Tissue eosinophilia in head and neck squamous neoplasia: an update
Eosinophils are multifunctional granulocytes that play an imperative role in health and disease. They have also been found to be a crucial component of peri- and intratumoral inflammatory infiltrate. Tumor-associated tissue eosinophilia (TATE) has been observed and described in many tumors, includin...
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| Zitieren: | Tissue eosinophilia in head and neck squamous neoplasia: an update / M. Jain, S. Kasetty, S. Khan, N. K. Jain // Experimental Oncology. — 2014. — Т. 36, № 3. — С. 157-161. — Бібліогр.: 52 назв. — англ. |
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| citation_txt | Tissue eosinophilia in head and neck squamous neoplasia: an update / M. Jain, S. Kasetty, S. Khan, N. K. Jain // Experimental Oncology. — 2014. — Т. 36, № 3. — С. 157-161. — Бібліогр.: 52 назв. — англ. |
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| description | Eosinophils are multifunctional granulocytes that play an imperative role in health and disease. They have also been found to be a crucial component of peri- and intratumoral inflammatory infiltrate. Tumor-associated tissue eosinophilia (TATE) has been observed and described in many tumors, including head and neck neoplasia. The process of eosinophil recruitment and its function in tumors has not been exactly defined yet. Correlation of tissue eosinophilia with prognosis has shown variable results ranging from favourable to unfavourable prognosis or even having no influence on patients outcome. Eosinophils are hypothesized to have tumor defensive as well as tumor promotive function. This dichotomous role of tissue eosinophilia with regard to prognosis has also been noted in head and neck neoplasia and premalignancies. So, the present review attempts to discuss TATE and its possible pros and cons in head and neck neoplasia. Key Words: eosinophils, tumor-associated tissue eosinophilia, head and neck squamous neoplasia, special stains.
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Experimental Oncology 36, 157–161, 2014 (September) 157
TISSUE EOSINOPHILIA IN HEAD AND NECK SQUAMOUS
NEOPLASIA: AN UPDATE
M. Jain1, *, S. Kasetty2, S. Khan3, N.K. Jain4
1Peoples Dental Academy, Bhopal 462037, Madhya Pradesh, India
2Peoples College of Dental Sciences and Research Center, Bhopal 462037, Madhya Pradesh, India
3Rishiraj Dental College, Bhopal 462036, Madhya Pradesh, India
4Uttar Pradesh Rural Institute of Medical Sciences and Research, Saifai, Etawah 206130, India
Eosinophils are multifunctional granulocytes that play an imperative role in health and disease. They have also been found to be a crucial
component of peri- and intratumoral inflammatory infiltrate. Tumor-associated tissue eosinophilia (TATE) has been observed and de-
scribed in many tumors, including head and neck neoplasia. The process of eosinophil recruitment and its function in tumors has not been
exactly defined yet. Correlation of tissue eosinophilia with prognosis has shown variable results ranging from favourable to unfavourable
prognosis or even having no influence on patients outcome. Eosinophils are hypothesized to have tumor defensive as well as tumor promo-
tive function. This dichotomous role of tissue eosinophilia with regard to prognosis has also been noted in head and neck neoplasia and
premalignancies. So, the present review attempts to discuss TATE and its possible pros and cons in head and neck neoplasia.
Key Words: eosinophils, tumor-associated tissue eosinophilia, head and neck squamous neoplasia, special stains.
