Commentary

Imprint Cytology: Invaluable Technique to Evaluate

Fresh Specimens Received in the Pathology Department
for Lymphoma Workup
1,2
Louis-­André Julien, MD, MSc ; and René P. Michel, MD, CM2

At the time of intraoperative consultation, cytologic preparations including smears and imprints can be used in com-
bination with frozen sections to increase diagnostic yield; however, these simple and rapid techniques are not adopted
by all pathologists and their use varies considerably between institutions. In patients under investigation for suspected
lymphoma, optimal triaging of tissue received fresh in pathology for lymphoma workup is paramount to maximize the
odds of obtaining an accurate and clinically meaningful diagnosis and to avoid the need for additional procedures and
delays in management, particularly in the current context in which core biopsies have become common practice as
a first attempt to attain this goal. Imprint cytology is invaluable in this regard, also as these patients may not have a
lymphoma but rather one of its clinical mimics. Herein, imprint cytology is used to approach fresh specimens received
intraoperatively for lymphoma workup. More specifically, how these specimens are triaged for ancillary studies, such as
flow cytometry, florescence in situ hybridization, or molecular analyses based on an interpretation of the touch imprints,
is described. Detailed imprint cytological findings of typical benign and malignant lymphoid and nonlymphoid lesions
are discussed and illustrated. Cancer Cytopathol 2021;129:759-771. © 2021 American Cancer Society.

KEY WORDS: cytology; flow cytometry; follicular hyperplasia; frozen sections; granuloma; intraoperative consultation;
lymphoma; lymphoma workup; metastasis; touch imprint.

INTRODUCTION
Investigation of patients with suspected lymphoma requires tissue sampling for an accurate diagnosis and
precise subclassification, and for appropriate management and therapy.1 Although these patients often present
with lymphadenopathy or extranodal masses, specimens received for evaluation in pathology are varied, often
lymph nodes, but also from other organs such as tonsils, spleen, gastrointestinal tract, lung, liver, and skin.
Furthermore, these patients may not have a lymphoma but one of its clinical mimics, such as granulomatous
inflammation, metastatic carcinoma, melanoma, or other entities.
The preferred method for diagnosis of lymphoma is typically excisional biopsy of a lymph node (or other tis-
sue), allowing careful evaluation of the architectural and cytological features of the lymphoid cells, also providing
adequate material for all appropriate ancillary studies. Indeed, the WHO classification states that sufficient tissue
is critical for the accurate classification of lymphoid neoplasms, and that caution is advised when core-­needle
biopsies are used for the primary diagnosis of lymphoma, and that fine-­needle aspiration (FNA) cytology may
not be adequate for that purpose.1 In practice, however, the method of tissue sampling varies greatly depending
on the indication for biopsy (initial diagnosis vs potential recurrence or progression of a known lymphoma),
Corresponding author: Louis-­Andre Julien, MD, MSc, Charles-­Le Moyne Hospital, CISSS Montérégie-­Centre, University of Sherbrooke, 3120 Boulevard
Taschereau, Greenfield Park, Longueuil, QC, Canada, J4V 2H1 (louis-andre.julien.med@ssss.gouv.qc.ca).
1
Department of Pathology, Charles-­ Centre, University of Sherbrooke, Longueuil, Canada; 2 Department of
Le Moyne Hospital, CISSS Montérégie-­
Pathology, McGill University, Montreal, Canada
We would like to thank and acknowledge the contribution of Dr Manon Auger for her expertise, assistance, feedback, and help in writing this article.
Received: October 23, 2020; Revised: February 2, 2021; Accepted: March 8, 2021

Published online May 20, 2021 in Wiley Online Library ­(wileyonlinelibrary.com)

