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Tuberculosis is a special type of bacterial infection caused by a strain known as Mycobacterium tuberculosis. In spite of significant advances in prevention and drug treatment, it still remains a major public health threat. It is estimated that 1/3 of the world's population is infected and about 3 million people die from the disease each year. The advent of AIDS as well as multi-drug resistant strains has brought this disease to the forefront of medicine.


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Facial granulomatous diseases

Am J Dermatopathol 2001;23:8-15

Four cases examined with nested PCR
2/4 positive
Poor correlation between PCR results and clinical outcome


Tuberculids as sentinel lesions of tuberculous epididymo-orchitis.

Department of Pathology, Nelson R Mandela School of Medicine, University of KwaZulu Natal and National Health Laboratory Services, Durban, KwaZulu Natal, South Africa.


J Cutan Pathol. 2007 Nov;34(11):830-6. Abstract quote

Background: Tuberculids are rarely associated with male genital tract tuberculosis (TB). Tuberculous epididymo-orchitis (TBEO) has been associated rarely with papulonecrotic tuberculid (PNT) but not with erythema induratum (EI) or the simultaneous occurrence of different tuberculids.

Methods: A retrospective assessment of tuberculids that occurred with underlying TBEO was carried out.

Results: Five patients, four with one and one with two skin biopsies, with clinical diagnoses of PNT (two), EI (one), impetigo (two) and calf ulcer (one), formed the study cohort. Histopathological evaluation confirmed PNT and EI in four and two skin biopsies, respectively. Two patients who returned for follow-up were commenced on anti-tuberculous therapy. All patients sought medical attention 3-34 months later for tender right-sided (two) and left-sided (three) testicular masses. Orchidectomy was undertaken following a poor clinical response to empirical treatment with trimethoprim sulfamethoxazole. Pathological examination of the testis and epididymis confirmed TBEO. The patients were initiated on anti-tuberculous therapy. There was dramatic healing of the skin lesions.

Conclusion: Tuberculids are a sentinel cutaneous manifestation of visceral TB and a valuable external audit of treatment compliance and response. Heightened recognition of and more rigorous genitourinary tract investigation are necessary to identify occult or asymptomatic TBEO as the underlying cause of tuberculids.

Viability of mycobacteria in formalin-fixed lungs.

Gerston KF, Blumberg L, Tshabalala VA, Murray J.
Hum Pathol. 2004 May;35(5):571-5. Abstract quote  

It is generally accepted that the risk of contracting tuberculosis is relatively high among medical laboratory workers and pathologists. Nevertheless, there is an assumption that once tissue is fixed in formalin, the risk for transmission and subsequent infection of mycobacteria is greatly reduced, if not altogether eliminated.

To test the viability of potentially infectious mycobacteria in formalin-fixed tissue, tissue specimens from autopsy lungs fixed in formalin were cultured for mycobacteria.

Of 138 cases with histologic evidence of acid-fast bacilli, 12 grew mycobacteria, including 3 Mycobacterium tuberculosis isolates, suggesting that there is a risk of contracting tuberculosis from tissue that has been fixed in formalin, if aerosolization or accidental inoculation should occur.

Comparison of the Automated Mycobacteria Growth Indicator Tube System (BACTEC 960/MGIT) with Lowenstein-Jensen medium for recovery of mycobacteria from clinical specimens.

Lu D, Heeren B, Dunne WM.

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.

Am J Clin Pathol 2002 Oct;118(4):542-5 Abstract quote

We examined whether the BACTEC/Mycobacteria Growth Indicator Tube (MGIT) system alone could supplant the use of a supplemental Lowenstein-Jensen (LJ) slant for routine recovery of Mycobacterium species from clinical specimens.