INTRODUCTION
Eosinophils are bone marrow derived multifunctional
granulocytes implicated in pathogenesis of allergic
reactions and parasitic infections [1, 2]. Tumor-asso-
ciated tissue eosinophilia (TATE) was first described
by Prezewoski in 1896 as “eosinophilic stromal infil-
tration of a tumor not associated with tumor necrosis
or ulceration” [3]. TATE is characterized by presence
of eosinophils as a component of peri- and intratumoral
inflammatory infiltrate [4]. Literature search showed that
TATE has been associated with malignancies of diffe-
rent sites such as oral cavity [4–12], nasopharynx [13],
la rynx [14, 15], esophagus [16], colon [17], cervix [18,
19], etc. Correlation of TATE with prognosis in malignan-
cies of different sites including head and neck squa-
mous cell carcinoma (HNSCC) have shown variable
results ranging from favourable [4, 6, 13, 16] to unfa-
vourable [12, 19] prognosis or even having no influence
on patients outcome [3, 9]. Thus, the link between TATE
and patients outcome is not exactly evident. Dualistic
role of eosinophils might be attributed to the fact that
eosinophils have direct and indirect tumoricidal activity
as well as, they may promote tumor angiogenesis via
production of se veral angiogenic factors [20]. The pre-
sent review aims to discuss TATE and evaluate possible
correlation between TATE and various clinicopathologi-
cal para meters in head and neck squamous neoplasia
through the data derived from available literature.
Detection of eosinophils in cancer
Eosinophils can be easily identified in tissue sections
stained with hematoxylin and eosin (Fig. 1) but at times,
these granulocytes assume an unusual morphology
making their identification difficult particularly in fibrous
tissue or inflammatory infiltrate. Such conditions entail
the usage of special technique like autofluorescence,
immunohistochemistry, luna staining and special stains
like Congo red (Fig. 2) and carbol chromotrope for re-
velation of intact or degranulating eosinophils [21–24].
Fig. 1. Eosinophils in oral squamous cell carcinoma (OSCC)
stained by hematoxylin — eosin, × 40
Fig. 2. Eosinophils in OSCC stained by Congo red, × 40
Submitted: March 24, 2014.
*Correspondence: E-mail: megha.vipin12@gmail.com
Abbreviations used: DFS — disease free survival; HNSCC — head
and neck squamous cell carcinoma; OSCC — oral squamous cell
carcinoma; SPT — second primary tumor; TATE — tumor-associ-
ated tissue eosinophilia.
Exp Oncol 2014
36, 3, 157–161
158 Experimental Oncology 36, 157–161, 2014 (September)
Criteria for identification of eosinophils
Literature reviewed suggested that only nucleated
cells with intensely red cytoplasmic granules should
be accepted as eosinophils. Care must be taken to ex-
clude red blood cells with superimposed mononuclear
and polymorphonuclear cells and also those confined
to lymphovascular space must be disregarded [9, 15].
In addition, an effort should be made to discount eosino-
philia associated with tumor necrosis or ulceration [3, 13].
Counting of tumor-associated tissue eosinophils
There are basically 2 methods described for eosi-
nophil counting. In classical counting, eosinophils are
counted per high power field (hpf) in sections of tumor
or tumor edge or surrounding stroma randomly. In den-
sity method, the highest eosinophil density per surface
area are counted using grid of definite dimensions [4,
25]. However, Alkhabuli and High [25] concluded that
assessment of density may be better than classical
counting and have more relationship with function.
Degree of TATE
Degree of TATE can be evaluated depending upon
either counts only (number of eosinophils/mm2 or hpf)
as absent/mild, moderate, intense 4 or on the basis
of both counts and distribution as focally and mo-
derately elevated, focally and markedly increased,
diffusely and moderately elevated, diffusely and
markedly increased [15]. However, grading of TATE has
got subjective variations since there is no consensus
about the classification of TATE and different grading
scales being used by various investigators [6, 8, 26].
Tissue eosinophils and HNSCC
TATE and clinical correlations in HNSCC
TATE and age and sex. Most of studies found that
there is no correlation of TATE with age [4, 11] and
sex [4, 5, 11, 13, 27] but, Ercan et al. [28] concluded
that there is a negative correlation between TATE and
age (in laryngeal squamous cell cancer) with lesser inci-
dence of TATE over age of 60 years suggesting that age
influences the tissue inflammatory response to tumor.
TATE and habits. Dorta et al. [4] and Oliveira
et al. [5] did not found any association between TATE
and tobacco and alcohol consumption in OSCC but
Oliveira et al. [11] found that intense TATE is sig-
nificantly associated with alcohol consumption only
or with a long history of combined alcohol intake and
cigarette smoking in OSCC.
