Frozzen sections

1. Interactive Microscopy Session:
Common and Challenging Diagnostic
Dilemmas on Frozen Section Service:
Intraoperative Diagnostic Issues in
Thoracic Pathology
Handout
Cesar A. Moran, MD
Professor of Pathology
MD Anderson Cancer Center, Houston, TX
Course Dates: October 4-7, 2019

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
The Approach to Frozen Section in Thoracic Pathology
General Considerations
The evaluation of frozen sections (FS) in thoracic pathology presents different
challenges as their approach may be slightly different depending on the anatomic
location that is being evaluated. Thoracic frozen sections may originate from the lung
proper, the pleura, or the mediastinum. In some circumstances, the FS may originate
from the chest wall; however, often that involves tumors of soft tissues and for this
presentation, we will limit the discussion to tumors of the prior 3 different anatomic
locations.
As expected, different tumoral conditions may affect those anatomic areas and one
must be aware that the spectrum of lesions in those areas is vast and heterogeneous.
Needless to say, the thorax is also a common site for metastatic disease. Therefore,
the evaluation of FS is not only limited to the assessment of malignancy but often to the
assessment of primary site. It is also important to highlight that in current medical
practice, it is possible that the evaluation of FS is mainly to provide orientation to the
surgeon as to what extent the surgery is needed as it is very possible that a prior biopsy
has already been evaluated and the diagnosis is also known. Nevertheless, it is not
uncommon that such clinical background is not available and then the interpretation of
the FS becomes crucial in proper assessment of the case in question.
Because of the nature of the thoracic cavity, we will divide the evaluation of FS based
on the anatomic location as there are important differences in the approach, which
impact surgical options.
LUNG
The current practice of FS in lung lesions can be separated in the different aspects:
Scenario 1
• The diagnosis is already known and the FS are essentially performed for staging
purposes. An example of it will be a patient with an intrapulmonary mass in
which the prior biopsy revealed a non-small cell carcinoma (adenocarcinoma,
squamous cell carcinoma, etc.) and now multiple lymph nodes are sent for FS
evaluation as well as the bronchial margin. In these cases, the interpretation of
the lymph nodes can be done in two different ways:
o Positive or negative for metastatic carcinoma
o Positive or negative for the specific carcinoma

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
o Important to document the origin of the lymph node as such interpretation
may affect N1 or N2 disease.
o The interpretation of the bronchial margin is either positive or negative.
§ If positive, it is important to determine whether the bronchial
epithelium is positive or whether the tumor is around peribrochial
soft tissue.
Scenario 2
• The diagnosis is already known. The procedure is a wedge resection and the
entire tumor is sent to pathology to evaluate on FS the parenchymal margin of
resection. If that is the case:
o Proper orientation of the specimen is required in order to make such
determination.
§ Parenchymal margin is either positive or negative.
§ Some pathologists provide an approximate distance from the
margin to the tumor (mm).
Scenario 3
1. Carcinoma
• The diagnosis is not known and a section from the tumor is provided for
interpretation. In this setting, one can provide the following interpretation:
o If convince that the tumor in question is a carcinoma, then make the
assessment whether it is small or non-small cell carcinoma.
o If the interpretation is that of non-small cell carcinoma, and if the sample is
adequate for further interpretation, then one can do so by stating c/w
squamous cell carcinoma or adenocarcinoma.
o It is important to separate one particular tumor and that is the
adenocarcinoma with lepidic growth pattern. Since this tumor has been
re-coded as In Situ Adenocarcinoma, one needs to be careful in the
interpretation of this tumor on FS. The entire tumor must be evaluated in
order to make such claim; therefore in the FS one is limited to the
interpretation of lepidic growth pattern.
o At the same time, one can also assess for the possibility of metastatic
disease. Common carcinomas metastatic to the lung include colorectal
and head and neck carcinomas. In those settings, the clinical history will
help just as the presence of multiple pulmonary nodules.

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
2. Neuroendocrine Carcinomas
• The FS interpretation of neuroendocrine carcinomas may pose significant
problems as the spectrum of these tumors go from low to intermediate to high
grade neoplasms. In addition, one is limited by the sample of the tissue available
for interpretation. However, one can assess these tumor as follows:
o Separate low and intermediate grade neoplasms (Carcinoid and Atypical
Carcinoid) from high grade neoplasms (small cell and large cell
neuroendocrine carcinoma)
o In the low and intermediate grade neoplasms, evaluate for necrosis and
mitotic activity and state the findings. However, one must state that final
classification is after complete evaluation of the neoplasm on permanent
sections.
o If small cell carcinoma, it is likely that the surgical procedure may stop.
o By definition, large cell neuroendocrine carcinoma is a non-small cell
carcinoma with neuroendocrine pattern. However, for such a diagnosis, it
is important to have neuroendocrine markers positive (chromogranin,
synaptophysin, or CD56). Therefore, one can only suggest the possibility
but the final interpretation is after performing IHC stains.
Scenario 4
3. Spindle cell neoplasms
• The evaluation on FS of intrapulmonary spindle cell neoplasms can be
challenging, namely if there is not pertinent clinical history. The spectrum of
tumors that may have spindle cell morphology is wide and encompasses
epithelial, neuroendocrine, and mesenchymal neoplasms. Therefore, their
assessment needs to be done carefully and although often one is not able to
make a definitive diagnosis on FSW, it is common to favor a particular neoplasm.
Needless to say, the occurrence of metastatic sarcomas to the lung (including
melanomas) is very common and special attention needs to be given for such
possibility.
Scenario 5
4. Unclassifiable neoplasm
• Often one is confronted with lesions that on FS cannot be classified or one can
be misled by the appearance of the neoplasm. One of those examples is the so-
called Sclerosing Hemangioma – Pneumocytoma. The epithelial appearance of

