granulomas. The granulomatous infiltrate in granulomatous mycosis fungoides varies from small tuberculoid to poorly formed interstitial granuloma. Immunohistochemicla stains will help classify this infiltrate. Granulomatous infiltrates mimicking interstitial granuloma annulare have also been reported. These often have an infiltrate of eosinophils. Interface change may also be present. Also, unlike granuloma annulare, there will not be necrosis with a drug-associated etiology. component. And finally, benign cutaneous lymphoid hyperplasia is classically a dense mixed infiltrate without epidermotropism and not infectious etiology identified. Multiple levels of tissue must be evaluated to confidently state the absence of acid fast organisms. Summary: Use benign cutaneous lymphoid hyperplasia after confident exclusion of all other granulomatous infiltrates. Infectious etiologies must be considered and a diligent search for organisms is prudent. In addition to special stains for organisms, immunohistochemical stains to confidently classify the infiltrate is helpful in refining the histologic differential diagnosis. Take Home Points Request a repeat biopsy if the lesion doesn't resolve or the pathology report doesn't fit clinically. Use immunohistochemistry to help identify histiocyte-like cells in the infiltrate. Are they activated lymphocytes, transformed lymphocytes, histiocytes? If clinical suspicion is high for infectious etiology, be persistent, even if culture negative. PCR can be very helpful References: Gerami, P. and J. Guitart (2007). "The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides." Am J Surg Pathol 31(9): 1430-8. Kozin, S. H. and A. T. Bishop (1994). "Atypical Mycobacterium infections of the upper extremity." J Hand Surg [Am] 19(3): 480-7. Scarabello, A., B. Leinweber, et al. (2002). "Cutaneous lymphomas with prominent granulomatous reaction: a potential pitfall in the histopathologic diagnosis of cutaneous T- and B-cell lymphomas." Am J Surg Pathol 26(10): 1259-68. Uslan, D. Z., T. J. Kowalski, et al. (2006). "Skin and soft tissue infections due to rapidly growing mycobacteria: comparison of clinical features, treatment, and susceptibility." Arch Dermatol 142(10): 1287-92.