TATE and tumor site. Dorta et al. [4] assessed TATE
in OSCC of tongue, floor of the mouth, retromolar area
and inferior gingiva and Oliveira et al. [11] analyzed
TATE in OSCC of tongue and floor of the mouth but they
did not found any statistically significant differences
in the distribution of eosinophils among these sites.
TATE and TNM staging. Oliveira et al. [5] found that
patients with OSCC in early stages T1/T2 presented
absent/mild TATE, whereas intense tissue eosinophilia
was strongly associated with tumors in advanced sta-
ges T3/T4. Dorta et al. [4] revealed that TATE is an in-
dependent prognostic factor and does not correlates
with T and N clinical stage. Also, Oliveira et al. [11] and
Thompson et al. [14] noticed statistically insignificant
association between TATE status and tumor T category
of patients with OSCC and SCC of larynx, respectively.
TATE and pathological correlations in HNSCC
TATE and stromal invasion. Said et al. [15] found
frequently elevated (focally or diffusely) eosinophilic
counts in invasive squamous neoplasia of larynx com-
pared to preinvasive squamous neoplasia. Furthermore,
increased eosinophil counts, specifically > 10/hpf and
> 20/10 hpf were statistically significantly associated
with stromal invasion. Thus, in an excisional specimen,
if eosinophil counts meet these threshold, thorough
evaluation of invasiveness is mandatory. Similar findings
were reported by Alrawi et al. [8] in patients with in situ
and invasive HNSCC. Our study [29] also found raised
eosinophil counts in OSCC compared to oral epithe-
lial dysplasia thus concluding that elevated eosi nophil
count is a histopathological marker associated with
tumor invasion. Falconieri et al. [30] also concluded
that eosinophil-rich SCC is constantly associated with
stromal invasion and is of noteworthy especially in oral
cavity cases where it becomes difficult to estimate
due to initial small biopsy specimens. In such cases,
marked tissue eosinophilia is suggestive of an SCC that
is no longer confined within mucosal surface.
TATE and histological tumor type and tumor diffe-
rentiation. Lowe and Fletcher [26] suggested that TATE
development in skin and mucous membrane is in some
way related to squamous differentiation of tumor since
it is rarely reported in basal cell carcinomas and malig-
nant melanoma. Also, it was proved that TATE is neither
a site specific reaction nor a general disposition of pa-
tient to exhibit eosinophilia around any tumor. Moreover,
they found that all of the tumors showing massive TATE
were large cell poorly keratinizing, moderately differenti-
ated and none was verrucous type SCC which possibly
reflects that a particular pattern of squamous differen-
tiation or dedifferentiation is linked in some way with
tissue eosinophil response. Rahrotaban et al. [24] found
that TATE was lower in poorly differentiated HNSCC but
correlation between TATE and histopathological grading
(Broders system) was not statistically significant. Also,
Tadbir et al. [9] and Ercan et al. [28] did not found any
significant relation between TATE and tumor differen-
tiation in OSCC and laryngeal SCC, respectively. Looi
et al. [13] observed TATE more frequently in non kera-
tinizing nasopharyngeal carcinoma (NPC) compared
to keratinizing SCCs and undifferentiated carcinomas.
TATE and its precise localization. Dorta et al. [4]
found that eosinophil infiltrate location was statistically
associated with TATE. In case of absent/mild/mode-
rate TATE, eosinophils were exclusively limited to tumor
stroma whereas in cases with intense TATE, eosinophils
showed accumulation both in neoplastic clusters and
tumor stroma. Another study [9] found mean eosinophil
count/10 hpfs to be higher in invasive front of tumor than
intratumoral stroma and stroma subjacent to epithelium
but the correlation was not significant.
TATE and peripheral tissue infiltration/invasion.
