Cribriform Adenocarcinoma of Minor Salivary Gland: A Report of Two Cases With an Emphasis on Cytology Michael P. Gailey, D.O.,1 Rodrigo Bayon, M.D.,2 and Robert A. Robinson, M.D., Ph.D.1*

Cribriform adenocarcinoma of minor salivary gland (CAMSG) is a recently characterized low grade salivary gland malignancy that most commonly presents as a mass in the base of the tongue, frequently with regional lymph node metastasis. Given its relative rarity and overlapping cytomorphology, CAMSG may be confused with polymorphous low grade adenocarcinoma (PLGA) in minor salivary gland sites and papillary thyroid carcinoma (PTC) in cervical metastasis, in both fine-needle aspiration and excisional specimens. As there are no cytology reports in the literature, we present two new cases of CAMSG and describe the aspiration cytology of the tumor taken from bench top aspirates, compare it with the histomorphology, and discuss the features that may help one avoid misdiagnosis of PTC in the setting of cervical lymph node metastasis. We found that like PTC, aspirates of CAMSG contain polymorphic fragments of epithelial cells arranged in monolayer sheets, papillary fronds and tips, and occasional cribriform configurations, and metachromatic stromal fragments, which may be misinterpreted as colloid. A background of myxoid/mucoid material also reminiscent of colloid was prominent. Differentiation from PLGA is more difficult based strictly on cytology. A review of the most current literature in relation to the molecular and immunohistochemical profiles, therapeutic options, and prognosis is also presented. It is critical for pathologists and clinicians to be aware of this tumor when presented with patients having a cervical lymph node mass in the absence of a primary tumor. Diagn. Cytopathol. 2014;42:1085–1090. VC 2014 Wiley Periodicals, Inc. Key Words: cribriform adenocarcinoma; minor salivary gland; tongue; aspiration cytology

1 Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 2 Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa *Correspondence to: Robert A. Robinson, M.D., Ph.D., Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA. E-mail: [email protected] Received 31 May 2013; Revised 30 October 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23111 Published online 18 February 2014 in Wiley Online Library (wileyonlinelibrary.com).

C 2014 WILEY PERIODICALS, INC. V

Cribriform adenocarcinoma of minor salivary gland (CAMSG) is a rare low grade malignant salivary gland tumor that was originally termed cribriform adenocarcinoma of the tongue (CAT).1 The entity was further refined and renamed in a multicenter report of 23 cases in which the tongue was a major primary site, but occurrences in the palate, retromolar mucosa, tonsils, and upper lip were also described.2 The name change more accurately reflects its likely origin. Few other reports are available.3–6 Prior to this appellation, many of these tumors may have been erroneously diagnosed as polymorphous low grade adenocarcinoma (PLGA) and prior published reports of PLGA presenting with or developing lymph node metastasis have been called into question given the distinct propensity of CAMSG to metastasize to regional lymph nodes.1,2,7–9 While the two tumors share the common feature of arising in minor salivary gland tissues, they are morphologically and clinically distinct entities. Another potential diagnostic pitfall during cytologic interpretation of lymph node FNA is when CAMSG presents with nodal enlargement and a clinically occult tongue lesion, given our finding of cytomorphological overlap with papillary thyroid carcinoma (PTC). To date, there are no reports describing the cytology of CAMSG. Herein, we describe two cases, both arising in the tongue and one presenting with cervical lymph node metastasis, and present the cytologic findings based on bench top aspirations of both a primary tongue lesion and cervical lymph node metastasis. We also discuss the cytologic differential diagnosis of CAMSG and review the literature in relation to its clinical, pathologic, therapeutic, and prognostic aspects.

