E-mail: moc. This article has been cited by other articles in PMC. Abstract Histoid leprosy is rare type of lepromatous leprosy characterized by unique clinical, histopathological, and microbiological features. It is characterized by cutaneous and subcutaneous nodules. Histoid leprosy cases represent probable resistant bacilli and a highly active lepromatous process. These cases may act as reservoirs of the disease and lead to further spread of leprosy.
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No funding has been declared. Competing Interests: No competing interests have been stated. Pathological Features of Leprosy Immunopathological Spectrum of Leprosy Mycobacterium leprae elicits a uniquely broad spectrum of clinical and pathological features from susceptible individuals. The basis for this diversity has been recognized to be the differing capability of individuals to develop a cellular immune response to M.
This concept, based on histopathological evidence, antedated the recognition of T and B lymphocytes and has made leprosy a major model for the understanding of human cellular immunity see Chapter 6.
A practical five-part clinical and histopathological classification system was subsequently developed by Ridley and Jopling . Among patients with established lesions, the five-part Ridley-Jopling system classifies, at one extreme, individuals who exhibit a high degree of cell-mediated immunity and delayed hypersensitivity, presenting with a single, well-demarcated lesion with central hypopigmentation and hypoesthesia.
Biopsies of such lesions reveal well-developed epithelioid granulomas and rare acid-fast bacilli; this category is termed polar tuberculoid TT disease Figure 1. Caseous necrosis is rare in TT leprosy granulomas and when observed is almost always seen in granulomas involving nerves. FIG 1 The imunopathological spectrum of leprosy.
The well-formed epithelioid granulomatous infiltrates seen in polar tuberculoid TT lesions become increasingly disorganized in each successive increment in the scale—borderline tuberculoid BT , mid-borderline BB , and borderline lepromatous BL —until they become completely disorganized aggregates of foamy histiocytes, with only occasional lymphocytes, in polar lepromatous LL lesions.
A search of more than 50 fields was required to find the two organisms shown in a cutaneous nerve in the TT sample. Bacilli are often similarly difficult to find in BT lesions. From . Reprinted with permission. At the other extreme are patients who have little or no cellular immunity to M. This immunologically non-M. The histological features correlate well with the bacterial load, and these findings should be congruent. Specifically, if a well-organized tuberculoid granulomas response is seen, bacilli are scarce or rare; if a poorly organized lepromatous response is observed, with many foamy histiocytes, bacilli are abundant and easily demonstrated.
These designations are based on counting the number of macroscopic lesions. This classification is useful in resource-limited situations with minimal medical facilities, but it is not appropriate when biopsy diagnosis and microscopic classification are available. Overall, the majority of patients are classified in the LL, BL, or BT categories, but the distribution of patients within the entire spectrum varies according to racial background e.
Patients in the two polar groups LL and TT are relatively stable in their immunopathological response to M. These widely dimorphic histopathological responses are the result of a correspondingly broad range of cellular immune responses see Section 6 to M. No unified immunological hypothesis has successfully explained how the entire range of cellular immunity can be expressed in response to this one organism.
Evidence does indicate that patients in the tuberculoid portion of the spectrum have a Th-1 type of immune response to M. Skin Cutaneous lesions may show a range of histopathological appearances, from well-formed epithelioid granulomas to disorganized, linear or irregular aggregates of lymphocytes and histiocytes Figure 1.
The epidermis may be flattened and attenuated and typically is not hyperplastic or acanthotic. A sub-epidermal clear Grenz zone is seen in lepromatous lesions, but the granulomatous infiltrates may extend up to the basal layer of the epidermis in tuberculoid lesions.
Perineural inflammatory infiltrates Figure 2 should prompt consideration of a diagnosis of leprosy, and a Fite-Faraco stain should be performed; demonstration of acid-fast bacilli within nerves is pathognomonic of leprosy.
However, the vast majority of M. Dermal appendages may be inflamed and destroyed, and the destruction of sweat glands and sebaceous glands can result in dryness of the affected skin. Leprosy rarely involves the scalp, possibly because it is warmer than the optimal growth temperature for M.
FIG 2 Inflammation and infection of cutaneous nerves across the leprosy spectrum. The inflammatory responses in and around cutaneous nerves are shown in the upper panel; arrows highlight recognizable nerve twigs. The immunopathological classifications of leprosy, TT—LL, are indicated at the top of the figure see text; mid-borderline, BB, is not shown.
The TT lesion upper left is composed of a well-organized epithelioid granuloma that has nearly destroyed the nerve, remnants of which are shown by S staining brown staining nerve fragments at arrow. The granulomatous inflammatory response becomes less organized across the spectrum until, at the LL extreme, it is composed of disorganized aggregates of foamy histiocytes, seen here surrounding a nerve upper right.
In the lower panel, Fite-stained sections reveal the corresponding intensity of M. In contrast, bacilli are abundant and easily recognized in BL and LL lesions.
Very early leprosy lesions, including some cases with a single lesion, may present as relatively non-specific perineural infiltrates in which rare acid-fast bacilli can be demonstrated, but without sufficient infiltrates to classify them.
FIG 3 Indeterminate leprosy. Nonspecific inflammatory infiltrates are seen in this low magnification of a skin biopsy A , but perineural inflammation of a cutaneous nerve is seen at the deep margin of the biopsy highlighted.
Closer examination of this nerve B reveals mononuclear inflammatory cells within as well as adjacent to the nerve. High magnification C of a Fite-stained section of a portion of this nerve reveals two acid-fast bacilli arrows within the nerve, pathognomonic of leprosy.
