Metastatic Adenosquamous Carcinoma, Unknown Primary Site (Possible Oropharyngeal Primary)
Raja R. Seethala
University of Pittsburgh Medical Center
This is a 55 year old male with an 'indolent' right level II neck mass, found incidentally on clinical inspection. The patient has no known history of tobacco use. A prior fine-needle aspiration was performed and demonstrated a lymphocytic population. Flow cytometric analysis was reportedly limited due to low cell viability. The patient subsequently underwent excision of this neck mass.
Grossly, the excision contained a 3.0 x 2.0 x 0.6 cm tan- white ovoid mass with focal cystic change.
Whole slide scan demonstrating a cystic mass (right) within lymphoid rich stroma
The cystic lesion shows architectural complexity comprised of macro and microcysts with papillary invaginations
The cystic spaces are line by a fairly monomorphic outer squamoid layer and an inner columnar layer.
Mucocytes are noted within the innermost layer of some of the cysts
A Mucicarmine highlights these mucocytes
Few of the columnar epithelial cells are ciliated (arrows)
Cystic lining focally demonstrates pronounced pleomorphism and mitotic activity
Focal keratinization is noted
A cytokeratin 5/6 is positive mainly in the outer more squamoid layers of the cystic spaces.
A p63 immunostain similarly highlights mainly the squamoid outer layers of the cystic spaces.
MAML2 breakapart FISH shows no evidence of a rearrangement
A p16 immunostain is diffusely strongly positive
In-situ hybridization for HPV DNA (pan- selective probe set) shows punctate positivity in tumor cells. Inset – the glandular and ciliated cells are also positive.
Lateral cervical cysts may pose diagnostic challenges, both clinically and histologically. The
spectrum of lesions to be considered initially encompasses: cysts of thyroid, thymus, parathyroid,
salivary gland, branchial cleft as well as cystic metastases. The incidence of malignancy in lateral
cervical cysts is overall, low
However, the prevalence of unsuspected metastatic carcinoma rises
significantly in patients over the age of 40, with squamous cell carcinoma being by far the most common
Occasionally cystic papillary thyroid carcinoma metastases may also present as
lateral cervical cysts
Over the past few decades, the strong association between cystic squamous
cell carcinoma metastases and oropharyngeal site of primary has become well recognized
Additionally, since it is evident that a high proportion of oropharyngeal squamous cell carcinomas,
particularly those of the non-keratinizing type, harbor human papilloma virus (HPV) DNA, HPV testing
and/or p16 immunostaining on a neck metastasis can be used as ancillary data to further support an
oropharyngeal site of origin for the primary tumor
Lesions with both squamous and glandular
differentiation presenting as cystic neck masses, as seen in this case, are however not as common.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
This is a complex macro- and microcystic lesion with a lymph node comprised of both squamoid and
glandular type cells. The columnar glandular component is in part populated by mucocytes, but also
scattered ciliated cells. While the majority of the lesion is bland there are discrete areas of
pronounced pleomorphism and mitotic activity. There are also foci of true keratinization.
Immunostaining p63 and CK 5/6 and mucicarmine staining support the presence of squamoid and mucinous
differentiation respectively. MAML2 breakapart FISH shows no evidence of the translocation commonly seen
in mucoepidermoid carcinomas. A p16 immunostain and in-situ hybridization for HPV DNA are however
- Mucoepidermoid Carcinoma a. Metastatic b. Primary (arising from intranodal salivary inclusions)
- Branchial Cleft Cyst
- Branchial Cleft Carcinoma
- Metastatic Adenosquamous Carcinoma
Metastatic Adenosquamous Carcinoma, Unknown Primary Site (Possible Oropharyngeal Primary).
This case represents a metastatic adenosquamous carcinoma to a lymph node mimicking a mucoepidermoid
carcinoma and to some extent a branchial cleft cyst, possibly even evoking the 'mythical' diagnosis of a
branchial cleft cyst (branchiogenic) carcinoma. However, MAML2 gene rearrangement studies were negative
arguing against a mucoepidermoid carcinoma. The p16 and HPV positivity within this lesion would suggest
an oropharyngeal site of primary for this tumor and argue against the (vanishingly thin) possibility of a
so-called branchial cleft cyst carcinoma. Even for an adenosquamous carcinoma, this case is unique in
how closely the constellation of histologic features simulates a mucoepidermoid carcinoma. Historically,
the terms 'adenosquamous carcinoma' and 'mucoepidermoid carcinoma' have been used interchangeably .