Case Reports Case 1 A 56-year-old diabetic woman presented with a right neck mass first noticed incidentally on routine visit to her Diagnostic Cytopathology, Vol. 42, No 12

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Fig. 1. Radiologic, gross, and microscopic findings. (a) Sagittal PET image revealing hypermetabolic foci of the right tongue base and right neck. (b) Partial glossectomy showing a solid white-tan, firm mass extending deeply into the intrinsic tongue musculature. H&E sections showing (c) hyalinized fibrous tissue cores with blue mucoid/myxoid matrix associated with the neoplastic cells (3200), and (d) nuclear features characteristic of CAMSG, including nuclear overlapping, nuclear grooves, and ground glass chromatin (3600). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

primary care physician. She related approximately six months of sore throat, right-sided neck pain, right-sided otalgia, dysphasia for chewy foods, and fatigue. She denied a history of hoarseness, alcohol or tobacco use, although she admitted to heavy second hand smoke exposure. Family history of prior head and neck cancer was negative. She was referred to an otolaryngologist where a flexible fiberoptic laryngoscopy was normal. CT imaging was obtained which revealed a right-sided neck mass and an infiltrative mass in the right base of tongue. The patient was subsequently referred to a tertiary care center for evaluation by a Head and Neck surgical oncologist. On physical examination, a firm mass was appreciated on the right aspect of the base of the tongue and firm right neck masses at levels II and III were palpable. A contrast enhanced CT scan revealed a 2.0 3 2.6 3 1.4 cm mass in the right tongue base that crossed midline and involved the right genioglossus muscle, intrinsic tongue musculature, and two right level II/IIIa lymph nodes measuring 1.9 and 2.5 cm, respectively. PET-CT revealed intense uptake in the tongue base and an intensely hypermeta1086

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bolic conglomerate of lymph nodes in the right level IIA, IIB, and III regions measuring 3.1 3 2.4 3 1.9 cm (Fig. 1a). Increased uptake was also noted in a left level III lymph node, 0.9 cm. No other pertinent radiographic abnormality was detected. Biopsy of one right neck lymph node showed a neoplasm with hyalinized fibrovascular cores lined by monomorphic cells with overlapping, optically clear nuclei, nuclear grooves, nuclear membrane irregularity, and rare nuclear inclusions. Blue myxoid/mucoid matrix was present within the hyalinized cores (Figs. 1c and d). No mitotic activity or necrosis was seen. Immunohistochemical studies showed the tumor cells to be positive for pancytokeratin, partially positive for CK 7, CK 8/18, p63, S100 protein, smooth muscle myosin, smooth muscle specific actin, calponin, and CD117, and focally positive for CK 5/6. They were negative for TTF-1 and thyroglobulin. The diagnosis of CAMSG was rendered and the patient underwent a partial glossectomy (Fig. 1b) and bilateral neck dissection. At the time of surgery, separate 25-gauge needles were used to perform bench top aspirates of

Diagnostic Cytopathology DOI 10.1002/dc

CYTOLOGY OF CAMSG

both the tongue neoplasm and a cervical metastasis, and air-dried and ethanol-fixed smears were prepared for Romanowsky and Papanicolaou stains, respectively. The diagnosis was confirmed on final pathology, which also showed lymphovascular space invasion within the glossal resection and extracapsular tumor extension within the lymph node metastases. The patient subsequently received adjuvant radiation therapy.

Case 2 A 55-year-old woman with advanced organic brain syndrome, diabetes mellitus, and hypertension presented with complaints of dysphagia and difficulty breathing. Intraoral examination revealed a large base of tongue mass that partially obstructed the airway. An incisional biopsy showed a neoplasm with large cleft-like papillae lined by monomorphic oval cells with frequent nuclear grooves and nuclear overlap. Immunohistochemical studies showed the tumor cells to be positive for AE1/AE3, partially positive for CK 7, p63, S100 protein, vimentin, and CD117 (c-kit), and focally positive for CK 5/6. The tumor cells were negative for TTF-1 and thyroglobulin. Given the patient’s underlying medical problems, further therapy was declined.

