B R I E F R E P O R T

Metastatic adenoid cystic carcinoma with high-gradetransformation (“dedifferentiation”) in pleural effusion andneck lymph node: A diagnostic challenge on cytology?

Marc P. Pusztaszeri | Victor Brochu

Department of Pathology, McGill University,

Montreal, Quebec, Canada

Correspondence

Marc P. Pusztaszeri, Department of Pathology,

Jewish General Hospital, McGill University,

3755, Chemin de la Côte Ste Catherine, H3T

1E 2, Montréal, Québec, Canada.

Email: marc.pusztaszeri@mcgill.ca

Abstract

High-grade transformation (HGT) or “dedifferentiation” is an uncommon phenome-

non among salivary gland carcinomas including adenoid cystic carcinoma (ACC),

which is important to recognize because it is associated with increased tumor aggres-

siveness, with a high propensity for lymph node and distant metastases. ACC with

HGT is histologically characterized by a distinct population of poorly differentiated

cells with loss of the typical biphasic ductal and myoepithelial differentiation seen in

conventional ACC, associated with pleomorphism, necrosis and increased mitotic

activity. We report the cytologic features of a case of metastatic ACC-HGT in cervi-

cal lymph node and effusion, which, to the best of our knowledge, have not been

described previously. When ACC presents both in atypical locations and with HGT,

the danger of misdiagnosis is increased if the clinical history is lacking, incomplete or

inaccurate. Since ACC-HGT are rare (and possibly underdiagnosed) and do not have

a specific set of cytological and/or immunohistochemical features, it is important for

practicing cytopathologists to be aware of the possibility of encountering them, espe-

cially in specimens from patients with a history of ACC, in order to render the correct

diagnosis.

K E YWORD S

adenoid cystic carcinoma, cytology, dedifferentiation, high-grade transformation

1 | INTRODUCTION

Adenoid cystic carcinoma (ACC) is a malignant neoplasm most com-

monly originating in salivary glands of the head and neck (H&N)

area.1 A protracted course of many years with multiple local recur-

rences and late appearance of metastatic disease, mainly in the lungs

and bone, is the characteristic clinical course for these slow-growing

tumors.1 Rarely, patients may initially present with metastatic dis-

ease of unknown origin. In such patients, further evaluation may

reveal an unexpected synchronous primary ACC or the patient may

have a remote history of ACC.2,3 A definitive cytologic diagnosis of

ACC, especially the cribriform type, in salivary gland FNA specimens

is feasible in a subset of cases.4,5 Typical ACC has characteristic

cytologic features with small, often angulated, hyperchromatic nuclei

with uniformly dispersed chromatin and scant cytoplasm imparting a

basaloid appearance.4,5 Mitoses, necrosis and significant pleomor-

phism are uncommon in the absence of high-grade transformation

(see below). The most important cytologic feature of ACC is its char-

acteristic matrix that forms variably sized spheres (aka hyaline glob-

ules), cylinders, and branching tubules with sharp edges (“cookie

cutter”).4-7 Diagnostic difficulties can be caused particularly by the

absence of matrix, especially in the solid variant of ACC, which can

mimic other basaloid neoplasms such as cellular pleomorphic ade-

noma or basal cell adenoma/adenocarcinoma.4-7 Therefore, without

supporting ancillary studies, a subset of ACC are diagnosed as “Sali-

vary Gland Neoplasm of Uncertain Malignant Potential” (SUMP) or

Received: 2 January 2020 Revised: 20 March 2020 Accepted: 31 March 2020

DOI: 10.1002/dc.24431

Diagnostic Cytopathology. 2020;48:679–683. wileyonlinelibrary.com/journal/dc © 2020 Wiley Periodicals, Inc. 679

