2022, Volume 38, Number 2, Page(s) 133-141
Hepatocellular Carcinomas with Granulomatous Inflammation In Tumor Stroma: Clinicopathologic Characteristics
Burcu SAKA1, Ferhat OZDEN1, Ayse ARMUTLU2, Gokhan ERTUGRUL3
1Department of Pathology, Istanbul Medipol University, School of Medicine, ISTANBUL, TURKEY
2Koc University, School of Medicine, ISTANBUL, TURKEY
3Department of General Surgery, Istanbul Medipol University, School of Medicine, ISTANBUL, TURKEY
Keywords: Hepatocellular carcinoma, Inflammation, Granuloma
To determine the frequency of granulomatous inflammation within hepatocellular carcinoma (HCC) and its clinicopathologic
Material and Method: Fifty-eight HCCs (51 explants, 3 lobectomies, and 4 segmentectomies) were reviewed.
Results: Five (8.6%) cases (F/M=1/4, mean age: 63.6) were identified with granulomas.1/5 had history of neoadjuvant therapy. 4/5 patients
presented with early stage (pT1/2). All were well-differentiated (Grade1-2/4). The mean number of tumor foci was 3.6, with a median size of 2.2 cm.
All of them had advanced fibrosis. No difference was identified from cases without granulomas (n=53) in terms of prognosis and aforementioned
parameters (p> 0.05). Granulomas were mainly concentrated in peripheral parts of the tumors. One case with nodule-in-nodule formation had
granulomas lined along the border of the inner nodule. In 2 cases, granulomas were identified in steatohepatitic areas, while another had clear
cell change. Only 1 had necrotizing granulomas, none with acid resistant bacilli. Two cases revealed concomitant granulomas in the adjacent
liver parenchyma in addition to the tumor stroma. Except for one with a history of tuberculosis, none of the cases had a granulomatous disease.
Conclusion: This is the largest case series of HCCs with granulomas by far. Our data revealed neither clinicopathologic and prognostic difference
nor definite etiology related to granulomas. Yet, association with steatotic and clear tumor cells suggests the role of cytoplasmic content, while
distribution of granulomas points to host immune response.
Granulomatous inflammation is a unique type of chronic
inflammatory response (1). Although it does not indicate
a definite etiology, its detection limits the differential
diagnosis list leading to effective treatment. Granulomas
may be associated with infectious [e.g. tuberculosis (Tbc)]
or noninfectious diseases (e.g. sarcoidosis, Crohn’s disease)
and local irritants (e.g. necrotic material) 1
granuloma stays as a rare etiology in this differential
Malignancy related granulomatous inflammation was
observed as early as 1911 and throughout the time, it has
been defined mainly in 3 locations; in tumor draining
lymph nodes (LNs), distant organs, or within tumor stroma
2-5. ‘Sarcoid-like reaction’ is a commonly used term
for all these 3 forms, but is mainly preferred to define a
systemic inflammatory response resembling sarcoidosis in
both clinical and pathologic aspects.
Hodgkin lymphoma and disgerminoma/seminoma (in
about 15% of cases) constitute well-known examples
of malignancies characterized by granulomas in tumor
stroma 6. They are followed by some rare types of
malignancies; mainly carcinomas but also a few sarcomas
7,8. Hepatocellular carcinoma (HCC) is one of these rare
carcinomas represented by only 4 case reports in the last
40 years 9-12, when patients with comorbidities such as
sarcoidosis and Tbc are excluded 13-15. There is virtually
no systematic analysis regarding the frequency and
clinicopathologic characteristics of HCC cases harbouring
This study aimed to determine the frequency of granulomatous
inflammation in HCCs (‘granulomatous cases’),
as well as to define the clinicopathologic features of
these cases. We also aimed to determine the etiology and
prognostic impact of this reaction by comparing them with
HCCs without granulomas (‘non granulomatous cases’).
Consecutive 58 hepatic resections (51 explants, 3 lobectomies
and 4 segmentectomies) diagnosed as HCC,
approximately in a period of five years were included.