A total of 6,062 specimens were included in the study. Of these, 273 specimens were positive for 278 mycobacterial isolates while 15 specimens were smear positive but culture negative using both media. Further analysis showed that 143 (51.4%) of the 278 total isolates were recovered from both the MGIT and LJ media. An additional 106 isolates (38.1%) were recovered from the MGIT only, while 29 (10.4%) isolates grew only on the LJ slant. The overall sensitivities of the MGIT and LJ media were 86.5% and 59.7%, respectively, for the recovery of mycobacteria from clinical materials.

This study shows that although the MGIT system demonstrates better sensitivity for the recovery of mycobacteria from clinical specimens, both media types are necessary to maximize the sensitivity of detection.


Amplified In Situ Hybridization With Peptide Nucleic Acid Probes for Differentiation of Mycobacterium tuberculosis Complex and Nontuberculous Mycobacterium Species on Formalin-Fixed, Paraffin-Embedded Archival Biopsy and Autopsy Samples

Pietro Zerbi, MD
Andreas Schønau, MScChemEng
Sara Bonetto, MD
Andrea Gori, MD
Giulio Costanzi, MD
Piergiorgio Duca, MD
and Luca Vago, MD

Am J Clin Pathol 1001;116:770-775 Abstract quote

The aim of this study was to evaluate sensitivity and specificity of in situ hybridization (ISH) using peptide nucleic acid (PNA) probes and tyramide-based amplification for the differentiation between Mycobacterium tuberculosis (MTB) and mycobacteria other than tuberculosis (MOTT) on formalin-fixed, paraffin-embedded tissue samples.

We performed ISH simultaneously with both probes on 86 specimens from different organs: 70 obtained at autopsy and 16 by biopsy, all with a histologic evidence of mycobacterial infection confirmed by Ziehl-Neelsen–positive staining. Taking culture as the "gold standard," the sensitivity and the specificity of the MTB probe were 100% (41/41) and 95% (38/40), respectively. In only 2 cases ISH failed to identify mycobacteria. Culture results were not available in 3 cases.

We propose ISH as a relatively simple and rapid method to differentiate mycobacteria on formalin-fixed, paraffin-embedded specimens (it is more specific than usual histologic stains) and as an alternative to polymerase chain reaction, allowing the morphologic evaluation of positive bacilli.


Use of polymerase chain reaction to diagnose tuberculous arthritis from joint tissues and synovial fluid.

Titov AG, Vyshnevskaya EB, Mazurenko SI, Santavirta S, Konttinen YT.
Arch Pathol Lab Med. 2004 Feb;128(2):205-9. Abstract quote  

CONTEXT: Tuberculosis of the joints and bones is a significant worldwide problem, often leading to joint and bone destruction. The diagnosis of this disease manifestation is difficult.

OBJECTIVE: To assess the role of conventional diagnostics compared to polymerase chain reaction applied to samples obtained at arthroscopy.

DESIGN: This was an open observational study that was blinded to the microbiologist, histopathologist, and molecular biologist responsible for assessing the main outcome measures.

PATIENTS: Seven patients (8 samples) with joint and bone tuberculosis and 14 patients (16 samples) with nontuberculous joint and bone disease.

INTERVENTION: Arthroscopic examination and tissue sample collection.

MAIN OUTCOME MEASURES: Mycobacterium tuberculosis staining, culture, and histopathologic assessment of caseating granulomas vs polymerase chain reaction.

RESULTS: Polymerase chain reaction was positive in all cases of true tuberculosis and falsely identified 2 samples as positive, both however, in patients who had lung tuberculosis in the past.

CONCLUSIONS: Conventional bacteriological methods for demonstration of M tuberculosis are not very sensitive and can be time-consuming. Polymerase chain reaction of arthroscopically obtained joint tissue biopsies appears promising in the early diagnosis of tuberculous arthritis.

Comparison of polymerase chain reaction with histopathologic features for diagnosis of tuberculosis in formalin-fixed, paraffin-embedded histologic specimens.

Park do Y, Kim JY, Choi KU, Lee JS, Lee CH, Sol MY, Suh KS.