DOI: 10.1002/cncy.22442, wileyonlinelibrary.com

Cancer Cytopathology  October 2021 759


Commentary
on the patient’s condition and comorbidities (the surgi-
cal risk may preclude an open or excisional biopsy), the
urgency of the situation, and the size and location of the
lesion(s) (some may not be readily accessible, eg, the medi-
astinum or the retroperitoneum).2 Hence, the use of core
biopsies or FNA, sometimes combined with endoscopic
procedures or radiologic guidance, have become common
practice for the diagnosis of lymphoma, particularly in the
current context of budgetary and operating-­room time
constraints. Although these diagnostic modalities are well
established, rapid, and safe, the precise diagnosis of lym-
phoma using them may be challenging, including in the
assessment of tissue architecture and in the provision of
optimal material for ancillary studies, the latter not un-
commonly requiring additional procedures, for example,
an excisional biopsy to make a diagnosis.2-­7
These challenges highlight the importance of appro-
priately triaging specimens received fresh for lymphoma
workup (or so-­called lymphoma protocol) in the pathology
laboratory, particularly with small specimens such as core
biopsies. Intraoperative consultation is generally required to
confirm that the tissue is indeed lymphoid and that enough
is available for all required studies and diagnosis. Many in-
stitutions have their own established protocols; in addition,
the College of American Pathologists has issued recommen-
dations and a protocol for the examination of specimens
from patients with lymphoma.8,9 Past publications describe
the use of cytologic preparations (smears and imprints) for
intraoperative assessment of lymph nodes or lymphoid le-
sions to facilitate the identification of entities not as easily
evaluable in conventional frozen sections: The clarity of the
cytologic details enables the identification of Hodgkin lym-
phomas, non-­Hodgkin lymphomas, and certain metastatic
tumors.10-­13 In contrast to smears, imprints are easily pre-
pared by gently touching the fresh-­cut surface of tissues to a
glass slide, without smearing, with minimal distortion and
without damaging fragile core biopsies.12 Here we report
how we use touch imprint cytology to triage nearly all of
our specimens received fresh for lymphoma protocol.
ASSESSMENT OF LYMPHOMAS WITH
IMPRINT CYTOLOGY: GENERAL
APPROACH AND PROCEDURES FOR
TRIAGE OF SPECIMENS
In this section, we detail our approach to the workup
of specimens suspected of harboring a lymphoma. Most
surgeons and radiologists at our institution are aware of
760
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our lymphoma protocol and are advised to biopsy the
most clinically suspicious or abnormal lymph node or
mass and to obtain as much tissue as possible, ideally
an excisional or incisional biopsy, or as many cores as
feasible to maximize the odds of obtaining an accurate
diagnosis, thereby avoiding an open biopsy. They are
asked to provide relevant clinical information, for ex-
ample, any past history of lymphoma (including sub-
type if known), of other malignancy or infection and
provide a provisional clinical diagnosis with the requisi-
tion form. We also ask that they flag urgent situations
such as airway compression or superior vena cava syn-
drome. Specimens should be sent fresh without delay,
specifically labeled “for lymphoma protocol.” Larger
specimens and excisions can be immersed in saline solu-
tion, whereas cores should be placed on filter paper well
moistened with saline (not on gauze because the cores
get tangled in its strands). The pathologist should also
be notified as soon as the specimen arrives in pathology,
preferably just before its arrival.
Upon receipt, the clinical information and pro-
visional diagnosis are reviewed, the specimen is exam-
ined grossly and measured; lymph nodes or excisions
are serially and thinly sectioned, and a direct touch
imprint is made for staining and microscopic assess-
ment. Preparing imprints is simple: A glass slide is gen-
tly touched to the surface of the specimen or of all the
cores aligned in parallel, rapidly fixed in alcohol, and
stained with hematoxylin and eosin (H&E) for rapid
assessment; alternatively, the slide can be air-­dried and
stained with Diff-­Quik, analogous to what is done for
rapid on-­site evaluation of FNAs.14 Although smear
preparations and frozen sections could also be prepared
in excisions, we do not perform these routinely, and
hardly ever on core biopsies as they are time consum-
ing and potentially damage the specimen. Instead, we
perform careful touch imprints that remove minimal
tissue and yield excellent results on excisions and small
cores (Fig. 1).
We triage the specimen upon microscopic exam-
ination of the touch imprint. Cytological findings are
detailed in the next section and summarized in Table 1;
flow charts showing our stepwise approach are depicted
in Figure 2. If a nonlymphoid neoplasm (eg, carcinoma,
melanoma) or definite granulomatous inflammation
is visualized, no further lymphoma workup ensues and
the tissue is fixed in formalin. If granulomas are seen,
Cancer Cytopathology  October 2021
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Imprint Cytology for Lymphoma Workup/Julien and Michel

Figure 1. Imprint, on 2 slides, from a case of low-­grade follicular lymphoma, looking for recurrence. Additional touch imprints were
prepared for florescence in situ hybridization analyses, core 4 was sent for flow cytometry (diagnostic of follicular lymphoma), cores
1, 2, and 5 were submitted in formalin in separate blocks, and core 3 was submitted in B+ (zinc-­formalin) fixative. No tissue was
frozen for molecular analyses; it was deemed unnecessary in this case.

TABLE 1. Helpful Features and Findings in Determining the Nature of a Specimen Received Fresh in Pathology
for Lymphoma Workup and Assessed With a Touch Imprint or Smear

