A 32-year-old man presented to the clinic complaining of high-grade intermittent fevers, night sweats, severe joint pain, and an erythematous maculopapular rash that had persisted for 1 month. His primary care physician obtained a skin biopsy that was suggestive of erythema nodosum and referred him to the University of Minnesota Medical Center for further assessment for a possible immune complex disorder. The physician had seen the patient a month earlier at the onset of his illness and prescribed a 7-day course of levofloxacin for a presumed upper respiratory infection. The patient was originally from Matamoros, Mexico but had lived in McLeod County, Minnesota for the past 10 years. He had not returned to Mexico during that time. On examination, the man was febrile with a temperature of 103.4 degrees F. He demonstrated alopecia areata and supercilliary madarosis. Numerous erythematous macules and papules were distributed over his body, mostly on his chest, back, thighs, and the volar surfaces of his forearms. Few lesions were found on the shins, a site classically involved with lesions of erythema nodosum. The lesions were painful, tender, and nonpruritic. The patient stated that the lesions would come in crops and subside within a few days, followed by residual pigmentation and lichenification. A tender left axillary lymph node, along with a right inguinal node, could be palpated. There was no ocular involvement. The patient complained of paraesthesias and dysesthesias in both forearms, with no evident neurological deficit. A clinical diagnosis of erythema nodosum was made which was thought to be secondary to an immune disorder such as sarcoidosis. To confirm this diagnostic impression before starting anti-inflammatory treatment an inguinal lymph node biopsy was performed.
Pertinent Laboratory Data:
WBC: 15.1 109/L 89% neutrophils. Microcytic hypochromic anemia with increased rouleaux formation CRP: 17.6 mg/dL ( normal 0-0.80 mg/dL) ANA: weakly positive. Serum ACE: 62 IU/L (normal 9-67 IU/L) Mycoplasma serology: negative. Blood bacterial and fungal cultures: negative Chest Xray: normal, no evidence of mediastinal or hilar lymph nodes. Skin biopsy: subcutaneous panniculitis consistent with erythema nodosum. PET scan: abnormal hypermetabolic activity in bilateral inguinal and iliac nodes. Increased activity in the nodules in the medial thigh supporting a presumptive diagnosis of sarcoidosis. HIV: negative Hepatitis B and C: negative
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The lymph node sinuses are expanded by numerous vacuolated histiocytes. A Fite stain for acid fast
organisms demonstrates large number of bacteria within their cytoplasm. (Fig 1) Molecular studies
performed on paraffin embedded tissue showed that the bacterium is Mycobacterium lepromatosis.
Case 4 - Slide 1
Case 4 - Figure 1
Fite stain shows numerous acid fast organisms within the vacuolated histiocytes.
The differential diagnosis of granulomatous lymphadenitis in leprosy includes numerous infectious and
non-infectious entities. When this type of lymphadenitis is present in a patient with chronic skin
lesions, leprosy should be a consideration even in the absence of demonstrable acid-fast organisms.
Infection by Mycobacterium avium in patients with AIDS may produce identical changes to those present in
lepromatous leprosy. The abundant intracytoplasmic bacteria within vacuolated cells (pseudo-Gaucher
cells) may closely resemble the globi seen in lepromatous leprosy. The proper clinical setting and
cultures of the organism will clarify the diagnosis.  Lymphadenitis in patients with Mycobacterium
tuberculosis infection either show non-necrotizing or, more commonly, necrotizing granulomas. In the
setting of immunosuppression, granulomas are absent. However, at variance with what is seen in
lepromatous leprosy, there is extensive necrosis with scattered histiocytes, neutrophils and occasional
eosinophils. Numerous blunt-ended straight to slightly cured bacilli are present. Foamy histiocytes
within lymph nodes can occur with other bacterial infections such as Whipple's disease and in metabolic
storage disorders (e.g., Gaucher disease).
Lymph node involvement by lepromatous leprosy caused by Mycobacterium lepromatosis.
Leprosy is a chronic infectious disease with protean clinical and pathological manifestations which
depend upon the immune response mounted against the causative agent, Mycobacterium leprae. This
rod-shaped, acid-fact bacterium is an obligate intracellular pathogen with a tropism for macrophages and
Schwann cells. The skin and peripheral nerves are the most affected organs followed by eyes and mucosa
of the upper respiratory tract.  The mode of transmission is through aerosol spread of nasal
secretions and uptake through the upper respiratory mucosa. Its low pathogenicity and virulence is in
part reflected in its long incubation period which ranges from 3 to 10 years. The disabilities secondary
to nerve damage, the deforming skin lesions and, more importantly, the attribution of moral
transgressions as the triggers of this disease account for the fear and stigma that these patients
suffered through the centuries. Its infectious nature was unveiled in 1873 by the Norwegian
microbiologist Armauer Hansen. With this discovery, M. leprae, also known as Hansen bacillus, became the
first bacterial pathogen known to cause a human disease. Although 138 years have elapsed since this
landmark discovery, there is still an incomplete understanding of its transmission, role of environmental
reservoirs and pathogenesis, in part due to the inability to culture the bacterium.
