Introduction
Necrotizing sarcoid granulomatosis (NSG) was initially separated as an entity by A.
Liebow [1 ]. In his initial cases only lung involvement was found. The morphologic features
of NSG were considered in between sarcoidosis and Wegener's granulomatosis (WG). The
cases showed granulomatous vasculitis and nodular aggregates of epitheloid cell granulomas
with foci of central necrosis. No organisms could be found. In subsequent years other
reports have shown involvement of non-pulmonary organs, namely eyes, liver, and spleen
[2 ]
[3 ]
[4 ]
[5 ]
[6 ]. In addition nodular sarcoidosis has become recognized as a variant of sarcoidosis
[7 ], and those cases showed an overlap with NSG. Since the introduction of video-assisted
thoracoscopy and the resultant larger than transbronchial biopsy specimen granulomatous
vasculitis is more often seen in sarcoidosis, which again eliminates one feature,
thought to be characteristic for NSG [8 ].
We therefore undertook a study of NSG and compared the features of NSG with sarcoidosis.
We specifically looked for features which might unequivocally differentiate NSG from
nodular sarcoidosis. Since we found mycobacterial DNA in some of our sarcoidosis cases
[9 ] we assumed that necrosis found in NSG might be associated with a positivity for
mycobacterial DNA. Therefore all cases were investigated for mycobacterial DNA using
PCR.
Methods and Materials
Slides and paraffin blocks from lung lesions were retrived from the archives of three
Institutions. Cases fullfilling the criteria of NSG were selected by the authors:
nodular aggregates of epitheloid cell granulomas, necrosis, and granulomatous vasculitis,
and the absence of identifiable infectious etiology by culture and/or special stains.
Only ten cases which fullfilled these criteria were collected. H & E and Movat pentachrome
stained sections and acid fast stains were made from formalin fixed paraffin embedded
lung tissue blocks. DNA was extracted from paraffin sections, and a PCR for the mycobacterial
chaperonin and for the insertion sequence (IS) 6110 was done exactly as described
previously [9 ]. Appropriate negative and positive controls cases were included.
Organ involvement other than pulmonary in these cases were: ocular in 1, liver in
2, spleen in 1, and hilar and mediastinal lymph nodes in 2 cases. In all these cases
non-pulmonary involvement was confirmed either by tissue biopsy or CT scan (Table
[1 ]).
For comparison six cases of nodular sarcoidosis, characterized by nodular aggregates
of epitheloid cell granulomas from 4 mm to 3 cm in diameter were chosen from the files
of one of the authors (HHP).
Table 1 Patient data; na = not available, OLB = open lung biopsy
Age (yr)
Sex
lung involvement
extrapulmonary involvement
unrelated disease
42
M
single nodule, OLB
ocular
42
F
2 nodules, OLB
liver, spleen
45
M
single nodule, OLB
no
49
F
3 nodules, OLB
pleura, liver
56
F
2 nodules, OLB
no
65
F
2 nodules, OLB
no
history of breast cancer
42
F
mass left UL, OLB
no
na
28
M
nodules, OLB
no
pleuritis, fever
12
M
bilateral nodules (autopsy)
no
glomerulonephritis, pleuritis, dead due to pneumococcal sepsis*
66
M
bilateral basal nodules (limited autopsy)
no
na
* In this case primarily there was a differential diagnosis of hypersensitivity pneumonitis,
Wegener's granulomatosis, infectious granulomatosis, necrotizing sarcoid granulomatosis.
All former three were excluded clinically and by special stains and culture
Results
In all cases granulomatous nodules and large areas of necroses could be found. In
serial sections the contributing pulmonary arteries were demonstrable, all showing
different stages of granulomatous vasculitis. The lumina of these arteries were either
narrowed or completely obstructed by multiple epitheloid cell granulomas. At the very
early stages an infiltrate of lymphocytes, macrophages, few epitheloid and Langhans
giant cells without granulomatous organization could be found (Fig. [1 ]), in later stages mature confluent epitheloid cell granulomas predominated, leading
to partial or total lumen obstruction (Fig. [2 ]
[3 ]
[4 ]). In very late stages the vessel lumina were completely obstructed and only remnants
of the inflammatory infiltrate could be found (Fig. [4 ]). Middle sized as well as small sized blood vessels were involved. Necrotic areas
were always found around this vasculitis. In all cases non-necrotizing large nodular
aggregates of epitheloid cell granulomas were seen in the lung parenchyma (Fig. [5 ]). The amount of Langhans giant cells was variable, ranging from a few to numerous
cells. Lung involvement including hilar lymph nodes was present in all cases, whereas
extrapulmonary involvement was documented in three cases, including ocular liver and
spleen.