as “Suspicious for Malignancy” according to the recent Milan System

for Reporting Salivary Gland Cytopathology.5

High-grade transformation (HGT) or “dedifferentiation” is an

uncommon phenomenon among salivary gland carcinomas includ-

ing ACC, which is important to recognize because it is associated

with increased tumor aggressiveness, with a high propensity for

lymph node and distant metastases.8-10 HGT is defined as the

transformation of a well-differentiated tumor into a high-grade

malignancy that lacks the distinct histologic characteristics of the

original neoplasm and usually corresponds to undifferentiated or

poorly differentiated carcinoma.9,10 HGT in ACC (ACC-HGT) was

first described in 1999 by Cheuk et al. as “dedifferentiated

ACC”,8 and since then >50 cases have been reported in the liter-

ature, most of them involving sinonasal and palatal minor glands

and the submandibular glands.9-11 ACC-HGT is histologically char-

acterized by a distinct population of poorly differentiated cells

with loss of the typical biphasic ductal and myoepithelial differen-

tiation seen in conventional ACC, associated with pleomorphism,

necrosis and increased mitotic activity.9,10 HGT in ACC may be

apparent at the time of primary excision of the tumor or may

develop in a recurrence, especially in patients who underwent

radiotherapy.9-12 Most common reported metastatic sites of ACC-

HGT include lungs, cervical lymph nodes, bones, liver, and

brain.9-11 Metastatic ACC involving an effusion has been excep-

tionally reported with only three cases, including a primary cuta-

neous ACC metastastic in pericardial fluid.2,3,13 In these three

cases, hyaline globules admixed with small cohesive round

basaloid epithelial cells were observed, corresponding to conven-

tional ACC. To the best of our knowledge, however, the cytologic

features of metastatic ACC-HGT in an effusion have not been

described previously.

2 | CASE PRESENTATION

A 72-year-old man complaining of shortness of breath was admitted

for the investigation of cervical lymphadenopathy and a large left

pleural effusion which were suspicious for metastatic disease. The

patient was a smoker and had a history of base of tongue ACC initially

staged T4 N2C in 2013. He was treated with neoadjuvant chemother-

apy and neutron beam therapy in 2014, because he refused surgery.

A local recurrence at the base of tongue was treated by radical sur-

gery and bilateral neck dissection in 2017. Current cervical and tho-

racic CT scans showed a large left pleural effusion with complete

whiteout/collapse of the left lung, associated with multiple bilateral

pulmonary parenchymal and pleural nodular densities consistent with

metastatic disease. There were also a left level IV 3 cm supraclavicular

necrotic lymphadenopathy and a mass-like area at the right floor of

mouth suspicious of local recurrence. FNAB of the cervical lymphade-

nopathy and thoracentesis were performed. The material was

received in the cytology laboratory the same day and was processed

into Cytospin and Cell block preparations which were stained with

Papanicolaou and H&E stains, respectively.

3 | CYTOLOGY RESULTS

Cytospin and Cell block preparations from the pleural effusion dem-

onstrated many clusters of large cohesive round epithelial cells with

abundant, sometimes vacuolated, cytoplasm, and large pleomorphic

nuclei with prominent nucleoli that were easily recognized as malig-

nant (Figure 1A,B). The background consisted of mesothelial cells, his-

tiocytes, and lymphocytes. No hyaline globules or matrix was

identified. By immunohistochemistry, the tumor cells showed strong

F IGURE 1 Cytologic findings of adenoid cystic carcinoma with high-grade transformation. A, Pleural effusion cytology shows large clusters ofepithelial cells with vacuolated, cytoplasm, and pleomorphic nuclei on Cytospin (Papanicolaou stain) and B, cell block preparations (H&E stain,×400). By immunohistochemistry, C, the tumor cells are diffusely positive for CK5/6 and D, CK8/18, and E, show focal positivity with CK7. F, Thelymph node aspirate also demonstrated similar cytological details, but a minor population of small basaloid cells, highlighted by p63 positiveimmunostain and G, admixed with larger pleomorphic cells, was also present in the latter (Cell block H&E stain) (A-G: ×400) [Color figure can beviewed at wileyonlinelibrary.com]

