—  SPECIALTY CONFERENCE  —

Head/Neck/Endocrine Pathology

Case 3 - Metastatic Adenosquamous Carcinoma, Unknown Primary Site (Possible Oropharyngeal Primary)

Raja R. Seethala
University of Pittsburgh Medical Center
Pittsburgh, PA





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Clinical History
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.

Pertinent Laboratory Data:

Grossly, the excision contained a 3.0 x 2.0 x 0.6 cm tan- white ovoid mass with focal cystic change.


Case 3 - Slide 1
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Case 3 - Figure 1
Whole slide scan demonstrating a cystic mass (right) within lymphoid rich stroma
Case 3 - Figure 2
The cystic lesion shows architectural complexity comprised of macro and microcysts with papillary invaginations
Case 3 - Figure 3
The cystic spaces are line by a fairly monomorphic outer squamoid layer and an inner columnar layer.
Case 3 - Figure 4
Mucocytes are noted within the innermost layer of some of the cysts

Case 3 - Figure 5
A Mucicarmine highlights these mucocytes
Case 3 - Figure 6
Few of the columnar epithelial cells are ciliated (arrows)
Case 3 - Figure 7
Cystic lining focally demonstrates pronounced pleomorphism and mitotic activity
Case 3 - Figure 8
Focal keratinization is noted

Case 3 - Figure 9
A cytokeratin 5/6 is positive mainly in the outer more squamoid layers of the cystic spaces.
Case 3 - Figure 10
A p63 immunostain similarly highlights mainly the squamoid outer layers of the cystic spaces.
Case 3 - Figure 11
MAML2 breakapart FISH shows no evidence of a rearrangement

Case 3 - Figure 12
A p16 immunostain is diffusely strongly positive
Case 3 - Figure 13
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.

Introduction:
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 [1, 2]. 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 malignancy [1, 3]. Occasionally cystic papillary thyroid carcinoma metastases may also present as lateral cervical cysts [2, 4]. Over the past few decades, the strong association between cystic squamous cell carcinoma metastases and oropharyngeal site of primary has become well recognized [5, 6]. 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 [7, 8, 9, 10, 11]. 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 positive.

Differential Diagnoses:
  1. Mucoepidermoid Carcinoma a. Metastatic b. Primary (arising from intranodal salivary inclusions)

  2. Branchial Cleft Cyst

  3. Branchial Cleft Carcinoma

  4. Metastatic Adenosquamous Carcinoma

Final Diagnosis:
Metastatic Adenosquamous Carcinoma, Unknown Primary Site (Possible Oropharyngeal Primary).

Case Discussion:
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 [12]. 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 type malignancy [13, 14]. Alos et al [15] 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 carcinomas [16]. 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 [10, 11], the squamous 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 mucoepidermoid carcinomas [16, 17, 18]. 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) [19], or CRTC3-MAML2 [20] 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 [21] 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. [1] 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 [22, 23], and has in fact been described in the veterinary pathology literature in one case of adenosquamous carcinoma of the nasal cavity [24]! 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. [25] 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 oropharyngeal primary [6, 7, 8], 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. [25] 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. [26]

Conclusion(s):
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.

References:
  1. Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts. Laryngoscope. Oct 2000;110(10 Pt 1):1637-1641.

  2. Pietarinen-Runtti P, Apajalahti S, Robinson S, et al. Cystic neck lesions: clinical, radiological and differential diagnostic considerations. Acta Otolaryngol. Feb 2010;130(2):300-304.

  3. Granstrom G, Edstrom S. The relationship between cervical cysts and tonsillar carcinoma in adults. J Oral Maxillofac Surg. Jan 1989;47(1):16-20.

  4. Seven H, Gurkan A, Cinar U, et al. Incidence of occult thyroid carcinoma metastases in lateral cervical cysts. Am J Otolaryngol. Jan-Feb 2004;25(1):11-17.

