Prominent Signet Ring Cell Morphology in a Pulmonary Squamous Cell Carcinoma
Nuri YİĞİT1, Ertuğrul ÇELİK2, İbrahim YAVAN1
1Department of Pathology, Gulhane Military Medical Academy and School of Medicine, ANKARA, TURKEY
2Izmir Military Hospital, IZMIR, TURKEY
Keywords: Signet ring cells, Intracytoplasmic vacuoles, Squamous cell carcinoma, Lung
In daily practice, signet ring cell morphology immediately brings to the mind the possibility of an adenocarcinoma at first glance. The signet ring
cell appearance has been described and is well-known in a wide variety of some other neoplasms as well. Surprisingly however, neoplastic cells
having the same morphology can unexpectedly be encountered in not previously well-documented tumors. Here, we present an 85-year-old
man diagnosed with primary pulmonary squamous cell carcinoma and a large signet ring cell population. Examination of the lobectomy
specimen and further radiological workup was consistent with stage I disease. Signet ring cell variant of squamous cell carcinoma is a very
infrequent tumor and has been reported in only eight cases from skin, cervical and oral cavity biopsies as well as in one case of pulmonary
acantholytic variant of squamous cell carcinoma with focal signet ring cells. To be aware of this entity is crucial for pathologists to reach the
correct diagnosis, particularly in cytological samples, because of its potentially modifying effect on treatment options and patient management
compared to adenocarcinomas. Our patient remained in clinical remission during the 9-month follow-up.
The term ‘signet ring cell morphology' describes a cell with
a large intracytoplasmic vacuole, resulting in compression
and eccentric displacement of the nucleus.
Malignant signet ring cells are more commonly seen in the
adenocarcinomas, particularly those of gastric, colonic,
pancreatic, breast, and lung origin. However, they are not
specific to adenocarcinomas and may also rarely be found
in a minor subset of various epithelial and non-epithelial
neoplasms such as urothelial carcinoma, mesothelioma,
leiomyosarcoma, liposarcoma, angiosarcoma, epithelioid
sarcoma, gastrointestinal stromal tumor (GIST), and even
In daily pathology practice, the presence of a dominant
population of atypical signet ring cells is almost always
associated with a diagnosis of an adenocarcinoma that is
specifically called “signet ring cell carcinoma”. Although
this scenario works in most cases, pathologists should be
cautious regarding the risk of overlooking the different
types of tumors, although very infrequently encountered,
with very similar morphology. Observation of these cells
immediately brings to the mind the possibility of an
adenocarcinoma at first glance, and this is mostly correct.
However, one must be careful during the differential diagnosis before the final report to be signed out. We would
like to remind pathologists that atypical signet ring cells
are most frequently seen in adenocarcinomas, but it is very
important and crucial to know that they can unexpectedly
be seen in other non-adenocarcinoma tumor types that
have not been well-described.
Signet ring cell variant of pulmonary squamous cell
carcinoma (SCC) is an extremely uncommon neoplasm
and only one such case containing focal signet ring cell
alteration has been recently described so far. Herein, we
present a case of primary pulmonary SCC with a significant
signet ring cell morphology.
An 85-year-old man, with a history of dementia, was
diagnosed with coronary atherosclerosis and pneumonia.
Chest computed tomography (CT) revealed a large mass
with an irregular margin in the middle lobe of the right lung.
Positron emission tomography-computed tomography
(PET-CT) scan did not show any other involvement.
The patient underwent concurrent coronary bypass and
lobectomy surgery. Grossly, cut surfaces of the middle lobe
had an ill-defined, yellowish colored, solid and soft mass,
measuring 4.2x3.5x3 cm, around the lobar bronchus.
The resection material was fixed in formalin, processed
routinely, embedded in paraffin, and stained with hematoxylin
and eosin. Histopathological examination showed an
infiltration of atypical squamous cells containing optically
dense eosinophilic cytoplasm with moderate keratinisation,
atypical pleomorphic nuclei, and prominent nucleoli. A few
scattered squamous pearls and clearly identifiable intercellular
bridges among tumor cells, suggesting squamous origin,
were also noted. Interestingly, as an unexpected feature
for SCC of the lung, approximately 50% of the malignant
cells contained a single, large and empty intracytoplasmic
vacuole which displaced the nucleus peripherally resulting
in signet ring cell morphology (Figure 1A-D). Their histologic
appearance did not seem to conform with well-known
mucin containing carcinoma cells or clear cell histologic
variant of SCC. There was no pleural, lymphovascular or
perineural invasion and the bronchial surgical margin was
free of tumor. Also, the 11 dissected hilar lymph nodes were
uninvolved. The remaining lung parenchyma demonstrated
focal emphysematous areas, alveolar microlithiasis and anthracotic
pigment deposition. The patient had no history or
physical examination finding of any extrapulmonary SCC,
which might metastasize to the lung. Furthermore, focal in
situ carcinoma was observed in the sections and this was
convincing evidence for a primary lung tumor.
On immunohistochemical study, the tumor cells were
diffusely stained with CK5/6 and p63, but not with TTF-1,
CK7, CK20, Napsin A or MOC31 (Figure 1E,F). Based on
the findings, a diagnosis of moderately-differentiated signet
ring cell variant of pulmonary SCC was made.