However, it is currently accepted that adenosquamous carcinoma of the head and neck is a surface derived
squamous malignancy with divergent glandular differentiation while mucoepidermoid carcinoma is a salivary
Alos et al
 recently outlined specific criteria to delineate adenosquamous
carcinoma from mucoepidermoid carcinoma, namely: the presence of surface dysplasia, infiltrative growth
pattern, pronounced keratinization, discrete adenocarcinomatous foci (often in deep portions of tumor),
absence of intermediate cells, and pronounced nuclear atypia. These criteria are most useful to
delineate primary adenosquamous carcinomas with keratinizing squamous components from mucoepidermoid
However, the current case is unique in several ways: 1) This is a lymph node
metastasis. As such, the most important criterion, namely the presence of a surface component cannot be
used. 2) This case shows a mixture of squamo-glandular elements lining cystic spaces akin to a
mucoepidermoid carcinoma rather than discrete tubular/cribriform adenocarcinomatous foci. This is not
uncommon, however, in a metastasis, this morphology adds significant challenge to the distinction. 3) In
keeping with the human papilloma virus driven, presumptive oropharyngeal phenotype
component is predominantly non-keratinizing which imparts a semblance to epidermoid and even intermediate
cells of mucoepidermoid carcinoma. 4) This tumor is surprisingly bland compared to most adenosquamous
carcinomas. The focality the pleomorphism and keratinization combined with the cystic configuration and
lymphoid stroma disturbingly mimic a low grade mucoepidermoid carcinoma, whereas the differential
diagnosis for most adenosquamous carcinomas is high grade mucoepidermoid carcinoma. There is not a body
of literature to define any specific approach, to this particular type of case. One lesson learned here,
however, is that even focal severe nuclear atypia and keratinization within a cystic squamoglandular
lymph node metastasis should raise skepticism for the diagnosis of mucoepidermoid carcinoma. Within the
spectrum of mucoepidermoid carcinomas, pleomorphism and (focal) keratinization are only acceptable in
high grade mucoepidermoid carcinomas and are as a rule accompanied by a solid, and often infiltrative
growth pattern. Thus, the juxtaposition of these high grade defining criteria with a low grade
architectural configuration represents a 'discordant' morphology that would be unexpected in
Ultimately, distinction between a cystic mucoepidermoid carcinoma and
cystic metastasis from an adenosquamous carcinoma with a bland non-keratinizing squamous component may
not be possible without supportive ancillary testing. Thus documenting the absence of a mucoepidermoid
carcinoma defining translocation, either CRTC1-MAML2 (previously known as MECT1-MAML2)
CRTC3-MAML2  would be further supportive evidence for an adenosquamous carcinoma. In this particular
case, the p16 immunoreactivity and HPV positivity were fortuitously positive. Since these markers define
a distinct phenotype mainly seen in surface derived malignancies, mucoepidermoid carcinoma is effectively
excluded. Despite the presence of ciliated epithelium and clinical impression of 'branchial cleft cyst,'
the cellular and architectural complexity of this lesion very quickly excludes this as possibility.
Conceptually, the so-called branchial cleft cyst carcinoma or branchiogenic carcinoma is a possible
consideration. This diagnosis has stirred controversy even at the time of its original description.
Current consensus is that essentially all such lesions are cystic metastases rather than true
malignancies arising from branchial cleft cysts. However, authors such as Khafif et al  allow for the
possibility of the existence of branchial cleft cyst carcinoma assuming that strict criteria were
employed: 1) The tumor located in the anatomic region of the branchial cleft cyst or sinus 2) The tumor
consistent with its origin from branchial vestiges(i.esquamous cell carcinoma) 3) Carcinoma is noted
within the lining of an identifiable cyst 4). There is a transition from the normal squamous or
respiratory epithelium of the cyst to carcinoma; 5) There is no identifiable primary malignant tumor
after exhaustive evaluation of the patient; this must include endoscopy (nasopharyngoscopy, laryngoscopy,
bronchoscopy, and esophagoscopy), radiographic examinations, full CT scan of the head and neck, and
appropriate biopsies. Many authors also advocate a minimum of 5 years follow-up without evidence of a
primary tumor.  One may argue that the ciliated columnar epithelium noted in this case represents this
'normal' cyst epithelium with the proliferative areas representing transition to tumor. Additionally,
the other criteria in this case have been fulfilled to date (with the exception of extensive follow- up).
However, the p16 and HPV positivity in this lesion argue again very strongly for a surface mucocutaneous
derivation, thus once again relegating 'branchial cleft cyst carcinoma' as a consideration to 'pathologic
folklore' status. Also, the assumption that the ciliated epithelium represents a benign process (i.e.
normal branchial cleft cyst elements) is inaccurate. The presence of ciliated carcinoma cells has
precedent in a variety of adenocarcinomas
and has in fact been described in the veterinary
pathology literature in one case of adenosquamous carcinoma of the nasal cavity ! Thus, this case
represents a similar process of ciliated cell differentiation within a tumor.
Review of the Literature/Treatment Options (if applicable):
The approach to treatment and clinical management in this case should closely mirror that for a
metastatic squamous cell carcinoma of unknown primary head and neck site. Squamous cell carcinomas of
the head and neck present as unknown primaries in 2-3% of cases.  Thus identification of a primary
site would be important in allowing more precise targeted excision/radiotherapy rather than wide field
irradiation which would have more morbidity. The cystic appearance and HPV positivity would suggest an
thus targeted biopsies of the Waldeyer ring and 'diagnostic' tonsillectomies
are typically performed. In roughly half of these cases, a primary site will be identified, almost
invariably tonsil or base of tongue.  In addition to treatment of the primary tumor, if identified,
management of the neck is important. The nodal stage is a primary determinant of treatment of the neck.
For N1 disease, a selective neck dissection on the involved side is the typical treatment. However for
aggressive nodal disease, namely stage N2-N3, or any N+ case with extracapsular spread, irradiation of
the neck is recommended. Additionally the neck dissection may be more extensive. 
This is an unusual case of metastastic adenosquamous carcinoma to a lymph node clinically mimicking a
branchial cleft cyst, and histologically simulating mucoepidermoid carcinoma. The ciliated component
raises theoretical consideration for the so-called 'branchial cleft cyst carcinoma.' Ancillary p16, HPV,
and MAML-2 testing helps to support this diagnosis, and even suggests an oropharyngeal site of primary.
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