  5. Goldenberg D, Sciubba J, Koch WM. Cystic metastasis from head and neck squamous cell cancer: a distinct disease variant? Head Neck. Jul 2006;28(7):633- 638.

  6. Thompson LD, Heffner DK. The clinical importance of cystic squamous cell carcinomas in the neck: a study of 136 cases. Cancer. Mar 1 1998;82(5):944-956.

  7. Begum S, Gillison ML, Ansari-Lari MA, et al. Detection of human papillomavirus in cervical lymph nodes: a highly effective strategy for localizing site of tumor origin. Clin Cancer Res. Dec 15 2003;9(17):6469-6475.

  8. El-Mofty SK, Zhang MQ, Davila RM. Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma. Head Neck Pathol. Sep 2008;2(3):163-168.

  9. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon. Head Neck. Jul 2008;30(7):898-903.

  10. El-Mofty SK, Patil S. Human papillomavirus (HPV)- related oropharyngeal nonkeratinizing squamous cell carcinoma: characterization of a distinct phenotype. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Mar 2006;101 (3):339-345.

  11. Chernock RD, El-Mofty SK, Thorstad WL, et al. HPV- related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol. Sep 2009;3(3):186-194.

  12. Damiani JM, Damiani KK, Hauck K, et al. Mucoepidermoid-adenosquamous carcinoma of the larynx and hypopharynx: a report of 21 cases and a review of the literature. Otolaryngol Head Neck Surg. Mar-Apr 1981;89 (2):235-243.

  13. Keelawat S, Liu CZ, Roehm PC, et al. Adenosquamous carcinoma of the upper aerodigestive tract: a clinicopathologic study of 12 cases and review of the literature. Am J Otolaryngol. May-Jun 2002;23(3):160-168.

  14. Cardesa A, Zidar N, Alos L. Adenosquamous carcinoma. In: Barnes L, Eveson J, Reichart P, Sidransky D, eds. Pathology and Genetics Head and Neck Tumors. Lyon: IARC Press; 2005:130-131.

  15. Alos L, Castillo M, Nadal A, et al. Adenosquamous carcinoma of the head and neck: criteria for diagnosis in a study of 12 cases. Histopathology. Jun 2004;44(6):570- 579.

  16. Seethala RR, Dacic S, Cieply K, et al. A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol. Aug 2010;34 (8):1106-1121.

  17. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer. Apr 1 1998;82(7):1217-1224.

  18. Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol. Jul 2001;25(7):835-845.

  19. Tonon G, Modi S, Wu L, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. Feb 2003;33(2):208-213.

  20. Nakayama T, Miyabe S, Okabe M, et al. Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma. Mod Pathol. Dec 2009;22(12):1575-1581.

  21. Khafif RA, Prichep R, Minkowitz S. Primary branchiogenic carcinoma. Head Neck. Mar-Apr 1989;11(2):153- 163.

  22. Hendrickson MR, Kempson RL. Ciliated carcinoma--a variant of endometrial adenocarcinoma: a report of 10 cases. Int J Gynecol Pathol. 1983;2(1):1-12.

  23. Imai T, Suga M, Kaimori M, et al. Peripheral pulmonary papillary adenocarcinoma with prominent cilia: report of a rare case that was difficult to diagnose preoperatively. Acta Cytol. Sep-Oct 2010;54(5 Suppl):949- 957.

  24. Fukui D, Bando G, Ishikawa Y, et al. Adenosquamous carcinoma with cilium formation, mucin production and keratinization in the nasal cavity of a red fox (Vulpes vulpes schrencki). J Comp Pathol. Aug-Oct 2007;137(2- 3):142-145.

  25. Cianchetti M, Mancuso AA, Amdur RJ, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. Dec 2009;119(12):2348- 2354.

  26. Miller FR, Karnad AB, Eng T, et al. Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy. Head Neck. Jan 2008;30(1):28-34.