Discussion CAMSG is a rare minor salivary gland tumor that was originally described as CAT in 1999 by Michal et al., who reported 8 cases, all occurring in the tongue and presenting with regional lymph node metastasis.1 The entity was diagnostically refined by Skalova et al., who shared a joint experience of 23 new cases, the majority also presenting in the tongue.2 However, several of their cases arose from other minor salivary gland sites, including the palate, retromolar mucosa, tonsils, and upper lip.2 These findings challenged the conclusion that CAT arose exclusively from the tongue and was a remnant of the thyroglossal duct.1 These two reports also questioned whether cases originally reported as PLGA arising in the tongue and presenting with regional lymph node metastasis were actually CAMSG based on better understanding and the dichotomous clinical behaviors of the two entities.1,2 Three particular studies showed unusually high rates of lymph node metastasis in tumors reported as PLGA that arose in the tongue and shared a very similar papillary appearance to CAMSG.7–9 Moreover, these are not the only published reports where CAMSG is called something else. Likely the first published report that represents CAMSG in the literature came from Crocker et al., who reported on a young child with what they called “papillary adenocarcinoma of minor salivary gland.”10 In 1989, Yajima et al. reported a lesion in the tongue of a middle aged man that was called tubular carcinoma.11 Given these few reports discussing the histomorphology of this neoplasm, there are currently no cytology reports

of CAMSG available in the literature. We feel it is especially critical to keep this entity in mind when reviewing smears from cervical lymph node aspirates from patients without thyroid nodules and potentially a clinically occult tongue or oral cavity primary. A misdiagnosis or unclear interpretation may result in thyroidectomy and subsequent morbidity. Based on the well-established reports of CAMSG in the literature (including the present report), the tumor has arisen in 16 males and 21 females (data for 4 patients unavailable) and occurs over a broad age range (21–85 years).1–6 The most reported location is the tongue (76%), followed by palate (7%), tonsils (7%), retromolar mucosa (5%), floor of mouth (2%), and upper lip (2%).1–6 Almost three-quarters of cases present with synchronous uni- or bi-lateral cervical metastasis, but distant metastasis is unreported. Metachronous lymph node metastasis was also reported up to 37 months following initial diagnosis.3 Table I summarizes reported cases of CAMSG. Fine-needle aspiration showed cellular smears with a mixture of monolayer sheets, long, broad papillae, papillary tips of the tumor cells, and occasional cribriforming configurations (Figs. 2a and b). Variable amounts of metachromatic stroma (Fig. 2c), similar to that seen in pleomorphic adenoma (PA) and which highlights the broad papillae of the tumor, were present on Romanowsky stain and abundant thick myxoid/mucoid material was evident at low magnification. At higher magnification, the cellular compartment showed tumor cells with round to elongated, overlapping nuclei with finely granular chromatin, punctate nucleoli, and moderate amounts of soft, fluffy cytoplasm. The nuclei were essentially identical to those seen in cases of PTC with irregular nuclear contours, nuclear grooves, and rare intranuclear inclusions (Figs. 2d and e). Perhaps the key distinguishing features to differentiate CAMSG from PTC were the quality and character of the background. While PTC can occasionally be stroma-rich, aspirate smears of CAMSG have a much more “salivary gland-type” background with frequent fragments of metachromatic stroma and flocculent pink myxoid/mucoid material that must be differentiated from colloid. A very important caveat we noted is that on Pap stain this flocculent background material is washed away, making a specific diagnosis even more difficult. Another likeness between the two is the varying architectural patterns maintained by CAMSG both at the primary and metastatic sites, containing crowded monolayer sheets, long, broad papillae, papillary tips, and occasional cribriform groups. Mitoses and necrosis were not present. The tumors are grossly unencapsulated, white to gray, firm masses that lack hemorrhage or necrosis (Fig. 1b) and can arise from various minor salivary gland sites, but the tongue is the most reported site.1,2 Microscopically, the tumor is submucosal and demonstrates infiltrative Diagnostic Cytopathology, Vol. 42, No 12

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NED, no evidence of disease; DOC, died of other cause; Pt, platinum; NA, not available; AWT, alive with tumor.