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
the tumor may be misinterpreted by the pathologist towards the possibility of
carcinoma. However, it is important to keep such possibility in mind in
intrapulmonary coin lesion in young or middle age women, as those tumors occur
predominantly in that age and gender group. The identification of areas
mimicking a vascular neoplasm admixed with more solid and papillary areas may
help in the interpretation. However, if in doubt there no other choice but to defer
the final interpretation for permanent sections.
The Pleura
Essentially primary tumors of the pleura are dominated by one particular entity and that
is malignant mesothelioma. Therefore, it is important to keep that in mind and to be
aware that mesotheliomas may also show a spectrum of differentiation that may go from
the most conventional morphology of anastomosing pseudoglandular areas with
papillary features to the more sarcomatoid neoplasms that may mimic a mesenchymal
neoplasm. Thus,
• Is it recommended to make an unequivocal diagnosis of mesothelioma in a
patient who has not had a previous biopsy? The most appropriate response will
be that it is not. Because the treatment options for mesothelioma are different
from other neoplasm, it is important not only to properly perform adequate IHC
but also to correlate the findings with the imaging.
• For an epithelioid neoplasm, the differential diagnosis will be that of
adenocarcinoma invading the pleura or in rare circumstance the so-called
Pseudomesotheliomatous adenocarcinoma. The latter tumor may invade the
pleura in a manner similar to that of mesothelioma.
• For a sarcomatoid neoplasm, the consideration would be a true sarcoma or a
spindle cell carcinoma that is invading the pleura.
o Recommendations for interpretation include:
§ Is there diffuse pleura thickening?
§ Is there a pleural based mass?
§ Is there a dominant intrapulmonary tumor?
§
• On occasion, the pleura may also be the site for metastatic neoplasms from other
sources below the diaphragm or above the thoracic inlet. Therefore, clinical and
radiological information are highly important in the final interpretation.
• One important consideration in pleural pathology for FS is solitary fibrous tumor
(SFT). SFT is a common neoplasm in the serosal surface and it is common in
the pleura. In these cases, the tumor is a pleural based mass that may be
pedunculated. The histology of SFT is variable; however, the presence of a
spindle cell proliferation with hypo and hyper cellular areas with a subtle HPC

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
pattern is highly suggestive of SFT. However, as the tumor shows variable
histology, SFT may also mimic other sarcomas.
The Mediastinum
The spectrum of mediastinal neoplasm is highly variable and may be challenging on FS
as the mediastinum can be the site of numerous neoplasms of epithelial, mesenchymal,
lymphoid, and germ cell tumors among others.
In the interpretation of FS for mediastinal neoplasm, some basic information may be of
high importance such as gender and age. For instance, germ cell tumors are neoplasm
predominantly occurring in younger men. On the other hand, thymomas are uncommon
in younger patients (<35 years). Also, MALT lymphomas of the thymus are more
common in younger women with the history of collagen vascular disease or Sjogren
syndrome. These are only a few examples of how, some basic information may help in
the interpretation of possible FS for mediastinal tumors.
If on the other hand, one wants to approach these lesions by histological features, here
are some possible scenarios:
Scenario 1
• Lymphocyte rich lesions
o Lymphocyte rich thymoma (WHO type B1) and normal thymus can be
indistinguishable on FS. The same applies for the solid areas of a
multilocular thymic cyst.
o Thymic lymphoma B cell type on FS may be indistinguishable from a
lymphocyte rich thymoma.
o MALT lymphoma of the thymus can be indistinguishable from thymic
hyperplasia.
Scenario 2
• Epithelial rich or mixed cellularity lesions
o The most common challenge would be attempting to differentiate epithelial
rich so called atypical thymoma (WHO B3) from thymic carcinoma. Often
such differentiation is difficult unless one finds unequivocal histology of
carcinoma.
o Important to distinguish is thymoma from seminoma as both tumors may
show some lymphocytic component.

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Interactive Microscopy Session | Common and Challenging Diagnostic Dilemmas on
Frozen Section Service: Intraoperative Diagnostic Issues in Thoracic Pathology |
Cesar A. Moran, MD | October 4-7, 2019
o Because of the lobulation that may be present in mediastinal tumors,
Hodgkin lymphoma also enter in the differential diagnosis of mixed
cellularity thymomas (WHO B2) on FS.
Scenario 3
• Spindle cell lesions
o Spindle cell tumor of the mediastinum may be represented by different
tumors of different lineage.
§ Spindle cell thymoma, Spindle cell neuroendocrine neoplasm
(Carcinoid tumor), or mesenchymal neoplasm such as synovial
sarcoma or SFT.
§ In such cases, unless one is very familiar with the histology of the
particular tumor, one can make a final interpretation on FS.
Otherwise, it may be necessary to defer for permanent sections.
§ Mediastinal sarcomas are rather rare but represent an important
part of mediastinal pathology. Their histology is variable and
includes smooth muscle tumors, vascular neoplasms, and
fibrohistiocytic tumors.
TAKE HOME MESSAGE
Often the interpretation of FS does not necessarily include a definitive diagnosis of a
particular lesion. As pathologist, we play a role in guiding the surgeon about the best
possible surgical approach. Therefore, in many cases, the mere interpretation of
positive for malignancy or negative for malignancy is the needed interpretation that the
surgeon needs to continue with his/her plan of treatment. Of course, the goal is to
provide the best possible information so that proper care is undertaken. However, in
some circumstances, the limitations of tissue dictate otherwise. However, no matter
what the interpretation is, the most important element is to have proper communication
with the surgical team in order to provide the best medical care.