This 64-year-old man with a history of diabetes mellitus presented with a 2-month history of weight loss, fever, chills, night sweats, frequent falls, and altered mental status. He was admitted to the hospital with the diagnosis of meningitis. Thrombocytopenia (35,000/cu mm) was noted. Chest radiography was performed. A CT of the head, which was normal on day 2, showed a left subdural hematoma the next day. The patient then became unresponsive and died.
Figure 1. Chest Radiograph
Chest radiography shows numerous, bilateral, small, well-defined nodules.
Figure 2. HRCT
HRCT shows numerous, bilateral, small, well-defined nodules randomly distributed throughout the lung.
What is the differential diagnosis?
Photograph contributed by Dr. Walter Finkbeiner
Figure 3. Slice of Postmortem Lung
The lungs were heavy (left 950 g, right 900 g; normal 250 g each). Fine nodules are scattered at random throughout the upper and lower lobes, although there is a tendency to spare the upper portion of the lower lobe (to the right) in this particular specimen. Note that the nodules tend to be slightly larger in the upper, than in the lower, lung.
Figure 4. Histologic Section of Nodule
This collection of ill-defined, epithelioid cells, lymphoid cells, and a single multinucleated giant cell is representative of the nodules seen on gross inspection. There is a small focus of necrosis.
Find the multinucleated giant cell. What type of giant cell is it?
Find the area of necrosis.
Gross and histologic examination of the liver, spleen, kidneys and adrenals showed similar lesions. What is the diagnosis of the lesion, and what is its differential diagnosis?
Scroll down after answering the questions.
Introduction: Tuberculosis, caused by M. tuberculosis (MTb), has been an infection of importance throughout history. Although MTb infection rates have been declining in the United States, worldwide, MTb infection rates remain quite high. MTb infection occurs with the inhalation of airborne droplets containing the organisms. Many factors influence the likelihood of contagiousness, including the presence of cavitation on imaging examinations, the burden of organisms, and the severity of cough. Person-to-person transmission is also more likely if exposure occurs in a poorly-ventilated area or if contact with the infectious person is prolonged, such as occurs in relatively confined situations like prisons, schools, and nursing homes. However, genotyping of MTb has suggested transmission to casual contacts, as well . Several different patterns of tuberculous infection have been described, each differing in pathologic, clinical, and radiologic manifestations. These include primary MTb, post-primary MTb, and miliary MTb.
Miliary tuberculosis, so-named because of the resemblance in size of lesions to millet, results from lymphohematogenous dissemination of organisms. It presents with fever, weakness, night sweats, and weight loss. About 1/2 of patients receive a diagnosis of fever of unknown origin. Diagnosis is aided by radiographic imaging of the lung, smears and cultures of fluids, and biopsies (bone marrow, lung, liver). A miliary pattern on chest radiographs may develop after admission, and CT is more sensitive than the radiograph for diagnosis. Acid fast stains are often negative on body fluids, but PCR increases the yield. Acid fast stains on tissues are often negative, and multiple stains may be necessary. In a study of 38 patients from Turkey, predisposing factors were present in 24%, and infected contacts could not be identified. Male sex, an atypical pattern on the chest radiograph, altered mental status, and failure to treat predicted mortality. Lesions on chest radiographs resolved over a period of 30 to 180 days in 12 patients who survived .
Radiographic Imaging: MTb infection may result in a miliary pattern, which manifests as numerous, well-defined nodules around 2 mm in size, diffusely distributed throughout the lungs. On HRCT, these small nodules show a random distribution. The miliary pattern represents lymphohematogenous dissemination of infection from an active focus, and may be seen in both primary and postprimary disease. Radiographs can occasionally appear normal in patients with miliary tuberculosis .
Active Versus Inactive Tuberculosis: Radiologists are often asked to determine whether a particular radiographic pattern suggests the presence of active tuberculous infection, or more frequently, whether active tuberculous infection can be confidently excluded by radiography. In general, one must have prior radiographs for comparison to determine disease activity, and the radiographic pattern should be stable for 6 months or more before suggesting that disease is not active. An exception to this rule is that one may confidently assume that calcified lung nodules represent inactive disease. Radiographic patterns that usually suggest active disease include consolidation, endobronchial spread patterns, the miliary pattern, and cavities. On HRCT, centrilobular nodules, particularly when "tree-in-bud" opacities are present, usually suggest active disease. Such nodules often resolve with treatment. Findings more often associated with inactive disease include bronchiectasis, linear opacities, and calcified nodules.
Pathology: Granulomas of miliary tuberculosis are generally ill-defined and of uniform small size, although they increase slightly in size from the lung base to the apex because of the increasing oxygen gradient. Granulomas at the same stage of development can be found in multiple organs. Epithelioid cells are poorly formed, and multinucleated giant cells and lymphocytes are sparse. Acid fast stains show few or no organisms. In contrast, in localized disease, the non-caseous granulomas, as well as the caseous granulomas, have better-formed epithelioid cells, more lymphoid cells, giant cells, and fibrosis.
In the present case, the mediastinal lymph nodes were enlarged by caseous necrosis. The lymphohematogenous dissemination of organisms presumably occurred from there. ARDS and multisystem organ failure have been described in patients with miliary MTb . Other organs typically involved (as in the present case) include the liver, spleen, kidneys, adrenal, and thyroid. For pathologic correlates of other manifestations of tuberculosis, click here.
Pathophysiology: In a study of cytokines in fluids of patients (without HIV infection) with two types of tuberculosis--those with pleural effusion (localized disease) and those with miliary tuberculosis--interferon-gamma (IFN) (reflecting Th1 activity) levels were higher in pleural fluid than in blood of those with effusions, whereas in patients with miliary tuberculosis they were higher in the blood than in BAL fluid. The ratio of IFN to IL-4 (IL-4 reflects Th2 activity) was much greater in the pleural fluid than in the BAL fluid. Further, analysis of intracellular IFN and IL-4 corroborated these findings . These results suggest that Th1 responses predominate in pleural MTb, and Th2 responses predominate in miliary tuberculosis, possibly explaining the difference in histologic appearance, as well as clinical behavior.
Final Diagnosis: Miliary tuberculosis, diagnosed at postmortem examination. The subdural hematoma was attributed to the thrombocytopenia.
References: To return to reference section after viewing abstract, click here before clicking on "abstract".
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Radiographic Differential Diagnosis: The differential diagnosis of small, well-defined, randomly-spaced nodules around 2 mm in size (the so-called "miliary" pattern) includes diseases hematogenously disseminated to the lung parenchyma, such as tuberculosis, fungal infections, and tumor metastases. Rarely, sarcoidosis, disseminated viral infections , or injection talcosis may present in this fashion.
Histologic Diagnosis: Necrotizing granuloma.
Differential Diagnosis: Multiple small granulomas (miliary) suggest tuberculosis, disseminated Mycobacterium bovis , coccidioidomycosis , histoplasmosis , and pneumocystosis [5,6]. An acid fast stain showed single organisms consistent with tubercle bacilli in several of the granulomas.
Diagnosis: Miliary tuberculosis
Small area of necrosis
Multinucleated giant cell of the Langhans' type (peripherally located nuclei)