NA NED (3 years) AWT (1; 8 months)NED (1; 6 months) Surgical excision and irradiation Surgical excision and irradiation Surgical excision (1) Adjuvant irradiation (1) Tongue Tongue Tongue (2) 1 1 2

Lateral neck Tongue 1

Borowski-Borowy et al.4 Prasad et al.5 Cocˇek et al.6 Current report

No lymph node metastasis Lateral neck Lateral neck, synchronous (1)

NED

NED (3; 8–14 months) Two patients alive with lymph node metastasis (15–40 months)

Surgical excision (5) Lymph node dissection (4) Irradiation (2) Pt-based chemotherapy (1) Surgical excision 5 Laco et al.3

Lateral neck, synchronous (4)

NED (8; 2–6 years) NED (12; 2 months–13 years) DOC NED (1) Recurrence (1) No follow-up (9) Excision and irradiation (8) Surgical excision (14) Lymph node dissection (10)Irradiation (9) Lateral neck, synchronous (8) Lateral neck (16) Synchronous (15) Metachronous (1)

Tongue (8) Tongue (14) Palate (3) Tonsils (3) Retromolar (2) Upper lip (1) Tongue (4) Floor of mouth (1) 8 23 Michal et al. Skalova et al.2

Lymph node metastasis (no. cases) Sites (no. cases)

1

Total cases reported Report

Table I. Summary of Cribriform Adenocarcinoma of Minor Salivary in the Literature

Treatment (no. cases)

Follow-up (no. cases; duration)

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margins that commonly extend into the intrinsic musculature of the tongue or adjacent sites. Architecturally, the tumor is not as heterogeneous as PLGA, being relatively limited in growth pattern. A solid and/or a cribriforming pattern is most common, but microcystic and papillary patterns can also be present. It is common for the tumor to contain a mixture of all growth patterns. Hyalinized fibrotic stroma with pale blue myxoid/mucoid matrix that divides the tumor into uneven lobules is characteristic. Cytologically the tumor is composed of one cell type, giving rise to confusion with PLGA, but the tumor cells are more reminiscent of those seen in PTC, with nuclear overlapping, membrane irregularity, grooves and optically clear, ground glass chromatin. These histologic features give reason to pause at low power and consider another diagnosis in these sites. As already mentioned, in the setting of metastasis, the tumor generally retains both its architectural and cytomorphologic features, thus differentiating them from other primary tumor types based on cytology is very difficult. By immunohistochemistry, the tumor cells react with AE1/AE3, CAM5.2, CK7, and CK8/18. They also highlight with basal and myoepithelial markers, including S-100 protein, p63, CK5/6 (variable), CK14, calponin, and smooth muscle actin.1–3 This co-expression of both epithelial and myoepithelial markers convinced early reporters that these cells were hybrid secretorymyoepithelial cells, which was supported by ultrastructure.1,2 While CK19, galectin-3, and HBME-1 may be positive, importantly, TTF-1 and thyroglobulin are negative.2,3 Epithelial membrane antigen, epidermal growth factor receptor, and HER-2/neu are also negative.2 CD117 (c-kit) positivity is variably present in 42% of cases.2 Variable cyclin D1, p16, and p53 positivity is reported, but the significance is unknown.2 Of 10 tumors studied by Skalova et al., only one was high risk HPV-positive.2 No mutations of BRAF, KRAS, HRAS, RET, c-kit, and PDGFRa have been detected.2,3 Laco et al. detected three separate polymorphisms in the RET proto-oncogene in three of five cases and the same polymorphism of HRAS in three separate cases.3 The main differential diagnosis of CAMSG when detected in the tongue or other sites in minor salivary glands is PLGA. PLGA is also a tumor composed of one cell type and is truly polymorphous in architecture. It commonly grows in a target-like fashion, with cords or thin trabeculae extending circumferentially beyond the main bulk of the tumor into the surrounding stroma. However, the cytology of tumor cells from these two tumors differs. PLGA tumor cells show regular, nonoverlapping nuclei, and evenly dispersed chromatin. In contrast, CAMSG shows nuclear overlapping, irregular nuclei with grooves, and optically clear, ground glass chromatin. Their immunohistochemical profiles are very similar, and