Department of Pathology, College of Medicine Pusan National University, Busan, Korea

Arch Pathol Lab Med 2003 Mar;127(3):326-30 Abstract quote

Objective.-To investigate the relationship between various histopathologic features and the results of the tuberculosis (TB)-polymerase chain reaction (PCR) method in routinely submitted histologic specimens for the histopathologic diagnosis of TB.

Design.-We used 95 formalin-fixed, paraffin-embedded tissue blocks from 81 patients who were clinically suspected of having TB. We assessed the presence of histopathologic features including well-formed granuloma, poorly formed granuloma, caseous necrosis, and Langhans-type giant cells. We performed nested PCR for IS6110 and Ziehl-Neelsen staining for acid-fast bacilli (AFB).

Results.-Of the 81 patients studied, 53 patients had chronic granulomatous inflammation, whereas 28 patients had only chronic inflammation without definite granulomatous inflammation. Of the 53 cases with chronic granulomatous inflammation, 17 (32%) were AFB positive and 36 (68%) were TB-PCR positive. Among cases with chronic granulomatous inflammation, the percentage that were positive and negative by TB-PCR differed significantly with the presence of various histopathologic features. All of the 13 cases with well-formed granuloma, caseous necrosis, and Langhans-type giant cells were TB-PCR positive; however, 10 (36%) of the 28 cases with chronic inflammation without granulomatous lesions were also TB-PCR positive.

Conclusions.-TB-PCR is a rapid, sensitive method for the diagnosis of TB in routinely processed formalin-fixed, paraffin-embedded histologic specimens and is readily available in histopathology laboratories. We recommend use of TB-PCR when TB is suspected clinically, especially in cases of chronic inflammation without definite evidence of granulomatous inflammation.

Rapid and Accurate Identification of Mycobacteria by Sequencing Hypervariable Regions of the 16S Ribosomal RNA Gene

Xiang Y. Han, MD, PhD, Audrey S. Pham, PhD, Jeffrey J. Tarrand, MD, Pramila K. Sood, MBA, and Rajyalakshmi Luthra, PhD

Am J Clin Pathol 2002;118:796-801 Abstract quote

We developed a method to identify mycobacteria by sequencing hypervariable regions of the polymerase chain reaction–amplified 16S ribosomal RNA gene.

This method is nearly specific for mycobacteria and uses positive culture from liquid or solid medium without the need for lengthy subculture. It shortens identification time to 3 days, which is much faster than the conventional biochemical method (mean, 8 weeks). It applies to all mycobacteria (approximately 100 species), unlike current nucleic acid hybridization methods, which probe only 4 species. The identifications are the same or are species specific for the well-characterized mycobacteria (59/68 [87%]) or more accurate for recently proposed species (9/68 [13%]).

The method requires a single sequencing reaction, which is efficient and cost-effective. Therefore, this method is clinically and academically useful.



J Am Acad Dermatol 1995;33:433-440

Occurs by exogenous inoculation, endogenous spread, and lymphatic or hematogenous dissemination

Primary inoculation tuberculosis

Accounts for <5% of total cases of primary tuberculosis

Nodule develops within 2-4 weeks after inoculation leading to a well-demarcated ulcer that heals with scarring

May have associated lymphadenitis

Acute miliary tuberculosis
(Tuberculosis cutis miliaris disseminata)

Clin Infect Dis 1996;23:706-710

Rare and usually fatal
More common in infants and children

Increased association with AIDS patients

Frequent on trunk, buttocks, genitalia, and thighs
Small papules with capped vesicles that rupture, crust, and heal with scarring

Lupus vulgaris

Reinfection tuberculosis in previously sensitized patients

Presents with plaques, hypertrophic, ulcerative, vegetating, and papulonodular
May involve mucous membranes with destruction of cartilage

Solitary or multiple small soft brownish papules with characteristic apple-jelly color on diascopy

Papules enlarge and become infiltrative with central atrophy

Tuberculosis verrucous cutis

Reinfection tuberculosis that occurs at sites of trauma in previously infected patients

Usually asymptomatic, erythematous papules that develop into verrucous plaque with fissures draining pus

Not usually associated with lymphadenopathy

(Tubercullosis colliquativa cutis)

Reactivation form of tuberculosis

Sinus tract in subcutaneous tissue, usually overlying a lymph node

Multiple metastatic tuberculosis abscesses in a patient with Pott disease and lung tuberculosis: a case report.