Nonspesific histiocytic reactions such as histiyocytes
around tumor necrosis, microsphere-related foreign body
reactions, or isolated histiyocytic giant cells dispersed in
tumor stroma were excluded. Collection of activated macrophages
(epithelioid cells) were recorded as ‘granuloma’
1. Accompanying cells (lymphocytes, eosinophils, Langhans
giant cells) and necrosis were also recorded. Small,
uniform, discrete, naked granulomas without necrosis
were accepted as ‘sarcoid-like’ granuloma 1.
Histopathological and Histochemical Analysis
All Hematoxylin-eosin slides were reviewed by a single
observer. Whenever needed for conflicting parameters,
two pathologists decided together.
All the relevant parameters required to determine pT (AJCC
8th ed.) were noted in additon to tumor size, histologic
grade (based on Edmondson and Steiner grading system),
histologic subtype, and tumor necrosis of five largest foci
16,17. Granulomas and their characteristics; distribution
throughout the tumor (in the center or at the periphery),
presence of necrosis, accompanying inflammatory cells
(lymphocytes and eosinophils), and Langhans type giant
cells were reviewed. Intratumoral inflammation (apart from
granulomatous inflammation) was screened at 10x and
arbitrarily scored as none, minimal (barely perceptible),
and moderate/dense (easily perceptible).
Slides of background liver (57 of 58) and regional LNs of
dissected cases (16 of 58) were also examined regarding
fibrotic stage and granulomatous inflammation.
Ziehl-Neelsen staining was performed in each tumor block
with stromal granulomas.
Evaluation of Clinical Parameters
Information on the patients’ gender, age, etiology of
chronic liver disease, history of neoadjuvant therapy and
follow-up information were obtained through pathology
databases, patients’ charts and national database of death
certificates. The patients who died within the first 30 days of
the postoperative period (9 patients in non granulomatous
group) were excluded from the survival analysis.
The analysis was performed using The jamovi project
(2021, Version 1.6, Computer Software, Retrieved from
https://www.jamovi.org.) and R Core Team (2020, Version
4.0, Computer software, Retrieved from https://cran.rproject.
org.). R packages retrieved from MRAN snapshot
Clinicopathological variables were compared according
to the presence of granulomas. Since the granulomatous
cases’ group was low in number, continuous variables were
compared with the Mann-Whitney U Test, and proportions
of categorical variables were compared with Fisher’s Exact
Test. Phi-coefficient and Cramer-V tests were used to
assess the strength of association.
Clinical outcomes were recorded and analyzed by Kaplan-
Meier curves, and the differences in clinicopathological
features and overall survival between groups compared by
The study was conducted in full accordance with local GCP
guideline and current legislations, while the permission was
obtained from the institutional ethics committee (Date:
7.17.2019, Approval number: 583) for the use of patient
data for publication purposes.
Among 58 cases of HCC, intratumoral granulomatous
inflammation was identified in 5 (8.6%).
Clinicopathologic Features of the Study Cohort
The patients were four males and one female [F/M=0.25,
vs 0.2 in cases without (w/o) granulomas]. The mean age
was 63.6 years (vs. 57.2 in HCC w/o granulomas) (Table I).
Click Here to Zoom
|Table I: Clinicopathological features of 5 cases with granulomas and 53 cases w/o granulomas comparatively.
Of the 5 cases with granuloma, 2 had Hepatitis B, 1 had
Hepatitis C, 1 had non-alcoholic steatohepatitis, and 1
had multiple factors (Hepatitis B and alcohol) leading
to cirrhosis. The non-granulomatous group had similar
etiological distribution, as viral hepatitis was the main cause
of chronic liver disease. In contrast to granulomatous ones,
approximately one-tenth (7.6 %) of the non-granulomatous
cases were devoid of advanced fibrosis. The proportion of
patients with neoadjuvant therapy was roughly similar
between the two groups (20% in granulomatous and 28%
in non-granulomatous cases). All the patients in study
cohort were organ confined (Table I).
Mean numbers of tumor foci were 3.6 and 2.6 in
granulomatous and non-granulomatous cases, respectively.
Mean and median tumor sizes of granulomatous cases
were smaller (3.9 cm vs. 4.75 and 2.2 cm vs. 3.2 cm in nongranulomatous
cases), although not reached statistical
significant difference (Table I).
Totally 131 tumor nodules were investigated in 58 cases,
while 17 of them were noted in 5 granulomatous cases.