Few studies [5, 9, 11, 28] evaluated association
of TATE with perineural, vascular, muscular glandular
Experimental Oncology 36, 157–161, 2014 (September) 159
and bone invasion but none of them found any sig-
nificant correlation. Oliveira [5] observed eosinophilia
in close association with damaged striated muscle
fibers. Also, majority of OSCC with absent muscular
infiltration showed absent/mild eosinophilia, although
the correlation was statistically insignificant. So, they
hypothesize that eosinophils might be involved in tis-
sue remodeling through the release of their granules
causing degradation of muscle fibers which are da-
maged by invasion of malignant cells.
Association of eosinophils with mast cells and in-
flammatory response. Debta et al. [10, 22] observed
increased number of tissue eosinophils in OSCC cases
accompanied by increase infiltration of mast cells.
Increase infiltration of these cells were associated with
improved prognosis indicative of antitumoral activity.
Dorta et al. [4] found statistically significant relation
between mononuclear inflammatory infiltrate intensity
and TATE in OSCC. This might involve a multifarious and
cumulative interplay of many molecules including release
of lymphocyte derived eosinophilotactic cytokines [4,
31]. Sassler et al. [27] observed an increased prevalence
of TATE in those laryngeal SCC which de mon strated high
degree of inflammatory response which might be at-
tributed to tumor derived peptides causing chemotaxis
of these cellular elements. Likewise, Lorena et al. [23]
found intimate association of eosinophils with strong
lymphoplasmacytic cell infiltration in OSCC. Looi [13] also
noticed that eosinophils were present mainly between
groups of neoplastic cells admixed with lymphocytes
and plasma cells in NPC. On the contrary, Goldsmith
et al. [6] did not found any correlation between grades
of inflammation and eosinophilia in OSCC. Findings
by Said et al. [15] also depicted that there is no associa-
tion of elevated tissue eosinophils with overall inflamma-
tory response denoting that ele vated tissue eosinophilia
is a specific cell response independent of a non-specific
inflammatory reaction.
TATE and second primary tumor (SPTs)
Very few studies [5, 11] correlated TATE with SPTs
but no statistically significant association was found.
TATE as a prognosticator in HNSCC
TATE and recurrence. Oliveira et al. [5] and Leighton
et al. [3] concluded that TATE is not a significant predic-
tor of locoregional and local recurrence in OSCC and
NPC, respectively, where as Oliveira et al. [11] in OSCC
noticed that TATE was highly correlated with regional
recurrence but not with local recurrence. Study by Alrawi
et al. [8] on HNSCC revealed potential association be-
tween higher eosinophilic index (EI >2) and locoregional
recurrence suggesting that elevated eosinophilic counts
is a predictor for aggressive tumor biology demanding
close surveillance and additional therapeutic measures.
TATE and metastasis. Our study [29] found signifi-
cantly increased eosinophil counts in non-metastatic
OSCC compared to metastatic OSCC justifying TATE
as a favourable prognosticator. Falconieri et al. [30]
found heavy eosinophilia in all metastatic lymph nodes
of eosinophil-rich OSCC indicating that tumoral rather
than local factors are involved in eosinophilic migration.
Moreover, eosinophili-rich SCC associated with meta-
static involvement followed less violent course in con-
trast to ordinary SCC. Oliveira et al. [11] suggested that
TATE is a significant marker to predict occult lymph node
metastasis in patients with early OSCC and also an ad-
junctive histopathological factor to emphasize the call
for elective neck dissection of patients with clinically
N0 early OSCC. Goldsmith et al. [32] found that high
grade TATE was statistically associated with absence
of distant metastasis but the underlying pathogenetic
mechanism remains unknown. Looi [13] observed that
in NPC, TATE in the primary tumor was not always as-
sociated with eosinophilia in the metastases. Leighton
et al. [3] concluded that TATE is not a significant marker
of distant metastasis in NPC. Tadbir et al. [9] and Ercan
et al. [28] did not found any significant correlation be-
tween TATE and locoregional metastasis in OSCC and
SCC of larynx, respectively.
TATE and treatment. Oliveira et al. [5, 11] did not noted
any significant association between intensity of TATE
and radiotherapy in OSCC. Sassler et al. [27] found that
presence of TATE could not be used to predict response
to induction chemotherapy.