Saral Y, Coskun BK, Ozturk P, Bulut Y, Cobanoglu B.

Department of Dermatology, Firat University, Elazig, Turkey.

J Cutan Pathol. 2005 Oct;32(9):629-33. Abstract quote  

The incidence of tuberculosis in Western countries is rising, and continued vigilance together with an awareness of its protean manifestations is essential. Cutaneous tuberculosis is a relatively rare manifestation of the disease, accounting for only 1% of extrapulmonary cases of tuberculosis and 0.14% of all reported cases of tuberculosis.

A 19-year-old male patient was admitted to our clinic with skin lesions both at the front and at the back of his body. With clinical findings, histopathology, polymerase chain reaction, PA lung graph, and computerised tomography, the patient was diagnosed with metastatic tuberculosis abscess associated with lung tuberculosis and Pott's disease. Antituberculosis drugs were administered.

An increased awareness of the re-emergence of cutaneous tuberculosis will allow for the proper diagnosis and management of this increasing common skin disorder.


Tuberculids Represent hypersensitivity response to circulating antigens of the tubercule bacillus
Lichen scrofulosorum
Variant of micropapular form
Grouped scaly follicular tiny 1-2 mm papules
Small tuberculoid granulomas in periadnexal or focally lichenoid pattern
Superficial and deep perivascular and periadnexal, slight to moderately dense lymphocytic infiltrate with epithelioid histiocytes
Epidermis may show slight spongiosis and parakeratosis
Neutrophils may collect in epidermis above the granulomas

Pseudotumor resulting from atypical mycobacterial infection: a "histoid" variety of Mycobacterium avium-intracellulare complex infection.

Wood C, Nickoloff BJ, Todes-Taylor NR.

Am J Clin Pathol 1985 Apr;83(4):524-7 Abstract quote

A 54-year-old immunosuppressed cardiac transplant recipient with a six-month history of progressive swelling of the hand, with nodules and linear lymph node chain enlargement, diagnosed as a sporotrichoid Mycobacterium avium-intracellulare pseudotumor is described. The microscopic features closely resembled the previously described histoid variety of lepromatous leprosy.

Routine hematoxylin and eosin staining suggested a spindle cell neoplasm rather than an infectious or inflammatory process. An infectious etiology was pursued on the basis of the clinical setting.


Mycobacterial spindle cell pseudotumor of lymph nodes.

Chen KT.

Department of Pathology, Saint Agnes Medical Center, Fresno, California 93720.

Am J Surg Pathol 1992 Mar;16(3):276-81 Abstract quote

Two cases of spindle cell pseudotumor in the lymph nodes of patients with acquired immunodeficiency syndrome caused by mycobacterial infection are reported and the literature reviewed.

The lesions mimicked neoplasms because they were composed predominantly of spindle cells arranged in a storiform pattern. Most of the spindle cells were phagocytic cells that contained large amounts of mycobacteria.

It is important for the pathologist to recognize the lesion so that a prompt tissue diagnosis can be provided because specific therapy is available.

Fine needle aspiration cytology of mycobacterial spindle cell pseudotumor. A case report.

Corkill M, Stephens J, Bitter M.

Department of Pathology, University of Colorado Health Sciences Center, Denver.

Acta Cytol 1995 Jan-Feb;39(1):125-8 Abstract quote

We report a case of mycobacterial spindle cell pseudotumor (MSP) in a lymph node from an acquired immunodeficiency syndrome patient diagnosed by fine needle aspiration (FNA). The FNA cytology was characterized by spindle cell proliferation without the typical foamy histiocytes usually seen in mycobacterial infections and mimicked a mesenchymal neoplasm, particularly Kaposi's sarcoma.