Mycobacterial DNA, neither mycobacterial chaperonin, nor insertion sequence 6110 was
not found in any of the 10 cases.
In nodular sarcoidosis similar large aggregates of epitheloid cell granulomas as in
NSG were seen and also granulomatous vasculitis (Fig. [6 ]). The only difference was the absence of necrosis and vascular lumen obstruction
in nodular sarcoidosis.
Fig. 1 Granulomatous vasculitis in NSG with epitheloid cell granulomas. In this early stage
there is no obstruction of the vascular lumen; H & E, original magnification × 100.
Fig. 2 Granulomatous vasculitis in NSG with epitheloid cell granuloma (upper left). In this
late stage vascular lumen is partially obstructed and there is some recanalization;
Movat pentachrome, original magnification × 65.
Fig. 3 Granulomatous vasculitis in NSG. The lumen of this large pulmonary artery is partially
obstructed, smaller arteries in the surrounding infarct-like necrosis, however, are
complete occluded. Epitheloid cell granulomas can be seen within but also outside
this necrotic focus. Movat pentachrome, original magnification × 40.
Fig. 4 Late stage of vasculitis: This small pulmonary artery is completely obstructed, remnants
of the elastic laminae are visible, but only a few inflammatory cells. The sourrounding
lung parenchyma is completely necrotic. Movat pentachrome, original magnification
× 100.
Fig. 5 Nodular aggregates of epitheloid cell granulomas in NSG. H&E, original magnification
× 65.
Fig. 6 Granulomatous vasculitis with epitheloid cell granulomas in a case of nodular sarcoidosis;
there is no lumen obstruction of this small vein; H & E, original magnification ×
100.
Discussion
NSG was originally defined by Liebow as a lung specific granulomatous disease with
vasculitis and necrosis, lying in between sarcoidosis and Wegener's granulomatosis
- hence the name [1 ]. Subsequent reports have shown that NSG is a systemic disease with extrapulmonary
involvement. Most often pleural, ocular, liver and spleen lesions were described [2 ]
[3 ]
[4 ]
[5 ]
[6 ].
The invention of video-assisted thoracoscopy has opened the opportunity to review
larger lung specimen in sarcoidosis too. This has enabled us to see granulomatous
vasculitis in sarcoidosis more often, than anticipated from our experience with transbronchial
biopsies and equals that seen in autopsy cases [8 ], and nodular sarcoidosis, a variant of sarcoidosis with larger, macroscopically
visible nodular aggregates of epitheloid cell granulomas is seen more often. This
has brought up the question, if NSG is another variant of sarcoidosis.
This has prompted us to retrieve cases from our institutional collections and to compare
the features with those of nodular sarcoidosis (NS). Nodular aggregates of epitheloid
cell granulomas are found in NSG and in NS. Granulomatous vasculitis too can be seen
in NSG and NS, however, complete obstruction of the vascular lumina was only seen
in NSG. And necrosis is still the hallmark of NSG. There is a coagulative infarct-like
type of necrosis in NSG, which could in most of our cases be attributed to the granulomatous
vasculitis with lumen obstruction. Therefore it might be speculated, that NSG is the
late stage of NS, when vacular lumen obstruction has occurred and in turn caused infarct-like
necrosis. Much rarer necrosis might also be caused by the confluence of degenerative
fibrinoid necrosis, sometimes also seen as necrobiotic foci in sarcoidosis.
In addition clinical investigations and comparative clinico-pathologic studies have
shown similar immunologic features for NSG and sarcoidosis, for example a dominance
of T-helper lymphocytes and a T-helper associated cytokine spectrum in BAL fluid ([10 ]
[11 ]
[12 ]; and personal unpublished observations).
In the differential diagnosis Wegener's Granulomatosis can easily be discerned by
the presence of granulocytic vasculitis in the early and lymphocytic vasculitis in
the late phase. Bronchocentric granulomatosis can be differentiated from NSG by the
absence of a granulomatous vasculitis and infarct-like necrosis, and lymphomatoid
granulomatosis (angiocentric high grade non-Hodgkin lymphoma) by a vascular infiltrates
composed of highly atypical lymphoid cells.
In contrast to previous findings in sarcoidosis, none of the NSG cases had an association
for mycobacterial DNA [9 ], ruling out a Mycobacteria based etiology.
In our opinion NSG should be classified as a variant of sarcoidosis, characterized
by extensive granulomatous vasculitis, which in turn causes coagulative necrosis.
NSG do no longer qualify as a separate entity.