Features of Processes Other Than Lymphoma Features of Lymphoma

Suspected clinical diagnosis • Nonlymphoid malignancy • Lymphoma
• Infection • Lymphoblastic lymphoma
Gross examination • Caseous necrosis (tuberculosis) • Homogeneous expansion of node
• White and hard (carcinoma) • Tan and fleshy color
• Brown or black (melanoma) • Nodularity and bands of sclerosis (NSCHL)
Cellularity • Paucicellular • Highly cellular
Background • Mucin (adenocarcinoma) • Presence of lymphoglandular bodies
• Tigroid (seminoma, Ewing sarcoma, others)
• Absence of lymphoglandular bodies
Cell distribution • Sheets or cohesive clusters (carcinoma) • Dispersed isolated cell pattern
• Glandular structures (adenocarcinoma)
• Papillary structures (adenocarcinoma)
• Pseudorosettes (Ewing sarcoma)
• Small or loose cell clusters (small cell carcinoma, melanoma,
Ewing sarcoma)
Cell morphology • Keratinization (squamous cell carcinoma) • Monomorphous population of small, medium of
• Mucinous cells (adenocarcinoma) large lymphoid cells: small lymphocytes, centro-
• Signet ring cells (adenocarcinoma) cytes, centroblasts or immunoblasts
• Cytoplasmic pigment (melanoma) • Hodgkin cells
• Nuclear molding (small cell carcinoma, Ewing sarcoma) • Reed-­Sternberg cells
• Powdery or salt and pepper chromatin (small cell carcinoma)
• Paranuclear blue bodies (small cell carcinoma)
• Rhabdomyoblasts (rhabdomyosarcoma)
• Granulomas (infection, other)
Abbreviation: NSCHL, nodular sclerosis classic Hodgkin lymphoma.
Features and findings include the clinical information available at the time of assessment, gross examination, and cytological findings from the touch imprints.

fresh samples can be sent for microbiological analyses,
or the surgeon or radiologist can send tissue directly to
the microbiology laboratory (to avoid contamination). If
the imprint shows lymphoid tissue, we proceed with the
lymphoma protocol as described below, but if lymphoma
is suspected and the amount of tissue is too small (only
a few small cores), the surgeon or radiologist is rapidly
advised to send additional tissue as clinically feasible.
Nonlymphoid neoplasms closely mimicking lymphoma
on imprints do occur (eg, small, round, blue cell tumors)
and should be kept in mind when triaging fresh speci-
mens, particularly when they are considered clinically or
are part of the differential diagnosis (discussed in the next
section).
Direct touch imprints, usually approximately 6, are
prepared on nearly all lymphoid specimens, including
very small cores, and fixed in Carnoy solution for poten-
tial florescence in situ hybridization (FISH) analyses. We

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Commentary

Figure 2. Suggested algorithm for lymphoma protocol. Flow charts for excisional/incisional biopsies (A) and for core biopsies (B).
See text for details. Should be tailored to local institutional practices and individual patients, depending on clinical information. Once
fresh tissue is triaged as depicted here, sections from excision specimens or cores are divided into several blocks (eg, 1 core per
block) and fixed in formalin to maximize tissue for ancillary studies. ** indicates imprints for FISH; B+, zinc-­formalin fixative; FISH,
florescence in situ hybridization; Optional*, if enough tissue; TB, tuberculosis.

routinely send these imprints for FISH analyses in Burkitt
lymphomas or in diffuse large B-­cell lymphomas to rule
in or out the possibility of a high-­grade B-­cell lymphoma
with MYC and BCL2 and/or BCL6 rearrangements,
and as indicated in potential mantle cell or follicular
lymphomas.
If sufficient tissue is available, a portion is placed
in transport medium such as Roswell Park Memorial
Institute medium and brought promptly to the flow
cytometry (FCM) laboratory for immunophenotyping
(results often available within hours or the next day).15-­18
Notably, although adequate tissue is available for FCM
on nearly all excisional biopsies, the decision to take a
complete core, or parts of a core, for FCM has to be taken
carefully to have enough cells to analyze by FCM on the
1 hand, and to ensure enough tissue remains for mor-
phological and ancillary studies on the other. Therefore,
this decision on core biopsies relies mostly on the num-
ber of cores, their diameter, their quality (well preserved
vs very fragmented), and importantly, matching the