This case illustrates the importance of including MSP in the differential diagnosis of lymph node FNAs from immunocompromised patients, particularly those that show spindle cell proliferation suspicious for Kaposi's sarcoma or another mesenchymal neoplasm.

Spindle cell tumors associated with mycobacteria in lymph nodes of HIV-positive patients: 'Kaposi sarcoma with mycobacteria' and 'mycobacterial pseudotumor'.

Logani S, Lucas DR, Cheng JD, Ioachim HL, Adsay NV.

Department of Pathology, Harper Hospital, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan 48201, USA.


Am J Surg Pathol 1999 Jun;23(6):656-61 Abstract quote

Patients infected with HIV often have unusual manifestations of common infections and neoplasms. One such example is "mycobacterial pseudotumor," an exuberant spindle cell lesion induced in lymph nodes by mycobacteria. Kaposi sarcoma also produces a spindle cell proliferation in lymph nodes of HIV-positive patients. These two entities must be differentiated from one another because of differences in treatment and prognosis.

We report here, however, three cases of intranodal Kaposi sarcoma with simultaneous mycobacterial infection, the occurrence of which has not been clearly documented. For comparison, we also studied three cases of mycobacterial pseudotumor, of which 14 cases have been described to date. There was considerable histologic overlap between these two lesions. Acid-fast bacilli were present in all cases, predominantly in the more epithelioid histiocytes in the cases of Kaposi sarcoma, and in spindle and epithelioid cells in the cases of mycobacterial pseudotumor.

The morphologic features that favored Kaposi sarcoma over mycobacterial pseudotumor were the prominent fascicular arrangement of spindle cells and slitlike spaces, the lack of granular, acidophilic cytoplasm, and the presence of mitoses. Immunohistochemistry was a reliable adjunct study in the differential diagnosis, as the spindle cells in mycobacterial pseudotumor were positive for S-100 protein and CD68 whereas those of Kaposi sarcoma were CD31- and CD34-positive but negative for S-100 protein and CD68. Awareness that Kaposi sarcoma may coexist with mycobacterial infection in the same biopsy specimen is important because these lesions may be misdiagnosed as mycobacterial pseudotumor.

The clinical impact of distinguishing between Kaposi sarcoma with mycobacteria and mycobacterial pseudotumor is significant because the presence of Kaposi sarcoma alters treatment and prognosis.

Mycobacterial spindle cell pseudotumor of the brain: a case report and review of the literature.

Morrison A, Gyure KA, Stone J, Wong K, McEvoy P, Koeller K, Mena H.

Armed Forces Institute of Pathology, Department of Neuropathology, Washington, DC 20306-6000, USA.

Am J Surg Pathol 1999 Oct;23(10):1294-9 Abstract quote

Spindle cell pseudotumors found in the skin, lymph nodes, bone marrow, spleen, lungs, and retroperitoneum have been reported recently in immunosuppressed patients, including those with acquired immunodeficiency syndrome.

The authors report a similar lesion limited to the brain in a 38-year-old human immunodeficiency virus-negative man receiving steroid therapy for treatment of sarcoidosis. Histopathologically the lesions were composed of spindle and epithelioid histiocytes, small foci of necrosis, and numerous acid-fast bacilli. The acid-fast bacilli were determined by culture and polymerase chain reaction to be Mycobacterium avium intracellulare.

Because of the uncommon histologic appearance of this lesion and the potential for treatment if recognized, mycobacterial spindle cell pseudotumors should be included in the differential diagnosis of spindle cell lesions in the brain in immunosuppressed patients.

Mycobacterial spindle cell pseudotumor of the appendix vermiformis in a patient with aids.

Basilio-de-Oliveira C, Eyer-Silva WA, Valle HA, Rodrigues AL, Pinheiro Pimentel AL, Morais-De-Sa CA.

