Special procedure: In order to detect mycobacterial DNA, a panel of specific PCRs was carried out. These PCR reactions integrated multiple specific primer combinations to detect Mycobacterium tuberculosis and some atypical mycobacteria like M. marinum. A specific PCR product amplified from the DNA of the inflammatory lesion using the primer combination for M. tuberculosis, but not for atypical mycobacteria (Figure 6).
Diagnosis: Concomitant sparsely granulated growth hormone cell pituitary adenoma and granulomatous giant cell hypophysitis with molecular pathological detection of M. tuberculosis DNA.
Pituitary adenomas (esp. the growth hormone producing ones) are not uncommon, they occur in approximately 20% of the general population (1). But the coincidence of a pituitary adenoma and a granulomatous hypophysitis irrespective of its etiology is a very rare event. The causes of granulomatous hypophysitis include syphilis, tuberculosis, sarcoidosis, mycotic granuloma, foreign body granuloma due to the rupturing of a Rathke's cleft cyst and idiopathic giant cell granulomatous hypophysitis (GGH) all of which appear with similar histological findings.
The radiological findings of a mass lesion is mimicked by all above mentioned inflammatory lesions, but especially the solitary tuberculomas of the pituitary gland show nearly identical pictures to the adenomas and the histological aspect of a granulomatous inflammation. This diagnosis is not inevitably considered during the diagnostic routine procedures for pituitary lesions in Europe and North America. In contrast to the unawareness in our countries of the isolated tuberculous infection of the pituitary gland there seem to be an awareness in the middle and far east, because currently the largest series of intrasellar tuberculomas has been reported by Sharma et al (12) and Desai et al. (4), as well as two case reports are given by Sharma (13) and Bhardwaj et al. (2). Their patients displayed clinical symptoms comparable to our case, but unlike ours the patients received an antitubercular therapy without a definite laboratory confirmation of an infection.
All of these cases display the diagnostic dilemma of a negative Ziehl-Neelsen stain, which is considered as the histological standard for the detection of florid tuberculosis.
In the present case, histology was ambiguous but the absence of necrosis and the acid fast bacteria pointed towards sarcoidosis or an idiopathic GGH.
However, since the advent of molecular methods to detect mycobacterial DNA, it has become more and more evident that M. tuberculosis may induce non classical granulomas and go undetected by Ziehl-Neelsen stains (8, 11, 13) but not undetected by molecular analysis, because usually the PCR analysis is able to detect less bacterial load than the Ziehl-Neelsen stain.
Nucleic acid analysis either by PCR or hybridization techniques (5, 8) represents a highly sensitive tool to detect infectious agents in paraffin embedded samples. Due to the sensitivity of the method the molecular pathological results should be reviewed carefully since several factors may influence the accuracy of the results including the correct selection of tissue samples and the experience of the laboratory.
An example is given by Saboor et al. (9), who reported the detection of mycobacterial DNA in sarcoidosis samples. Gerdes (6) and Thakker (14) reviewed Saboor's assumption carefully but were unable to confirm it. Which might have two reasons: Either the mycobacterial DNA is present due to an acute or chronic infection with mycobacteria or the DNA is present as a residua after a previous infection.
The present case raises an important question: Should we rely on the molecular pathological diagnosis of the tuberculosis in cases with or without typical histopathology and / or negative Ziehl-Neelsen stain? This is important in cases alike ours, where no clinical symptoms where found and the patient appeared otherwise healthy.
In the present case our conclusion is that the patient must have a tuberculous hypophysitis in addition to the growth hormone producing adenoma because the PCR analysis yields specific amplification products. The PCR reactions were performed according to different protocols. These include a nested PCR approach and the simultaneous detection of IS6110 and M65 DNA [modified from Zimmermann et al(15)].
Our conclusion is further supported by the clinical course of the patient, who developed pulmonary symptoms nearly two years after the surgery of the pituitary mass lesion was performed. No other cause for her illness had been found; therefore she received an antitubercular therapy
The present case with its atypical histopathology (no caseous necrosis, no acid-fast bacteria in Ziehl-Neelsen stains) and without clinical symptoms of tuberculous infection points to the previously described cases of idiopathic granulomatous hypophysitis (3, 7, 10). Are these cases also caused by mycobacteria and just failed to be proved by conventional histological methods? These cases should be reviewed, because the majority of the cases have been published in the 80s, when molecular pathological analyses were uncommon.
Contributed by Frauke Neff, MD; Gregor Weirich, MD; Peter Herzog, MD; Heinz Schlöser, MD; Claudia Kiebach, MD and Jügen Schlegel, MD.