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|Figure 1: A,B) Pulmonary squamous cell carcinoma surrounding lobar bronchus (H&E; x100). C,D) Many tumor cells contain a single,
large and clear intracytoplasmic vacuole pushing nuclei to the periphery and causing an obvious signet ring cell appearance (inset) (H&E;
x400). E) CK5/6 antibody sparing the vacuoles and highlighting the concentric ring of cytoplasm of the neoplastic cells (CK5/6; x200).
F) Strong p63 expression in the tumor cells (p63; x400).
Subsequently, relevant histochemical stainings including
Periodic Acid-Schiff, Alcian Blue, Mucicarmine as well
as Oil Red-O for formalin-fixed and routinely processed
tissues were performed to determine the nature of the
vacuoles and the results were found to be unremarkable.
Furthermore, Adipophilin (clone AP-125) immunostaining
was utilized. Whereas both external and internal positive
controls (sebaceous glands of the skin appendages and
peribronchial innocent adipocytes, respectively) were
highlighted with Adipophilin antibody, the vacuoles were
negative. We were sure that this appearance was not the
result of an artificial effect that can be caused by fixation or
the tissue processing procedure because all of the remaining
conventional neoplastic cells as well as non-neoplastic host
cells were seen with an expected morphology.
The patient was considered to have stage I disease and
continued regular follow-up without any additional therapy.
The most recent CT scan 6 months after the surgery showed no evidence of recurrence and the patient has been well at
the 9-month follow-up.
Depending on the biopsy site and tumor types, the vacuoles
of signet ring cells were found to contain large amounts
of mucin, glycogen, lipid, or immunoglobulin5,6
Additionally, artificial or degenerative changes can cause
such morphology. Most of the accumulated substances
can easily be identified by specific histochemical or
immunohistochemical auxiliary studies such as anti-MUC
antibodies and Mucicarmine stain for mucin, Periodic
Acid-Schiff stain for glycogen, and Oil Red-O stain for
lipids, particularly in fresh tissues. Artificial or degenerative
changes may also be disclosed with an intimate comparison
of the neighboring cellular components.
In addition to classical SCC, different histologic variants
such as basaloid, clear cell, acantholytic, spindle, pigmented,
papillary, non-keratinizing, and pleomorphic are welldescribed7,8. Signet ring SCC was first reported in a skin
tumor by Cramer and Heggeness9. Only eight cases of
extrapulmonary signet ring SCCs, including 5 cutaneous
SCC, 2 cervical SCC and one oral cavity SCC, have been
documented until now9-15. To the best of our knowledge,
there is only one case report that has been recently published
about an acantholytic variant of pulmonary SCC with focal
signet ring cell morphology16.
Although the appearance of the vacuoles is reminiscent
of the macrovesicular lipid droplet, their nature could not
be exactly elucidated in the previously described signet
ring SCCs, as was in our case. Kupryjanczyk and Kujawa
described two cases of cervical SCC with signet ring cell
histology where electron microscopy indicated multiple
oval or irregular empty spaces within the cytoplasm, but
their nature could not be determined10. McKinley et
al. reported a signet ring cell SCC of the skin11. They
performed ultrastructural examination and found that the
vacuoles were large dilatations of cisternae of the rough
endoplasmic reticulum. We did not encounter any other
explanatory data to clarify their origin in SCCs, in the
literature review. Although not specific for all types of lipid
molecules, we studied Adipophilin immunohistochemistry
and other histochemical stainings for mucinous
accumulations, and concluded that these intracytoplasmic
vacuoles were neither likely be caused by lipid or mucin
based on the negative stainings.
Differential diagnosis mainly includes adenocarcinoma with
or without signet ring cells. To be aware of that pulmonary SCC can exhibit signet ring cell morphology and the
distinction between signet ring SCC and adenocarcinoma
is crucial to render the correct diagnosis because of the
different patient management. In particular, this issue can
be very challenging in cytological samples owing to the
possible inadequate specimens for necessary ancillary techniques
such as immunocytochemistry. Histopathologically,
a dense eosinophilic cytoplasm, pleomorphic atypical
nuclei, existence of keratinisation, dyskeratotic cells,
whorled pattern, squamous pearls, and intercellular bridges
provide definite evidence of squamous differentiation of
the tumor and reliable clues for discriminating from an
adenocarcinoma in the differential. The oresence of an in
situ component in the sections and absence of preexisting
or synchronous SCC in different locations are strong
supportive features to exclude the possibility of a metastasis
from extrapulmonary sites. Additionally, positive staining
with CK5/6, p63 and p40 while lack of any immunoreactivity
against TTF-1, CK7, Napsin-A, and MOC-31 favors the
diagnosis of SCC.
Due to its rarity, it is not clear whether the pulmonary signet
ring variant of SCC has a different clinical course or therapy
response depending on the stage compared to conventional
cases. Nine months after the surgery, our patient has been
doing well without any signs of recurrence. Nevertheless,
the biological behavior needs to be further analyzed to
determine the most effective clinical management.
In conclusion, the signet ring variant of SCC should be kept
in mind in addition to the commonly suspected adenocarcinomas
on examination of lung biopsies consistent with a
malignancy showing signet ring cell morphology,. Specific
morphological features and immunoexpression profile of
SCC as well as the presence of an in situ component help
to make the correct diagnosis. To rule out a metastasis, the
possibility of a non-pulmonary SCC should be queried at
the time of biopsy or in the patient's history before making
a definite diagnosis.
We would like to thank Dr. Şule Öztürk Sarı from Istanbul
University Capa Faculty of Medicine, for helping us with
some confirmatory immunohistochemical studies.
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2015 Jun 25. [Epub ahead of print]