TATE and survival. Dorta et al. [4] found that in OSCC,
5 year disease free cumulative survival and overall cu-
mulative survival was better in patients with intense TATE
(72% and 63%, respectively) compared to those with
absent/mild (32% and 27%, respectively) and mode rate
(44% and 37%, respectively) TATE. Thompson et al. [14]
also demonstrated that over 5 years, TATE positive pa-
tients with laryngeal SCC have significantly improved
survival compared with TATE negative patients. More-
over 1 year disease free survival (DFS) for TATE positive
patients was 84% compared with 67% for TATE negative
patients. Debta et al. [10] in OSCC cases found that
patients who had survived for 3 years or more have
raised tissue eosinophil counts in contrast to those who
had survived for less than 3 years. So, above mentioned
findings suggests that patients with higher numbers
of tumor associated tissue eosinophils had a better
prognosis than patients with intermediate or low counts.
On the contrary, study by Alrawi et al. [8] in head and
neck neoplasia cases demonstrated that patients with
high EIs (3 and 4) had a statistically significant lower
survival than those with lower EIs (1 and 2). In addi-
tion, patients with higher EIs had a significantly worse
disease specific survival. However, Oliviera et al. [5,
11] observed that there is no differences in the 5 year
and 10 year overall survival and DFS rates between
the OSCC patients with absent/mild and intense eosi-
nophilia and thus tissue eosinophilia is not a signifi-
cant risk factor for death in OSCC patients. Similarly,
Leighton et al. [3] in NPC, Ercan et al. [28] and Sassler
et al. [27] in laryngeal SCC concluded that TATE is not
a significant predictor of survival. Hence, TATE has got
variable prognostic role in head and neck neoplasia.
DISCUSSION
Cancer induced inflammatory response, further
termed as “immune surveillance” by F.M. Burnet
160 Experimental Oncology 36, 157–161, 2014 (September)
involves host defensive response against tumors via
array of infiltrating lymphoid and myeloid cells which
might either promote or retard tumor progression [33,
34]. Leucocyte infiltrate often fluctuate with type and
size of tumor implying that immune responses are
neither consistent nor static events [35, 36].
Eosinophils found to have dual and divergent func-
tion, i.e., tumor promotive as well as tumor destructive.
Role of eosinophils in remodeling of connective tissue
and formation of collagen was first proposed by Bassett
in 1962 [21, 37]. Pincus et al. demonstrated that eosino-
phil can stimulate fibroblast DNA synthesis [38]. Eosino-
phils are found to express transforming growth factor
β1 (TGF-β1) and also contain preformed MMP-9 and
inhibitors of MMPs, TIMP-1 and 2 having potent effects
on the extracellular matrix modulation [39, 40]. Eosino-
phils can amend the tissue remodeling process through
the release of their distinct granule proteins. Eosinophil
cationic protein inhibits proteoglycan degradation and
promotes intracellular glycosaminoglycan accumulation
in fibroblasts [41]. Major basic protein and eosinophil
derived neurotoxin exhibit profibrogenic features stimu-
lating fibroblast proliferation [42]. Eosinophils infiltrating
tumors also known to release angiogenesis promoting
factors like transforming growth factor-α (TGF-α) [43],
vascular endothelial growth factor (VEGF) and basic
fibroblast growth factor (b-FGF) [44]. On the contrary,
eosinophils can exhibit antitumor response via direct
and/or indirect mechanism. In vitro studies have shown
that eosinophils might cause direct cytotoxicity to tumors
through release of their granules [45]. Indirectly, eosino-
phil peroxidase can act synergistically with macrophage
reactive oxygen species and augment cytolysis of tumor
cells [46] or catalyse the oxidation of nitrite to generate
cytotoxic reactive nitrogen radicals [47].
Eosinophils can be related to cytokines of Th1 and
Th2 response via synthesis and release of IFN-γ and
IL-4, IL-5, and IL-10 [48, 49]. In HNSCC, it has been
shown that the Th1 response is mainly associated
with a better prognosis than those with the Th2 re-
sponse [50, 51]. Early stage of OSCC was found to ex-
press mainly INF-γ and IL-2 genes (Th1 responses)
whereas the advanced stage tumors have IL-4 and
IL-10 expression (Th2 response) [52].