Four of 5 cases were multifocal, with 1 of 4 (Case 1), 2 of 5
(Case 3), 3 of 5 (Case 4) and 2 of 2 (Case 5) tumor foci with
granulomas. Collectively, granulomas were detected in 9
tumor foci (Table II).
All of granulomatous cases were lower histologic grade (1
was grade 1/4 and remaining were grade 2/4) compared to
non-granulomatous ones, in which 17 were (29 %) grade
3-4/4 (Table I).
Regarding histologic subtypes of 17 foci in 5 granulomatous
cases, two foci (Case 1 and dominant focus of Case 3) were
the steatohepatitic (SH) subtype (more than 5% of tumor
represents SH features) while another (one focus of Case
4) was characterised with focal (less than 5%) SH features.
SH characteristics (16 cases with> 5% and 1 case with <%5)
were identified in totally 17 of 114 tumor foci investigated
in 53 HCC w/o granulomas. Of note, 3 foci of 114 foci were
clear cell subtype (> 50% of tumor with clear cells), while 8 of
them had clear cell features (<50% of tumor with clear cells).
The macrovascular invasion was not identified in granulomatous
cases, in contrast to one-tenth of non-granulomatous ones (5 of 53, 9.4%). The microvascular invasion was
detected 40% and 32% of cases, respectively in granulomatous
and non-granulomatous groups.
Except for one case, all granulomatous cases presented with
early stage (pT1/2) in comparison with 74% of HCC cases
No statistically significant difference was found between
the groups regarding these documented features (Table I).
No drug history was identified except for anti-hypertensive
and anti-diabetic medications. Only 1 of 5 patient was
treated for Tbc 7 years before (Case 1), with sequel changes
at the apex of the lung. Of note, this was a nonnecrotizing
case (Table II).
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|Table II: Clinicopathologic details of 5 HCC cases with intratumoral granulomas.
Histopathologic Details of Granulomatous
Granulomas were localized mainly in circumferential
regions of tumor stroma (n=6), within ~2 mm (approximately
10x objective diameter) from the tumor/nontumor
interface, even very rarely in touch with tumor pseudocapsule (Case 2). In 2 foci with steatohepatitis-like features,
granulomas were concentrated specifically in these areas,
instead of tumor periphery (Case 1 and 4, Figure 1A) while
intermingled with clear cells in two foci (Case 3, Figure
1B). One focus with nodule-in-nodule formation had
multiple granulomas located on the fibrotic pseudocapsule
surrounding the inner nodule (Case 5). This focus also had
granulomas at the peripheral part of the outer nodule.
All foci had discrete granuloma formations, except one with
confluent granulomatous inflammation (Case 4, Figure 2).
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|Figure 1: A) Stetohepatitic hepatocellular carcinoma with dispersed histiocytic giant cells forms a granuloma in the left upper quadrant
of the image (Case 1), H&E, X20 B) Granuloma in relation to tumor cells with clear cytoplasm (Two foci of Case 3), H&E, x20.
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|Figure 2: One focus of case 4 was characterized by a prevalence of granulomas with a tendency to confluence (A). The dense histiocytic
infiltration accompanied the tumor cells even in a microscopic focus where the tumor capsule was exceeded (B), H&E, x20.
Only 1 case revealed necrotizing granulomas with
palisading histiocytes (Case 5, Figure 3). Langhans-type
giant cells were common and identified in 6 of 9 foci.
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|Figure 3: Necrotizing epithelioid cell granulomas with palisading
histiocytes and multinucleated giant cells (One focus of Case 5),
The moderate density of lymphocytic infiltration was
intermingled with histiocytes in all granulomas. No
eosinophils were identified. Granulomas did not contain
any tumor cells, either.
Two tumor foci revealed rare granulomas in the adjacent
liver parenchyma (Case 3 and 4). Lymph nodes were
dissected in only one patient (Case 1) which did not reveal
any granulomas. No acid-resistant bacilli were identified
with Ziehl Neelsen staining.
Follow-up and overall survival times (min-max: 1-60
months) were available in all cases. Nine patients died perioperatively.
Of the remaining 49 patients, 44 were non-granulomatous
cases. Since only 4 patients died in this group, and the data
of 9% (4/44) does not allow the Kaplan-Meier analysis,
median survival could not be calculated. Cases without
granulomas had 1-yr, 3-yr and 5-yr survival rates of 89.4%.