680 PUSZTASZERI AND BROCHU

positive staining for Ber-EP4, CK5/6, and CK8/18; focal positivity for

CK7, p40, and p63 (rare tumor cells); and were negative for CEA,

CD117, TTF-1, Napsin-A, and S100 (Figure 1C-E). The tumor in the

pleural fluid was similar to what was aspirated from the neck lymph

node. A minor population of small basaloid cells, highlighted by p63

positive immunostaining (Figure 1F), admixed with larger pleomorphic

cells was also present in the latter (Figure 1G). The tumor was then

compared to the previous resection specimen from 2017 (see below);

in the latter, the ACC contained high-grade areas which were initially

overlooked. These foci of ACC-HGT were comparable to the current

specimens. Therefore, the lymph node FNAB and pleural effusion

specimens were both diagnosed as metastatic carcinoma, high grade,

consistent with a HGT (dedifferentiation) of the known ACC.

4 | PATHOLOGY RESULTS

A retrospective review of the surgical resection from 2017, consisting

of a total glossectomy, total laryngectomy, and bilateral neck dissec-

tion, was performed. The tumor was located at the tongue base, bilat-

eral, measuring 6.4 × 4.9 × 3.1 cm. On microscopic examination, the

tumor was primarily composed of conventional ACC (grade II)

(Figure 2A,B). Extensive perineural and intraneural invasion by tumor

cells was seen. Focally, sheets and nests of larger cells with pleomor-

phic nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, fre-

quent mitosis (20/10 hpf), and small foci of necrosis were present,

corresponding to areas of ACC-HGT (Figure 2C-E). These tumor nests

were lacking myoepithelial cells, and focal squamous areas and micro-

papillary growth, which are unique features of ACC-HGT as compared

to conventional ACC, were also present.9,11 There was one metastatic

lymph node out of 46 in the lymph node dissection, showing mostly

conventional ACC, with extranodal extension. The submandibular

glands showed post radiation atrophy. By immunohistochemistry, the

primary tumor was negative for p16, androgen receptor and HER2,

ruling out an HPV-associated carcinoma and a salivary duct

carcinoma.

5 | DISCUSSION

In ACC-HGT, the high-grade carcinoma is usually either poorly differ-

entiated adenocarcinoma or less commonly “undifferentiated” carci-

noma.9-12 Because of its rarity and the lack of specific features,

cytologic specimens from metastatic ACC-HGT may be easily con-

fused with a variety of poorly differentiated primary or secondary car-

cinomas that may be more commonly encountered at the site of

distant metastasis. Therefore, the differential diagnosis of metastatic

ACC-HGT can be broad. In our case, the main differential diagnosis

given the clinico-radiological findings, included metastatic lung carci-

noma. The diagnosis was greatly facilitated in our case because of the

patient's known history of ACC with a current imaging suggestive of

recurrent and widespread disease and a concomitant cervical lymph

F IGURE 2 High-grade transformation of adenoid cystic carcinoma on histology. A, Low-power view showing two distinct carcinomatouscomponents: conventional adenoid cystic carcinoma (left portion) and high-grade carcinoma with a predominantly solid growth pattern, formingirregular and confluent tumor nests (right portion) (H&E stain, ×100). B, Conventional adenoid cystic carcinoma exhibiting cribriform pattern withexcessive extracellular basal lamina material and two cell-layered tubular structures (H&E stain, ×200). The tumor cell nuclei have a bland, uniformappearance. C-E, High-grade carcinoma component. Solid and micropapillary growth (D, H&E stain, ×200) patterns of carcinoma cells exhibitinglarge pleomorphic nuclei with a moderate amount of cytoplasm (E, H&E stain, ×600). Comedonecrosis is also present (C, H&E stain, ×200) [Colorfigure can be viewed at wileyonlinelibrary.com]