762 Cancer Cytopathology  October 2021


Imprint Cytology for Lymphoma Workup/Julien and Michel
interpretation of the touch imprint to the actual cores,
thereby determining if sufficient material is available to
send for FCM. Ideally of 4 or more good cores of ap-
proximately 1.5 cm in length with good numbers of lym-
phoid cells on the imprint, one 1.5-­cm-­long core or core
segment can be submitted for FCM (Fig. 1), particularly
in cases where the imprint suggests a low-­grade non-­
Hodgkin lymphoma; indeed in these, FCM is particu-
larly useful for clonality analyses,17,18 whereas FCM on
very small specimens is less contributory in cases of large
B-­cell lymphomas (cells easily damaged) or Hodgkin
lymphomas.19,20 In cases suspicious for classic Hodgkin
lymphoma, with an imprint showing cells highly sugges-
tive of Hodgkin or Reed-­Sternberg cells, formalin fixation
and paraffin-­embedding (FFPE) should be prioritized if
the specimen is very limited because well-­fixed sections
and immunophenotyping by immunohistochemistry are
necessary in the diagnosis of nearly all cases of Hodgkin
lymphoma, whereas FCM, molecular, and FISH studies
are less likely to contribute.9
If sufficient tissue is available, small fragments of
fresh lymphoid specimens can be snap frozen and stored
at -­80°C for molecular analyses of B-­or T-­cell clonality
or for some of the translocations, such as t(14;18) and
t(11;14) in follicular lymphoma and mantle cell lym-
phoma, respectively, although FISH remains more sensi-
tive than PCR for these rearrangements.8,21,22
Prioritization at triage is crucial: In all situations,
including with very small specimens, the priority re-
mains formalin fixation to obtain H&E-­stained sections
for diagnosis and ancillary studies, most of which can be
performed from the FFPE tissue block, including immu-
nohistochemistry, FISH, and molecular studies. Thus,
once the specimen has been triaged as described above,
and to maximize tissue for ancillary studies, sections from
the excision specimen or the cores are divided into sev-
eral blocks, ideally 1 thin section or 1 core per block, and
fixed in formalin. When there is tissue for more than 1
to 2 blocks, we put part in zinc-­sulfate fixative because
it yields superior cytomorphologic details and remains
amenable for immunohistochemistry.8,16
Cytological Findings and Management of
Benign and Malignant Lesions Commonly
Seen on Imprints
Interpretation of the touch imprint begins by confirma-
tion it is representative of the tissue touched and that the
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technique was done correctly, by the quality of staining
and absence of air-­drying or crushing artifact. Cellularity
is usually appreciated at low power, as is the presence of
extracellular material such as necrosis or mucin, which
is then confirmed at higher magnification. Lymphoid
tissue is typically characterized by the presence of dis-
persed and isolated cells without cohesive groups, though
germinal centers can occasionally form loosely cohesive
clusters.23 In Romanowsky-­or Diff-­Quik–­stained smears
and imprints, lymphoglandular bodies aid in identifying
lymphoid lesions, but these are difficult to find on H&E-­
stained imprints, which we use in our center.23 With
technical issues ruled out, touch imprints from lymph
nodes or excisions that are paucicellular may point to a
nonlymphoid malignancy or a fibrotic process, reactive
or malignant, for example, a sarcoma or nodular sclero-
sis classic Hodgkin lymphoma. The possibility of the lat-
ter should prompt a careful search for atypical cells (see
below). Otherwise, if the tissue is scant, FFPE is given
priority; if the material is sufficient (eg, an excisional bi-
opsy), a smear from the tissue or a frozen section may
reveal an underlying process.10,16
Metastatic disease, nonlymphoid mimics of
lymphoma, and granulomatous inflammation
Even if a lymphoid population is seen on the imprint, the
possibility of metastatic disease or a nonlymphoid neo-
plasm should be ruled out, particularly with a prior his-
tory of a nonlymphoid malignancy or clinically suspected
metastatic disease.
Cells from metastatic carcinoma are generally read-
ily identified on imprints. They form distinct cohesive
clusters or sheets of atypical cells, usually larger than even
large lymphoid cells. The presence of papillary or glandu-
lar formations with or without mucin, or signet ring cells,
often with prominent nucleoli, favors adenocarcinoma,
whereas the presence of atypical keratinized or even
poorly keratinized cells with hyperchromatic large and
irregular nuclei favors squamous cell carcinoma.24 For ex-
ample, nasopharyngeal carcinoma (Fig. 3A-­C), although
infrequent, often presents with enlarged cervical lymph
nodes suspicious for lymphoma. The distinction between
lymphoma involving the nasopharynx and nasopharyn-
geal carcinoma with cervical lymph node metastasis may
be difficult on clinical grounds, requiring histopatho-
logical examination.25 This neoplasm can further be
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Commentary

Figure 3. Common and uncommon metastatic lesions encountered intraoperatively at the time of lymphoma workup. (A-­ C)
Excisional biopsy of a cervical lymph node with metastatic nasopharyngeal carcinoma. Imprint is paucicellular but exhibits several
cohesive clusters of large atypical cells with thick cytoplasm (A). No lymphoma workup was initiated. Hematoxylin and eosin
(H&E)-­stained permanent section shows typical features of (B) metastatic nasopharyngeal carcinoma. (C) Cells are positive for
Epstein-­Barr virus (Epstein-­Barr encoding region by in situ hybridization) and for cytokeratin AE1/AE3 (not shown), confirming the
diagnosis. (D-­F) Excisional biopsy of a lymph node for suspected lymphoma in a case ultimately diagnosed as metastatic melanoma.
Gross examination reveals an enlarged completely black lymph node (D), whereas the imprint shows discohesive atypical cells with
a few loose clusters, some binucleated cells with prominent nucleoli, granular intracytoplasmic melanin pigment, and admixed small
lymphocytes and pigmented histiocytes (E). Diagnosis of metastatic melanoma was made on the gross and imprint. No lymphoma
workup was initiated. H&E-­ stained permanent sections confirmed the diagnosis (F). (G,H) Metastatic seminoma in a patient
suspected of a lymphoproliferative disorder. Medium power of imprint shows large, atypical cells, mostly discohesive, mimicking
large cell lymphoma with scattered small lymphocytes in the background (G). The diagnosis of seminoma cannot be made by
cytomorphology alone, but requires permanent sections and immunohistochemistry, emphasizing caution not to overdiagnose (and
misdiagnose) lymphoma intraoperatively. H&E-­stained permanent section showing large tumor cells with abundant cytoplasm and
associated lymphocytic infiltrate (bottom right), typical of seminoma (H); immunohistochemistry for OCT3/4, CD117 and podoplanin
was positive (not shown) consistent with the diagnosis.