One of them was alive with multiple intraabdominal
recurrences at 29th month.
Among cases with granulomas (n = 5), 2 died of disease.
Median survival was 33.6 months. One of them was alive
with the humerus metastasis at 18th month.
Cases with granulomas had 1-yr survival of 80% and 3-yr
survival of 40%.
The overall survival was not found to be different between
the groups (p = 0.12) (Figure 4).
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|Figure 4: Overall survival comparison of granulomatous vs.
nongranulomatous hepatocellular carcinoma cases.
Among the 58 HCCs included in this study, which to our
knowledge represents the first cohort to date analyzed
for this purpose, 5 cases (8.6 %) had granulomas.
Granulomatous inflammation in HCC appears to be a very
rare histologic finding in the literature, reported in middleaged
patients with viral hepatitis and/or cirrhosis (Table
) (9-12). There are also 2 more cases not included in
the table since there is no detailed information about the
patient’s characteristics. One of these is a HCC case with
intratumoral granulomas written by Neville et al. 18,
and the other is a rare case diagnosed as hepatocellular
neoplasm of uncertain malignant potential 19
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|Table III: Clinicopathologic features of Hepatocellular Carcinoma Cases without accompanying established granulomatous diseases.
Granulomas accompanying malignancy can be located
within tumor stroma in a randomly dispersed fashion.
They can also show tendency to the peripheral regions of
neoplastic lesion, such as beneath the tumor pseudocapsule
in capsulated lesions (but still within the tumor) or at
the edge of tumor stroma, creating a border between
neoplasia and surrounding parenchyma 7,20-22. The
latter was the predominant pattern detected in this cohort
(6 of 9 foci). Bässler and Birke reported lymphocyte-poor
(naked) and compact ‘sarcoid-like’ granulomas relatively
in circumferential regions 21. Since lymphocytes were
accompanying the histiocytes in all granulomas, no sarcoidlike
granulomas were detected in this study and it was not
possible to comment on such a distribution difference.
In addition to tumor stroma, granulomas may also be
detected in the nonneoplastic parenchymal part of the
tumorous organ 22. This phenomenon was seen in only
2 of 58 cases (Case 3 and 4).
The granulomas were not fairly uniform. There were
predominantly non-necrotizing (7 foci, 4 cases) and less
frequently necrotizing ones (2 foci, 1 case), some with
palisading histiocytes (1 foci), similar to the infrequent
reporting of necrotizing granulomas in the literature 23.
All of them had a mononuclear infiltrate as reported in
literature 21. However, none of them had eosinophils,
unlike Kojima et al.’s findings 24.
When it comes to the underlying mechanism of granuloma
formation, T cell-dependent reaction to degrade tumor
particles is the recognized pathogenesis although the exact
antigens in each type of tumor are not known 25. In our
opinion, their propensity to locate circumferentially as well
as the conspicuous alignment around inner nodule of one case (Case 5) are supportive histologic features of the host
reply to tumor antigens.
Soluble tumor antigens also induce a granulomatous
response wherever they drain (i.e., regional LNs, liver)
3,25. This cohort revealed only one example for
granulomatous lymphadenitis (in a case w/o granulomas
in his tumor) and 4 cases with rare granulomas in the
nonneoplastic liver (2 cases w/o granulomas and 2 cases
with granulomas in their tumor - Case 3 and 4).
Specific to necrotizing granulomas, two additional
mechanisms are also discussed. Bassler and Birke
interpreted necrosis as a hypersensitivity reaction
triggered by persistent antigen expression due to their
patient’s recurrence history of breast carcinoma 21. And
since nonviable tumor cells were detected in necrotizing
granulomas, Coyne pointed out the role of necrotic tumor
cells 23. However, the one necrotizing case (Case 5) in
this series had neither a previous history of malignancy nor
necrotic tumor cells in the granulomas.
The cytoplasmic content of tumor cells is another suspected
reason of granulomatous reaction. The high glycogen
content seen in seminomas, and clear cell and papillary renal cell carcinomas is stated as a trigger of this reaction.