PUSZTASZERI AND BROCHU 681

node FNAB that yielded similar findings. Gathering complete and

accurate clinical history and radiological data, obtaining adequate

diagnostic material for ancillary studies (Cell block), and comparing the

morphology of the tumor with that of the patient's known primary are

essential for the diagnosis of metastatic ACC, with or without HGT, in

effusion or in other unusual locations. Since ACC-HGT has far more

propensity than conventional ACC to metastasize to lymph node

(43%-57% vs 5%-25%) and distant metastatic sites including

effusion,11,12 the non-specific features of a high-grade carcinoma

would be more likely at metastatic sites than in the primary tumor,

and the classification may be limited to “high-grade carcinoma.” In

contrast, an adequately sampled tumor from the primary site may

show features of both the conventional and the higher grade compo-

nent facilitating the diagnosis.14 Especially, recognition of occasional

clusters of basaloid cells and/or hyaline globules, when present, in

association with larger poorly differentiated malignant cell population

in aspiration smears can be a helpful clue in cytological diagnosis.14

In our case, a minor population of basaloid cells, positive for p63,

admixed with larger poorly differentiated malignant cells was present

in the metastatic lymph node (Figure 1F,G) but not in the pleural

effusion.

Immunohistochemistry results may be misleading since there is an

altered immunoprofile in ACC-HGT as compared to conventional

ACC.9-11 The expression of myoepithelial markers is typically lost in

ACC-HGT, along with CD117 and S-100.9-11 Immunohistochemistry is

essentially helpful to rule out other common sources of metastatic carci-

nomas with a panel of “organ specific” markers such as TTF-1, Napsin A,

CDX-2, Gata-3, and PAX-8, depending on the clinico-radiological fea-

tures. Detection of the specificMYB-NFIB gene translocation by FISH or

molecular testing, which is present in ~60% of ACCs, could also be help-

ful for diagnostic purposes.12,15 However, to the authors' knowledge,

the specificity and sensitivity of MYB immunohistochemistry in the set-

ting of a high-grade metastatic carcinoma are unknown. One should be

very cautious before concluding that MYB overexpression can be useful

to suggest the origin or type of neoplasm in a metastatic high-grade car-

cinoma. While overexpression of MYB protein is present in about 80%

in ACC with or without MYB gene rearrangement, other mechanisms of

MYB activation may have a role in MYB protein overexpression, as has

been demonstrated in colon and breast cancers where MYB oncogene is

activated, thereby reducing its specificity, especially at metastatic

sites.16 MYB protein expression is also not helpful when trying to distin-

guish ACC from the uncommon HPV-related Multiphenotypic Sinonasal

Carcinoma (formerly known as HPV-related Carcinoma With Adenoid

Cystic Carcinoma-like Features).17 Finally, in ACC, the presence of MYB

rearrangement and/or MYB overexpression between conventional areas

and areas with HGT, based on limited data, appears to be inconsistent,

and theMYB-NFIB translocation is not necessarily an early event or fun-

damental for the progression to ACC with HGT.18

A meticulous review of the previous pathology, if available, is essential

since HGT in ACC may be very focal11 and easily overlooked or under-

diagnosed as a “solid” component in the resection specimens, even by a

H&N pathologist, as in our case. Importantly, a morphologic spectrum with

significant overlap between solid ACC and ACC-HGT is recognized, but

the latter should have larger cells with more pleomorphism than solid ACC

and a complete or partial loss of the myoepithelial component.9,10,12

In conclusion, since ACC-HGT are rare (and possibly under-

diagnosed) and do not have a specific set of cytological and/or immu-

nohistochemical features, it is important for practicing cytopathologists

to be aware of the possibility of encountering them, especially in speci-

mens from patients with a history of ACC, in order to render the cor-

rect diagnosis. Indeed, when ACC presents both in atypical locations

and as a HGT, the danger of making an erroneous diagnosis is increased

if the clinical history is lacking, incomplete or inaccurate.

ORCID

Marc P. Pusztaszeri https://orcid.org/0000-0001-6490-4189

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How to cite this article: Pusztaszeri MP, Brochu V. Metastatic

adenoid cystic carcinoma with high-grade transformation

(“dedifferentiation”) in pleural effusion and neck lymph node:

A diagnostic challenge on cytology? Diagnostic Cytopathology.

2020;48:679–683. https://doi.org/10.1002/dc.24431

PUSZTASZERI AND BROCHU 683