misinterpreted as lymphoma because of the frequently
associated prominent reactive lymphoid infiltrate with
lymphoglandular bodies that may obscure and overrun
the malignant cells, whereas the latter must also be differ-
entiated from Hodgkin cells or a large cell lymphoma.23
Metastatic melanoma also commonly mimics lym-
phoma clinically. Cytologic preparations show discohe-
sive or loose clusters of atypical cells with a wide spectrum
of cytologic features, often with abundant cytoplasm, oc-
casionally but not always with granular intracytoplasmic
melanin pigment, eccentric nuclei, commonly binucle-
ated or with intranuclear inclusions, and prominent nu-
cleoli.6,10,23 Although small foci of metastatic melanoma
may also be more easily identified on cytologic prepara-
tions than on frozen sections, it can occasionally be highly
suspected simply on gross examination when pigmented

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Imprint Cytology for Lymphoma Workup/Julien and Michel

Figure 4. Soft tissue lesion received for lymphoma workup showing a small, round, blue cell tumor in a case ultimately diagnosed
as Ewing sarcoma. (A) The highly cellular imprint shows sheets of partly cohesive and isolated cells. (B) At high power, the cells
are large, at least 3-­fold the size of a normal small lymphocyte (arrow), have fine blast-­like chromatin and small nucleoli, and
appear to be separated by a small-­to-­moderate amount of cytoplasm. These findings are indicative of a small round blue-­cell
tumor, and performing complete or near-­complete lymphoma protocol is indicated (touch imprints, fresh snap-­frozen tissue, and
paraffin-­embedded tissue can be used for florescence in situ hybridization (FISH) and molecular studies, if deemed necessary
later on), but one must entirely ensure that sufficient tissue is available for all other ancillary studies before sending parts for
flow cytometry, as such a sample will be lost if dealing with a nonlymphoid malignancy. (C) H&E-­stained permanent sections
showed a diffuse population of large overlapping cells and nuclei with open chromatin, small nucleoli, and rare pseudorosettes,
seen here at high power. Immunohistochemistry confirmed the nonlymphoid nature of this tumor, cells were positive for CD99 by
immunohistochemistry (not shown), whereas FISH analyses using the touch imprints prepared at the time of lymphoma workup
revealed rearrangement of EWSR1, essential for the diagnosis (not shown).

(Fig. 3D-­F), in which case the lymphoma protocol is can-
celled. Similarly, metastatic seminoma (Fig. 3G,H) may
present on smears as discohesive cells with a small lym-
phocytic background infiltrate, thereby mimicking a large
cell lymphoma (see below).
Cells of small cell carcinoma, Merkel cell carcinoma,
and other nonlymphoid small or not so small, round,
blue cell tumors, such as alveolar rhabdomyosarcoma and
Ewing sarcoma, may closely mimic lymphoma clinically
and on smears and imprints (Fig. 4). Morphologic clues
that may point to the true nature of a tumor include dis-
persed isolated cells also forming loose aggregates, with
nuclear molding, powdery salt-­ and-­pepper chromatin,
and paranuclear blue bodies in small cell carcinoma, or
pseudorosettes with nuclear molding and a tigroid back-
ground in Ewing sarcoma.23 However, these clues are not
always present or found on imprints, especially intra-
operatively, where rapidity of assessment is an issue and
confidently differentiating these entities using cytologic
preparations or frozen section may not be possible; max-
imum caution is advised not to overdiagnose (and mis-
diagnose) any of these entities intraoperatively. Although
clinical presentation including age and distribution of the
lesions aid in narrowing the differential diagnosis, im-
munohistochemistry and/or ancillary studies are gener-
ally necessary to arrive at a definite diagnosis. Although
molecular and cytogenetic analyses are crucial to establish
diagnosis and prognosis of many small, round, blue cell
tumors (eg, rhabdomyosarcoma, Ewing sarcoma, Wilms
tumor, others), we consider that performing most of the
lymphoma protocol (FCM aside) remains indicated when
those entities are considered, even if lymphoma remains
only remotely in the differential diagnosis. In fact, FISH
and molecular studies can be performed on fresh snap-­
frozen tissue or paraffin sections, and FISH can be per-
formed on touch imprint preparations.
Granulomatous inflammation is identified on
imprints by the presence of clusters of epithelioid
histiocytes with elongated, spindle-­ shaped, and/or
curved (boomerang) nuclei, with abundant cytoplasm
and indistinct cell borders, appearing as a syncytium
(Fig. 5).23,26 Multinucleated giant cells may be seen,
and the presence of prominent necrosis and debris,
or of numerous admixed neutrophils should strongly
suggest an infectious etiology—­fungal or mycobacte-
rial; if gross examination reveals caseous necrosis, tu-
berculosis should be considered and the touch imprint
can confirm necrotizing granulomatous inflammation,
obviating the need for a frozen section, thereby avoid-
ing inconvenient contamination of the cryostat.10,26
In such cases, the tissue is put in formalin; acid-­fast
bacilli may be found on permanent sections with a
Ziehl-­Neelsen stain. Notably, however, the differential
diagnosis of granulomatous inflammation is broad as
it may be a nonspecific finding associated with ma-
lignancies including carcinomas and lymphomas, in