Types of leprosy: Since the pioneering work of Ridley and Jopling, it is thought that the spectrum of
clinical and histological phenotypes reflects the host immune response directed against M. leprae. 
Based on clinical, histopathological and immunological criteria, five forms of leprosy are identifies:
tuberculoid polar form (TT), borderline tuberculoid (BT), mid-borderline (BB), borderline lepromatous
(BL) and lepromatous polar leprosy (LL). To these forms an indeterminate category is added in some
classifications. Except for lepromatous leprosy which those not naturally regress, all other forms may
resolve spontaneously, persist or advance to other forms. The WHO classifies cases according to the
number of bacteria. The paucibacillary subtype lumps the TT and BT forms of the Ridley and Jopling
classification and the multibacillary subtype the BB,BL and LL forms. 
Indeterminate leprosy: Few hypopigmented or erythematous macules usually involving the limbs
characterize this form of leprosy. Sensation is normal or minimally impaired.
Tuberculoid leprosy (TT): This is the most common type of leprosy in India and Africa. Patients
present with few, generally large, well-circumscribed hypopigmented skin lesions on the trunk or limbs.
An important clue to the diagnosis is the associated anesthesia with loss of pain, tactile and thermic
sensations. Neural involvement, manifested by nerve enlargement, may be present. The lepromin or
Mitsuda reaction is positive.
Borderline tuberculoid leprosy (BT): The lesions resemble those present in TT but are generally
smaller and more numerous with less nerve enlargement. Hypoesthesia and impairment of hair growth within
the lesions are generally present.
Mid-borderline leprosy (BB): Numerous erythematous, anesthetic annular patches asymmetrically
distributed characterize this form of disease. Regional adenopathy may be present.
Borderline lepromatous (BL): Numerous ill-defined macules, papules, plaques and nodules appear at
different sites. The lesions are generally less anesthetic.
Lepromatous leprosy (LL): This form should be considered a systemic disease which manifests primarily
in the skin. Diffuse and symmetric pale macules initially appear followed by infiltrated plaques and
nodules (lepromas) which frequently affect the face. Alopecia with loss of eyebrows and eyelashes is
commonly present. Nerve involvement leads to anesthesia, limb weakness and aseptic necrosis. A rare
nodular variant of LP called histoid leprosy is characterized by cutaneous and / or subcutaneous nodules
and plaques on apparently normal skin. The lepromin reaction is negative.
 The diagnosis of the different subtypes of this disease is based on the
recognition of the types of histiocytes present in the inflammatory reaction, whether epithelioid or
vacuolated, and their organization as well or ill-formed granulomas or diffuse (non-granulomatous)
infiltrates. Indeterminate leprosy: Superficial and deep dermal infiltrates composed of lymphocytes and
few histiocytes surround dermal appendages, blood vessels and nerves. Acid fast organisms are absent or
very occasionally present in small dermal nerves.
Tuberculoid leprosy (TT): The characteristic lesions are well-form non-necrotizing granulomas
composed of epithelioid cells, Langhans giant cells and lymphocytes. These lesions may erode the
epidermis and extend into peripheral nerves and dermal adnexa. Less than half of the cases show
Borderline tuberculoid leprosy (BT): At variance with what is seen in TT, granulomas are less well
form, giant cells are less frequent and there is less nerve injury and a subepidermal grenz zone is
present. Organisms are difficult to find.
Mid-borderline leprosy (BB): Epithelioid cells do not cluster as well-defined granulomas. Giant
cells are absent. Organisms are generally present.
Borderline lepromatous leprosy (BL): As in BB, histiocytes do not form granulomas, loose their
epithelioid appearance and appear as granular of foamy cells. Bacilli are easy to find.
Lepromatoid leprosy (LL): There are numerous collections of foamy macrophages (Virchow cells) which
are heavily parasitized. In addition to macrophages, organisms are present in sweat glands, nerves,
Schwann cells and vascular endothelium. In the variant known as histoid leprosy, the proliferating
inflammatory cells acquire a spindle shape and grow as intertwining fascicles resembling a
fibrohistiocytic tumor. These heavily parasitized cells express factor XIIIa and are believe to be
dermal dendritic cells.