The striking accumulation of granulomas in close relation
with steatohepatitic tumor cells appears to support this
mechanism (Case 1 and Case 4) as well as clear cells in Case
3. In this regard, Kai et al. reported an unusual HCC case
with dense fat-loaded histiocyte infiltration, suggesting
the role of lipid in tumor cells driving macrophages for
phagocytosis. High levels of chemokines and colonystimulating
factors for macrophages were detected in their
case as supportive of this pathogenesis 26.
Drugs are also reported as a causative factor of granulomas
in hepatocellular lesions. Ichikawa et al. recorded chemo
embolic lipiodol droplets, while others reported the
role of oral contraceptives (OC) 11,27. None of the
granulomatous cases had neoadjuvant therapy or OC
history in this study.
Bieze et al. reported 5 hepatocellular adenomas (HCA) with
granulomas in the tumor stroma and/or background liver
tissue. Since 4 of them were inflammatory type HCA, they
pointed to the impact of prolonged chronic inflammatory
stress 27. Unlike this report, the inflammatory infiltrate
score was minimal for 4 of 5 cases except Case 4 with moderate/dense infiltration, with no statistically significant
difference between the groups (p>0.05).
It is worth noting that since granulomatous inflammation
has a wide range of etiology, their presence in a malignant
case raises the question of exclusion of the other reasons
to argue the aforementioned pathogenesis. The differential
diagnosis can be extremely difficult, especially in cases
with systemic granulomatous response known as ‘tumorrelated
sarcoid-like reaction’ 7,28. In this cohort, none
of the patients had a history of any other granulomatous
disease not only before the surgery but also along the
follow up period, except one granulomatous case had a
history of Tbc, which had been effectively treated 7 years
ago (Case 1). In Case 1, the small, noncaseating structure
of the granuloma, and additionally and more importantly
the presence of accompanying giant cells in its immediate
vicinity and concentration of this histiocytic reaction solely
to the steatotic area of tumor, were the most suggestive
features that it was not associated with Tbc (Figure 1A).
The hilar lymph nodes of the explant were also devoid
of any granulomas, which minimizes the possibility of
systemic/infection related inflammatory response. Besides,
the patient had no clinical findings for Tbc.
The prognostic impact of the granulomas remains
an unanswered question that has recently generated
remarkable interest among cancer researchers, especially
with the introduction of immune checkpoint inhibitors
(ICIs) 22. Despite some previous conflicting reports, there
is progressively increasing literature indicating its role in
local tumor regression as well as metastasis prevention 21,29. Recently, sarcoidosis-like granulomatous reactions
(SLR)- similar to sarcoidosis in aspects of both histology and
clinical manifestation - have been described as a side effect
of ICIs. There is evidence that these drugs show their effect
as an anti-tumor agent through this reaction 30. They
inactivate proteins (synthesized by immune cells or tumor
cells) that inhibit antitumor T cell activity 31. In several
malignancies, comparison of patients with and without
SLR supports an association between this reaction and a
better clinical response, as well as better overall survival
32. Our findings were open to interpretation in either
way in terms of prognostic effect of granulomas. Although
no overall survival difference was identified in this study,
the granulomatous cases had worse survival rates. On the
other hand, they were associated with better prognostic
factors. Higher grade (3-4/4), macrovascular invasion,
and relatively larger tumor size were identified in the nongranulomatous
In summary, hepatocellular carcinomas with granulomatous
inflammation are not a very rare finding (8.6%),
discovered in smaller tumors with lower grades (Grade 1-2).
Granulomas are usually the non-necrotizing type. Their
peripheral location within tumor stroma and relation to
clear cells and steatohepatitic tumor areas are remarkable.
Clinicopathologic features and prognosis appear to be
similar to hepatocellular carcinomas without granulomas,
although definitive interpretation is not possible due to the
limited numbers and follow-up time. Since the number
of patients was low, these non-significant results may not
represent a true indifference.
This study suggests the interference of the host immune
system against tumor antigens and the role of cytoplasmic
content. However, further studies are needed to elucidate
the underlying mechanisms of this reaction type and to
establish the clinical impact.
CONFLICT of INTEREST
All authors declare that they have no conflict of interest.
Concept: BS, AA, Design: BS, AA, Data collection or
processing: BS, FÖ, GE, Analysis or Interpretation: BS,
FÖ, Literature search: BS, Writing: BS, FÖ, Approval: BS,
FÖ, AA, GE.
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