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Commentary

Figure 5. Core biopsy of a lymph node with granulomatous inflammation, ultimately diagnosed with tuberculosis. (A) Imprint
showing clusters of epithelioid histiocytes with elongated curved nuclei and abundant cytoplasm forming a syncytium, consistent
with granulomas. No lymphoma protocol was initiated. (B) Hematoxylin and eosin-­stained permanent section showing necrotizing
granulomatous inflammation with multinucleated giant cells. A Ziehl-­Neelsen stain showed presence of mycobacteria, consistent
with the diagnosis (not shown).

Figure 6. Imprints showing typical features of nonspecific reactive hyperplasia, but in a case ultimately diagnosed as toxoplasmic
lymphadenitis. Low power reveals a very cellular imprint (A), showing at high power a polymorphic population of small and larger
lymphoid cells (B), tingible-­body macrophages (arrow in B), occasional follicular dendritic cells and mitoses (not shown), and
immunoblasts (asterisk in B). Full lymphoma protocol is indicated to exclude a neoplastic process and to confirm its reactive
nature, as in this case (results not shown). (C) Hematoxylin and eosin-­stained section showing typical features of toxoplasmic
lymphadenitis, revealed upon evaluation of architecture from permanent sections, with, from left to right, germinal center with
aggregates of histiocytes, mantle zone lymphocytes, and marginal zone hyperplasia.

particular, T-­cell lymphomas (eg, Lennert lymphoma)
and Hodgkin lymphomas.26-­28 Thus, a careful search
for atypical lymphoid or nonlymphoid cells on the
imprint is advised before abandoning the lymphoma
protocol.
Polymorphous and monomorphous lymphoid
populations
Imprints showing polymorphous lymphoid cells of
variable sizes, predominantly small lymphocytes with
scattered larger cells such as centroblasts or immuno-
blasts and with admixed histiocytes, tingible-­ body
macrophages, and plasma cells are most suggestive
of nonspecific reactive hyperplasia (Fig. 6A,B).6,10,23
Although nonspecific on imprints, these features may
be related to more specific causes of reactive lymphade-
nopathy that can only be revealed upon evaluation of ar-
chitecture from permanent sections, such as in this case
ultimately diagnostic with toxoplasmic lymphadenitis
(Fig. 6A-­C). These features are also found in a variety of
neoplastic lymphoproliferations such as Hodgkin lym-
phomas, T-­cell lymphomas, posttransplant lymphopro-
liferative disorder, and some low-­grade and high-­grade
B-­cell lymphomas, such as marginal zone lymphoma or
T-­cell/histiocyte-­rich large B-­cell lymphoma.6,23 Thus,
the definite distinction of reactive lymphadenopathy
from malignancy may be difficult, if not impossible,
based solely on interpretation of the touch imprint,

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Imprint Cytology for Lymphoma Workup/Julien and Michel

Figure 7. Nodular sclerosis classic Hodgkin lymphoma. (A,B) The imprint is cellular, with admixed small and few very large atypical
Hodgkin cells. Diagnosis can be predicted on the cytology, and lymphoma protocol modified accordingly (see text for details). (C,D)
Hematoxylin and eosin-­stained permanent sections and immunohistochemistry (not shown) confirmed the diagnosis.

ultimately relying on permanent sections and ancil-
lary studies.29 Therefore, such findings should prompt
a full lymphoma protocol with FCM, which can be of
great value as clonality may be otherwise difficult to
prove or rule out using the FFPE tissue, particularly
on very small specimens or cores. Notably, although
classic Hodgkin lymphoma may be difficult to identify
on imprints because of its characteristic polymorphous
reactive infiltrate with eosinophils, neutrophils, histio-
cytes and plasma cells, Hodgkin or Reed-­Sternberg cells
are often found upon careful examination (Fig. 7). In
such cases, or when there is clinical suspicion for classic
Hodgkin lymphoma, FFPE tissue should be prioritized
because histology and immunohistochemistry are es-
sential for diagnosis.9
A monomorphous population of lymphoid cells
raises the possibility of a lymphoproliferative disorder;
as in most non-­ Hodgkin lymphomas, particularly of
B-­cell phenotype, the range of lymphoid cellular sizes
is more limited.10,23,30 Such infiltrates on imprints may
be broadly subdivided into lesions composed mostly of
small-­, intermediate-­, or large-­size lymphocytes.23
The descriptions of the cytomorphology of the small
cell, generally low-­grade lymphomas emanate mainly from
smears.6,13,23,31-­33 The principal entities in this group are
chronic lymphocytic leukemia/small lymphocytic lym-
phoma (CLL/SLL), follicular lymphoma, marginal zone
lymphoma, classic mantle cell lymphoma (discussed
below), and rarely lymphoplasmacytic lymphoma. The
cells in these entities are generally less than twice the size of
a small lymphocyte. Imprints of CLL/SLL show a monot-
onous population of small round lymphoid cells having
slightly irregular nuclei with finely dispersed chromatin,
inconspicuous nucleoli, with interspersed larger cells with
nucleoli and more abundant cytoplasm (prolympho-
cytes and paraimmunoblasts; Fig. 8A), whereas in accel-
erated or histologically aggressive CLL/SLL, also termed
prolymphocytoid transformation of CLL/SLL, more