Referred to as diffuse lepromatous leprosy or Lucio's phenomenon is another variant of lepromatous
leprosy which is more frequent in Mexico and the Caribbean. It is characterize by diffuse non-nodular
lesions which may ulcerate as a result of an underlying vascular occlusion secondary to endothelial
infection causing injury and proliferation of these cells followed by thrombosis. When present,
leukocytoclastic vasculitis with fibrinoid necrosis is regarded as a reactional change. 
Lymph node involvement in leprosy: The histopathologic changes in lymph nodes form patient with
leprosy reflect the effectiveness of the immune response in controlling the infection. Well form
granulomas closely resembling those of sarcoidosis are present primarily in lymph nodes form patients
with borderline tuberculoid forms. Acid-fast organisms are either undetectable or very scant. These
granulomas are form by histiocytes with a typical epithelioid appearance and typically contain Langhans
type giant cells. Although granulomas of this type are also expected to be present in patients with TT,
most lymph nodes either show no evidence of immunological stimulation or mild paracortical hyperplasia
with occasional immunoblasts. This is probably due to the fact that cutaneous lesions are more abundant
in BT than in TT. In patients with the BB subtype, well-formed granulomas are not seen. The histiocytes
acquire an indistinct appearance with more oval nuclei and less eosinophilic cytoplasm. Langhans type
giant cells are less common. Acid fast bacilli are generally present. In BL, indistinct (neither
epithelioid nor foamy) histiocytes are scattered through the paracortical areas and subcapsular regions.
Acid-fast bacilli are invariably present, often forming clusters referred to as globi. Germinal centers
show varying degrees of hyperplasia and interfollicular plasma cells are increased. In lepromatous
leprosy huge sheets of foamy histiocytes (Virchow cells) containing large numbers of mycobacteria are
present in the paracortical and subcapsular areas. These cells may persists after many years of
treatment and either show fragmented or no bacteria. 
During the course of the disease, acute exacerbations may occur, a
condition known as leprosy reaction. Two types have been recognized: type I (reversal reaction; RR) and
type II (erythema nodosum leprosum; ENL). Type I, reversal reaction (RR): This form occurs in a third
of patients with borderline subtypes. It presents within the first 6 months of therapy but may occur in
untreated patients with other conditions such as pregnancy, stress or concurrent infections. Clinically
RR is characterized by edema and erythema of the preexisting skin lesions which may ulcerate. New skin
lesions may develop as well. Sensory and motor loss may be a consequence of worsening neuritis.
Histologically there is edema and increase in lymphocytes and sometimes giant cells accompanied by small
clusters of epithelioid histiocytes. In severe cases there may be fibrinoid necrosis and scarring.
These microscopic features generally indicate an upgrading towards the tuberculoid spectrum. Replacement
of epithelioid histiocytes by vacuolated cells points to downgrading towards the opposite pole.
Type II, erythema nodosum leprosum (ENL): Typically this reaction appears in patients with borderline
or lepromatous forms usually during the second and third year following the start of multidrug therapy.
Rarely, untreated patients may present de novo as ENL. Tender, erythematous subcutaneous nodules covered
by normal skin develop and are frequently accompanied by systemic symptoms such as fever, malaise,
lymphadenopathy, weight loss, arthralgias and edema. Other organs affected include the testes, joints,
eyes and nerves. This reaction is the result of immune complex-mediated vasculitis. Histologically
there is a mixed dermal infiltrate compose of neutrophils, lymphocytes and collections of macrophages.
Vasculitis may be present. When the subcutaneous tissue is involved, the infiltrate adopts the
appearance of lobular and septal panniculitis.
Biology of M. leprae: An important advance was discovery in 1973 that the cool body temperature of
armadillos allowed for the propagation of M. leprae.  The abundance of bacteria obtained through
this method made possible the extraction of large quantities of DNA and the whole sequencing of its
genome.  When compared to other mycobacteria, a mere 49.5% of M. leprae genome accounts for the 1614
genes coding for proteins and the 50 that encode stable RNAs. The remainder is made of inactive reading
frames or pseudogenes. Compared to Mycobacterium tuberculosis, Hansen bacillus underwent extensive
reductive evolution with loss of about 2000 genes, half of its metabolic functions and absence of entire
metabolic pathways, which has been interpreted as passage through an evolutionary bottleneck.  M.
leprae lost genes required for replication ex vivo and is therefore dependent on host metabolic products
which explains its long generation time and inability to grow in culture.  Various protein antigens
are shared with M. tuberculosis and /or other environmental mycobacteria. These antigens can induce a
protective immune response.  Infection of Schwann cells is determined through the binding of the
bacterium to a laminin component (G domain of the alpha-2 chain of laminin 2) which is restricted to
peripheral nerves.  After many years of intracellular replication, T cells recognize mycobacterial
antigens. Through the expression of HLA class 2 molecules, Schwann cells present mycobacterial peptides
to CD4-positive T cells. The nerve swelling which ensues and its compression by a non-distensible
perineurium leads to ischemia, axonal damage and death. 