Eosinophils have been recognized and reported as in-
flammatory cellular infiltrate of various human cancer
particularly of epithelial origin including OSCC [4–19].
However, the precise role of eosinophils in tumor
growth and patient survival is still doubtful. Eosinophil
recruitment in these tumors might be allied to release
of several factors which have been shown to be effective
eosinophil attractant in in vitro and in vivo studies [21].
So, in nutshell, with regards to above data and available
literature, although eosinophil recruitment in head and
neck neoplasia has been supported by various facts and
evidences but the functional role of eosinophils in human
cancer remains obscure i.e, are eosinophils restraining
tumor growth as a part of host surveillance mechanism
or do they augment tumor growth by remodeling and
immunoregulation of tumor microenvironment or even
have no effect on tumor evolution? Studies related
to prognostic value of TATE in HNSCC has emerged with
conflicting results which demands further investigations
elucidating precise function of eosinophils as a prognos-
ticator in head and neck neoplasia.
CONCLUSION
Present review is an effort to converse about dif-
ferent facet of TATE and its possible role and upshots
in various head and neck squamous neoplasia. To our
knowledge very little literature is available regarding
same hence we hope that this review will contribute and
add to present literature. Referred articles illustrated
that TATE is an adjunctive microscopic feature that has
momentous contribution to various clinico-histopa-
thological parameters in HNSCC including the patient
outcome. So, it is recommended that quantitative as-
sessment of eosinophils should become part of the rou-
tine diagnosis. Exact mechanism of these cells whether
they are involved in tumor inhibition or tumor promotion
is still unknown and warrants further researches.
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Copyright © Experimental Oncology, 2014
|
| id | nasplib_isofts_kiev_ua-123456789-145359 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T17:20:48Z |
| publishDate | 2014 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Jain, M. Kasetty, S. Khan, S. Jain, N. 2019-01-20T20:50:10Z 2019-01-20T20:50:10Z 2014 Tissue eosinophilia in head and neck squamous neoplasia: an update / M. Jain, S. Kasetty, S. Khan, N. K. Jain // Experimental Oncology. — 2014. — Т. 36, № 3. — С. 157-161. — Бібліогр.: 52 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145359 Eosinophils are multifunctional granulocytes that play an imperative role in health and disease. They have also been found to be a crucial component of peri- and intratumoral inflammatory infiltrate. Tumor-associated tissue eosinophilia (TATE) has been observed and described in many tumors, including head and neck neoplasia. The process of eosinophil recruitment and its function in tumors has not been exactly defined yet. Correlation of tissue eosinophilia with prognosis has shown variable results ranging from favourable to unfavourable prognosis or even having no influence on patients outcome. Eosinophils are hypothesized to have tumor defensive as well as tumor promotive function. This dichotomous role of tissue eosinophilia with regard to prognosis has also been noted in head and neck neoplasia and premalignancies. So, the present review attempts to discuss TATE and its possible pros and cons in head and neck neoplasia. Key Words: eosinophils, tumor-associated tissue eosinophilia, head and neck squamous neoplasia, special stains. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Tissue eosinophilia in head and neck squamous neoplasia: an update Article published earlier |
| spellingShingle | Tissue eosinophilia in head and neck squamous neoplasia: an update Jain, M. Kasetty, S. Khan, S. Jain, N. Reviews |
| title | Tissue eosinophilia in head and neck squamous neoplasia: an update |
| title_full | Tissue eosinophilia in head and neck squamous neoplasia: an update |
| title_fullStr | Tissue eosinophilia in head and neck squamous neoplasia: an update |
| title_full_unstemmed | Tissue eosinophilia in head and neck squamous neoplasia: an update |
| title_short | Tissue eosinophilia in head and neck squamous neoplasia: an update |
| title_sort | tissue eosinophilia in head and neck squamous neoplasia: an update |
| topic | Reviews |
| topic_facet | Reviews |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145359 |
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