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Commentary

Figure 8. Imprint findings in low-­grade lymphomas. Although a definite diagnosis cannot be made from imprints in most cases,
some morphologic clues should raise the possibility of a lymphoproliferative disorder and prompt a full lymphoma protocol, a
monomorphous population of lymphoid cells, in particular, but others can suggest the final diagnosis, as shown in these cases.
(A) Chronic lymphocytic leukemia/small lymphocytic lymphoma, typically showing very cellular imprints, with many small cells
and scattered larger prolymphocytes (arrows in A). Full lymphoma protocol was initiated. Hematoxylin and eosin (H&E)-­stained
permanent sections revealed many small cells with proliferation centers, whereas immunohistochemistry and flow cytometry
revealed the B cells coexpressed CD20, CD5, CD23, CD43, and BCL2, consistent with the diagnosis (not shown). (B) Low-­grade
follicular lymphoma, with an imprint that hints at follicle formation, whereas the lymphoid infiltrate is composed of small centrocytes
with cleaved or “twisted” nuclei. Full lymphoma protocol was initiated. H&E-­stained permanent sections, immunohistochemistry,
and flow cytometry showed follicles of monotypic B cells with coexpression of CD20, BCL6, and BCL2, confirming the diagnosis (not
shown). (C-­H) Marginal zone B-­cell lymphoma, showing a cellular imprint (C) with predominantly small mildly irregular lymphoid
cells with partial monocytoid features and scattered larger transformed cells (arrows in C). Full lymphoma protocol was initiated.
H&E-­stained permanent section (D) showing similar findings, including a few transformed cells (arrows in D). Immunohistochemistry
for CD20 (E) revealed a marked predominance of B lymphocytes. It also showed expanded follicular dendritic cell networks, and
B cells that were negative for CD5, CD10, BCL6, CD23, and CD43 (not shown). (F) Chromogenic in situ hybridization revealed λ
monotypic plasma cells (κ was negative, not shown), consistent with a clonal process. (G,H) Flow cytometry gated on CD19/CD20-­
positive B cells showed the small to medium-­sized cells (λ-­expressing lymphoma cells [pink dots] have a higher forward scatter/FSC
and side scatter/SSC than the few small κ-­expressing normal cells (blue dots) in [G]). Nearly all the cells express λ light chains (pink
dots in [H]), with only rare κ-­positive cells (blue dots in H).

prolymphocytes become evident.6,32,34 Follicular lym- larger centroblasts seen mostly in the higher grades (Fig.
phomas are characterized by a predominant population 8B).6,31,32 Marginal zone B-­ cell lymphomas are com-
of small, cleaved lymphocytes (centrocytes) with increased posed of a heterogenous populations of predominantly

768 Cancer Cytopathology  October 2021

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Imprint Cytology for Lymphoma Workup/Julien and Michel

Figure 9. A case of diffuse large B-­cell lymphoma. (A,B) Low and high power of a very cellular imprint composed of cells (arrows
in B) at least 3-­fold larger than a normal small lymphocyte (arrowheads in B). Lymphoma workup was initiated, and touch imprints
taken for florescence in situ hybridization (FISH) during lymphoma protocol revealed no rearrangement of MYC. (C) High power
of hematoxylin and eosin (H&E)-­stained permanent section show a similar diffuse proliferation of large lymphoid cells and few
small reactive lymphocytes (arrowheads in C). (D) The cells are positive for CD20 by immunohistochemistry, and for CD10 (inset),
consistent with germinal center B-­cell-­like (GCB) immunohistochemical subgroup (Hans algorithm). (E,F) Flow cytometry gated on
CD19/CD20-­positive B cells showed cells with increased size (pink dots with high forward scatter (FSC) and side scatter (SSC) in
[E]), nearly all expressing λ light chains (pink dots in [F]) and positive for CD10 (not shown), with rare κ-­positive cells (turquoise
dots in [E] and [F]). Compare with the small to medium cells in the marginal zone lymphoma (Fig. 8G).