Immunopathology of leprosy: The immunologic response to the infection by M. leprae determines the
clinical form of the disease. A vigorous cellular immune response with a Th1 profile develops in
patients with tuberculoid leprosy. Well-formed epithelioid granulomas containing multinucleated cells
are the result of the presence of CD4-positive, interferon-γ-secreting T lymphocytes. Organisms are
scant or absent. Antibody responses to M. leprae antigens are absent.
By contrast, in
lepromatous leprosy. There is absence of specific cellular immunity. There are few CD4-positive, more
CD-8 positive T lymphocytes, no secretion of interferon γ, no epithelioid histiocytes and
granulomas, and numerous parasitized cells. The CD4:CD8 ratio of these patients is 1:2 with a
predominant Th2 response and high titers of antibodies to the species-specific phenolic glycolipid PGL-1
and other protein antigens.  Most patients have the clinically unstable borderline forms which
either slowly evolves towards the lepromatous pole or experience sudden type I or reversal reactions.
Genetics of the host response It has been suggested that the predisposition to the infection and the
type of disease is influenced by genetic factors. The genetic susceptibility was established by twin
studies that demonstrated increased predisposition to the infection and concordance in disease subtype in
twins, the association being higher in monozygotic than dizygotic twins.  Genome wide linkage
studies have identified susceptibility loci on chromosome 10p13, in proximity to the gene for the mannose
receptor C type 1 which is a phagocytic receptor on macrophages.  Strong linkage for patients with
LL and BL types has also been detected for chromosome regions 6p21 within the MHC. Linkage has also been
shown in other regions of chromosome 6 (6q25-q26) irrespective of the clinical leprosy subtypes. Four of
the six SNPs associated with leprosy were located to the promoter of the Parkinson's disease gene PARK2
and its corregulated gene PACRG. Other linkage studies have pointed to other genes such as those coding
for tumor necrosis factor, toll-like receptor 2, NOD2, etc. .
This patient came to our attention with the clinical picture of erythema nodosum. He was initially
suspected of having an acute variant of sarcoidosis called Lofgren's syndrome characterized by high-grade
fevers, severe systemic symptoms, arthritis, erythema nodosum and lymphadenopathy.  Review of a skin
biopsy performed elsewhere showed parasitized vacuolated cells. Other clues to the proper diagnosis of
leprosy included the supercilliary madarosis and the presence of paraesthesias suggesting peripheral
neuritis although no palpable superficial nerves were ever found. It is possible that the type II
reactional presentation could have been precipitated by the use of quinolones which were administered to
this patient one month before the skin biopsy for a respiratory infection.
Numerous drugs including iodides, bromides, dapson, sulfonamides and fluoquinolones may trigger this
reaction.  In 2008 Xiang Y. Han et al reported a new Mycobacterium species that was isolated from
two Mexican patients who died of diffuse lepromatous leprosy and named it Mycobacterium lepromatosis.
 Purified DNA obtained at autopsy and from a paraffin embedded skin biopsy was used to partially
sequence five genes (mmaA, hsp65, rpoT, rpoB and rif-rpoS) and fully sequence one gene (rrs, 16S RNA).
The sequences were compared with M. leprae consensus sequences as well as with other mycobacteria. The
authors concluded that the genetic differences were significant to warrant the classification of this
bacterium as a new species. A more in-depth DNA analysis subsequently reported where 20 genes and
pseudogenes were analyzed further reinforcing their conviction that the bacteria represents a new
species.  Other authors have questioned whether the "new" Mycobacterium could be a contaminant by an
environmental mycobacteria or whether it represents a variant of M. leprae. They proposed the
performance of a series of experiments to verity that the "new" bacterium causes leprosy. 
Paraffin embedded tissue from this case was sent to the M.D. Anderson Hospital in Houston to Dr.
Han's who kindly accepted to perform the molecular analysis of the bacterium. The genetic composition of
the organism from the present case is identical to that isolated from the other Mexican patients.
Histopathologic examination may be the first clue to the diagnosis of leprosy, particularly in
countries where this disease is infrequently encountered. Current evidence points to the existence of a
new organism different from Mycobacterium leprae which may explain some of the clinical variants of the
disease which prevail in some countries.
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