These are characteristic findings in indeterminate leprosy, when a definite diagnosis of leprosy can be made but the type cannot be determined because the lesion has not yet developed features that enable classification according to the Ridley-Jopling system, such as well-defined granulomas or substantial collections of foamy histiocytes.
This infection is usually observed in cutaneous nerves, but is also seen in biopsies of the sural nerve or a sensory branch of the radial cutaneous nerve. The range of pathological changes in nerves see Chapter 9. In lepromatous lesions, nerves may be highly infected, with a minimal inflammatory response Figure 2. In tuberculoid lesions, bacilli may be rare and difficult to demonstrate, but pronounced, focal granulomatous inflammation may replace nerves Figure 2. Nerves in borderline lesions present a variety of intermediate patterns.
A nerve biopsy is seldom performed, however, limiting the information directly available regarding the mechanisms of nerve injury, but sensitive imaging techniques  and animal modeling in the armadillo; see Chapter Nasopharynx Infection of the nasal mucosa, sometimes presenting as a nasal polyp, may reveal a diffuse histiocytic infiltrate that may be misinterpreted as a form of histiocytosis, but upon Fite staining, reveals abundant acid-fast organisms Figure 4.
The upper respiratory tract is widely believed to be the usual portal of entry of M. Infection of the cartilaginous tissues of the nose may lead to perforation of the septum, and inflammation of the auricular pinnae often produces characteristic nodular thickening of the ears.
Both the hard and soft palates may be involved, sometimes leading to septal ulceration and perforation if not treated . In advanced disease, the posterior pharynx and epiglottis may also be infected  Figure 5. Laryngeal involvement with stridor may be seen in very advanced cases and can lead to thickening of the mucosa Figure 5D, 5E and fatal laryngeal obstruction.
The Mycobacterium leprae infection does not extend to the lung, presumably because the warmer environment is not conducive to the survival and proliferation of the bacilli. FIG 4 M. If nerves cannot be examined in the specimen, so that the capability of the organisms to infect nerves cannot be determined, the possibility of atypical mycobacteria should also be considered e.
Cultures for atypical mycobacteria should be performed, and molecular identification by nucleic acid amplification techniques such as PCR may be indicated.
FIG 5 Advanced lesions of oropharynx. The natural progression of lepromatous leprosy in the oral cavity is documented in watercolor illustrations prepared by Yoshie  in the s, prior to the discovery of effective treatment. A re-examination five months later B revealed discoloration of the soft palate, ulceration of previous lesions, elongation of the uvula, and coalescence of lesions on pillars and tonsils.
After another 13 months C , the hard and soft palates were ulcerated and deep ulcerations on the soft palate had reached the muscularis. The tongue and lips were also infiltrated. From . Post-mortem examination of a different patient, who died of laryngeal obstruction after long-standing, untreated lepromatous leprosy, revealed D thickening of the submucosa of the laryngeal folds due to extensive, disorganized lepromatous infiltrates of lymphocytes and foamy histiocytes.
Fite stains E disclosed abundant acid-fast organisms throughout the infiltrate. Mycobacterium leprae is weakly acid-fast. Some bacilli will stain with the Ziehl-Neelsen technique, although this stain can be negative; a higher percentage of bacilli will be stained by the Fite method  Figure 6.
Nevertheless, M. FIG 6 Staining of M. The earliest lesions in the nasal mucosa cause mild, non-specific symptoms and are not biopsied, so the histopathological features of this lesion are not known. Established nasal lesions are sometimes biopsied. Reported nasal lesions  ,  are typically lepromatous, with abundant bacilli Figure 4. Tuberculoid granulomas may occur but probably cause such minor symptoms that they are usually not biopsied.
Hematogenous dissemination is the likely mechanism of the spread of bacilli. In lepromatous patients, M. Although M. Autopsy series published long ago have documented the ability of M. Many of the visceral infections described—such as of the adrenal glands or spleen—were seen after many years of infection. These transient infections are now seen very rarely, because effective antimycobacterial treatment interrupts the progression of the infection. Glomerulonephritis may occur in leprosy patients, and although an immune-complex pathogenesis involving M.
This change may be due to effective anti-mycobacterial treatments that reduce the long-term bacterial burden and inflammation formerly seen in progressive infections. The infection of the testes is still observed in lepromatous leprosy, and the irreversible destruction of Sertoli cells often results in hypogonadism and gynecomastia in patients who are not diagnosed until their infection has been present for several years.
FIG 7 Systemic infection by M. Hematogenous dissemination of M. Occasionally M. Since M. Bone Bone marrow may be infected with M. The infection is sometimes encountered in bone marrow biopsies performed to evaluate a fever of unknown origin or other indications in which tuberculosis is being considered.
Anemia occurs in leprosy and is usually attributed to chronic disease or as a side effect of dapsone treatment. Although marrow may be heavily infected focally, there is no clear evidence to indicate that infection of the marrow can cause functional suppression or anemia. Trauma to anesthetic limbs in any type of leprosy may result in ulceration and, without diligent care of early injuries, secondary infections may culminate in secondary osteomyelitis due to common Gram-positive or -negative organisms.
Even in patients who take very good care of their insensitive limbs, the damage to parasympathetic innervation of blood vessels can result in the absorption of bone in phalanges. This absorption can be extensive, even resulting in the absorption of all digits from an extremity . Liver Transient, focal infections by M.
Pathogenesis and Pathology of Leprosy