small lymphoid cells, some with pale staining cytoplasm
(monocytoid), variable numbers of plasma cells, and few
large, transformed lymphocytes (Fig. 8C-­H).6,32
The principal entities that fall under the um-
brella of medium-­size lymphoid cells (approximately
2-­2.5 times the size of a small lymphocyte) include
the blastoid variant of mantle cell lymphoma, Burkitt
lymphoma, and lymphoblastic lymphoma. The cells of
mantle cell lymphoma are small to intermediate (the
classic variant) or intermediate (the blastoid variant),
monotonous with variably irregular nuclei resembling
centrocytes, clumped chromatin often with mitotic fig-
ures.6,23,31-­33 Burkitt lymphoma cells are medium-­sized,
monotonous with round or squared-­off nuclei, several
basophilic nuclei, in a background of necrosis or apop-
tosis.6 B-­or T-­lymphoblastic leukemia/lymphoma cells
are small to medium or medium with a high nucleocy-
toplasmic ratio, irregular often convoluted nuclei ex-
hibiting fine chromatin, and inconspicuous nucleoli.6
It remains that the precise diagnostic differentiation of
small and medium-­size lymphoid lesions, reactive or
malignant, is difficult if not impossible on cytologic
preparations and imprints, and it is essential that these
be identified as such and triaged for lymphoma workup
as detailed above.6,16,29
Imprints from lymphomas composed of medium
to large or large cells are overrepresented by diffuse
large B-­cell lymphoma, not otherwise specified (Fig. 9).
These lymphomas are usually readily identified on
touch imprints by a diffuse proliferation of predomi-
nantly medium to large or large atypical lymphocytes
whose nuclei are over twice the size of normal small
lymphocytes (often 3-­4 times), often highly pleomor-
phic, with vesicular or coarse chromatin and frequently
single or multiple prominent nucleoli, and endowed
with variable amounts of cytoplasm.6,7,13,23 Tingible-­
body macrophages and mitotic figures may be conspic-
uous. As discussed previously, touch imprints for FISH

Cancer Cytopathology  October 2021 769


Commentary
analyses should be done on such cases, and although
identification and characterization of large lymphoma
cells may be challenging by FCM, it may contribute to
the diagnosis (Fig. 9E,F). Large cell morphology spans
a variety of lesions including subtypes of large B-­cell
lymphomas, the pleomorphic variant of mantle cell
lymphoma, occasional mature T-­cell and natural killer
cell lymphomas, or nonhematopoietic neoplasms such
as seminoma, poorly differentiated carcinoma and mel-
anoma, among others. These should be characterized
on the FFPE tissue with ancillary studies.6,13,23,33,35
DISCUSSION
During intraoperative consultation, cytologic prepara-
tions including smears and imprints, which have been
used to diagnose lesions removed surgically since the early
19th century, are nowadays more commonly performed
in conjunction with, or occasionally instead of, frozen
sections in some institutions.10,30,36-­39 Imprint cytology
is particularly useful in the assessment of brain lesions
or mediastinal masses, among others.40,41 Authors of a
number of publications, often case reports or case series,
describe the use of imprint cytology in the diagnosis of
lymphoid lesions. However, it is also helpful to identify
nonlymphoid neoplasms and to rule out lymphoprolifer-
ative disorders as part of a clinical differential diagnosis, as
discussed herein and as depicted in the figures. However,
the lack of quantitative and systematic analyses of large
series of imprint material may hinder its recognition as
a useful and reliable tool for intraoperative evaluation
and/or lymphoma workup, and may explain why many
pathologists—­also possibly related to the lack of experi-
ence in cytology—­are not using the technique.37,39
Our own experience, reflected in our review of the
literature, confirms that touch imprints of excisions, and
particularly of core biopsies, are invaluable in providing
a preliminary diagnosis and in triaging specimens from
patients suspected of a lymphoproliferative disorder,
with diagnostic accuracy rates sometimes rivaling those
of frozen sections.37,39,40,42 The advantages of touch im-
prints can be summarized as follows. First, large portions
of a specimen can be sampled, and multiple imprints are
ready for evaluation in 2 to 3 minutes. Second, it permits
sampling of all the cores on 1 slide (or at most 2 slides)
without any damage, enabling the partitioning of each
core for fixation or ancillary studies according to findings
770
19346638, 2021, 10, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncy.22442 by Nat Prov Indonesia, Wiley Online Library on [23/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
and cellularity. Third, cytologic details are well preserved,
with few artifacts, whereas they are often distorted or
obliterated on frozen sections. Fourth, in no way does it
detract from doing a frozen section if needed (eg, on a
larger biopsy).10,16,30
Careful preparation and examination of the imprint
are required for optimal triage of the specimen.43 Indeed,
errors in interpretation can occur with poor preparations
or hypocellular specimens, when trying to distinguish
reactive hyperplasia from low-­grade non-­Hodgkin lym-
phoma, or when findings do not permit even a prelim-
inary diagnostic impression.29 In contrast, the diagnosis
of large cell lymphoma or of metastatic disease is usually
straightforward, whereas Hodgkin lymphoma can be sus-
pected when Hodgkin cells are carefully sought for and
identified.
To conclude, the examination of touch imprints
is an important first step in the workup of a potential
lymphoma to arrive at a precise diagnosis. Triage of fresh
specimens is readily accomplished using imprint cytology
and a systematic approach.
CONFLICT OF INTEREST DISCLOSURES
The authors declare no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
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