Departments of Pathology and Clinical Immunology, Gaffre e Guinle University Hospital, Rio de Janeiro, RJ, Brazil.

Braz J Infect Dis 2001 Apr;5(2):98-100 Abstract quote

Mycobacterial pseudotumor (MP) is a rare pathologic presentation of both Mycobacterium tuberculosis and non-tuberculous mycobacterial disease, hitherto reported to occur only in immunosuppressed patients with or without human immunodeficiency virus infection. This lesion shares close pathologic resemblance to certain mesenchymal neoplasms, particularly Kaposi's sarcoma (KS), from which it must be properly differentiated due to distinct prognosis and therapy.

We report a case of MP obliterating the lumen of the appendix vermiformis in a 34-year-old patient who died of complications of AIDS at our hospital in Rio de Janeiro. A total of 24 cases of MP (including our patient) have been described in the literature. MP has been found especially in lymph nodes, but extranodal lesions have been described in the skin, spleen, lung, bone marrow, brain and, in our patient, the appendix vermiformis.

We offer a review of the other 23 published case reports of MP in both HIV-infected and uninfected patients and discuss the pathologic features that differentiate MP from KS.




Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study.

Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH, Rhoades ER, Harrison LH.

Department of Medicine, Infectious Disease Division, Uniformed Services University of the Health Sciences, Bethesda, Md 20814, USA.
JAMA. 2004 May 5;291(17):2086-91. Abstract quote  

CONTEXT: The duration of protection from tuberculosis of BCG vaccines is not known.

OBJECTIVE: To determine the long-term duration of protection of a BCG vaccine that was previously found to be efficacious.

DESIGN: Retrospective record review using Indian Health Service records, tuberculosis registries, death certificates, and supplemental interviews with trial participants.

SETTING AND PARTICIPANTS: Follow-up for the period 1948-1998 among American Indians and Alaska Natives who participated in a placebo-controlled BCG vaccine trial during 1935-1938 and who were still at risk of developing tuberculosis. Data from 1483 participants in the BCG vaccine group and 1309 in the placebo group were analyzed.

MAIN OUTCOME MEASURES: Efficacy of BCG vaccine, calculated for each 10-year interval using a Cox regression model with time-dependent variables based on tuberculosis events occurring after December 31, 1947 (end of prospective case finding). RESULTS: The overall incidence of tuberculosis was 66 and 138 cases per 100 000 person-years in the BCG vaccine and placebo groups, respectively, for an estimate of vaccine efficacy of 52% (95% confidence interval, 27%-69%). Adjustments for age at vaccination, tribe, subsequent BCG vaccination, chronic medical illness, isoniazid use, and bacille Calmette-Guerin strain did not substantially affect vaccine efficacy. There was slight but not statistically significant waning of the efficacy of BCG vaccination over time, greater among men than women.

CONCLUSION: In this trial, BCG vaccine efficacy persisted for 50 to 60 years, suggesting that a single dose of an effective BCG vaccine can have a long duration of protection.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
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DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Acid Fast-This is a peculiar histologic staining pattern associated with the cell walls of mycobacteria. Common stains used are Fite and Ziehl-Nielson stains.

Atypical Mycobacterium

Ghon Complex-This is both a clinical and radiologic term identified as primary infection within a calcified scar in the lung associated with a hilar (adjacent to the lung) lymph node.

Miliary-This is a pattern of spread through the bloodstream of an infected patient. As it disseminates, it leads to hundreds of small yellow-white lesions studding many organs. The name derives from millet seeds, fed to birds.

Pott's Disease-A variant of the disease affecting the vertebral (spinal) column. Advanced disease may lead to considerable bony destruction with collapse and impingement of the spinal nerves. Fistulas or channels may form along the muscles which line the vertebral columns leading to abscesses.

Basic Principles of Disease
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Commonly Used Terms
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Last Updated November 15, 2007

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