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CYTOLOGY OF CAMSG

Fig. 2. Aspirate cytology of CAMSG. Low power Romanowsky (a) and Pap (b) stains showing papillary fragments and papillary tips lined by neoplastic cells. Note that in the Pap-stained smear the conspicuous myxoid/mucoid matrix seen on Romanowsky stain is absent (3200). (c) Metachromatic stromal fragments, reminiscent of pleomorphic adenoma, are associated with admixed neoplastic cells (Romanowsky stain, 3600). (d) Small clusters of tumor cells with round to oval nuclei and conspicuous pink, flocculent myxoid/mucoid background material (Romanowsky stain, 3600). (e) Pap stain showing a monolayer sheet of tumor cells with elongated, overlapping nuclei with irregular nuclear membranes and several nuclear grooves (3600). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

accurate histologic diagnosis requires familiarity with the clinical presentation and primary site. CAMSG most frequently arises in the tongue and frequently presents with regional lymph node spread, and PLGA rarely metastasizes. An accurate cytologic diagnosis hinges on recognizing the nuclear changes of CAMSG, and in less cellular aspirates, it may not be possible to distinguish the two.

Other salivary gland tumors in the differential include adenoid cystic carcinoma (ACC), PA, and other basaloid tumors that once fell under the rubric of monomorphic adenoma, including basal cell adenoma and adenocarcinoma. ACC is generally limited in architecture with round, acellular “gumballs” of basement membrane material that stain metachromatically on Romanowsky stain. Diagnostic Cytopathology, Vol. 42, No 12

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In our experience, the stromal fragments of CAMSG more closely resemble PA that have geometry and a fibrillar quality that contains entrapped epithelial cells, a distinct difference from the acellular gumballs of ACC. Occasionally, stroma-rich basal cell adenomas and adenocarcinomas may be included in the differential. We believe that these other tumors come into the differential of CAMSG not so much for their cellular cytology, but because the stroma is such a prominent finding and one’s eyes are drawn to it. Thus, it is important to examine the cells closely as basaloid neoplasms tend to have angulated nuclei with scant cytoplasm and CAMSG tends to have larger, irregular nuclei with relatively more abundant, soft cytoplasm. In metastatic lesions, the main differential diagnosis is PTC and it may be very difficult to distinguish the two based strictly on cytology, as both tumors show prominent nuclear overlapping, nuclear grooves, and ground glass chromatin. Both tumors can also present in sheets, papillary groups, and papillary tips. Extreme caution is warranted in the setting of fine-needle aspiration of cervical lymph node metastases in the setting of a tongue mass or in the setting of no identifiable tumor in the thyroid. When sufficient material is present for ancillary studies, TTF-1 and thyroglobulin are consistently negative in CAMSG.1–3 As noted previously, galectin-3, HBME-1, and CK19 can show variable expression and are not helpful in this differential.3 Although CAMSG frequently presents with synchronous lymph node metastasis, all reported series and cases show even those who present at high clinical stage experience a favorable prognosis following definitive surgery with negative margins. Adjuvant radiation therapy has been given in several cases.1–6 Only one reported case received treatment with platinum-based (cisplatin) chemotherapy.3 It is thought that, like PTC, CAMSG is a tumor that shows early lymphotropism to regional lymph nodes, but does not generally metastasize distantly. No tumorrelated death has been reported thus far.1–6 CAMSG is a rare minor salivary gland tumor that mimics PLGA at minor salivary gland sites and PTC in cervical lymph node metastases. While the tongue is the most common reported primary site, cases from other sites in the oral cavity are now in the literature. Nearly

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three-quarters of reported cases have presented with synchronous regional lymph node metastases. Its propensity to spread to cervical lymph nodes raises the very real possibility that CAMSG could be misdiagnosed on aspirate or excisional biopsy as PTC and that thyroidectomy may be performed unnecessarily. However, when sufficient material is available for ancillary tests, it is always negative for TTF-1 and thyroglobulin. No reliable gene alterations have been reported to date. Treatment with surgical excision with or without adjuvant radiation appears to be sufficient management to cure the disease. It is critical that both pathologist and clinician are aware of this uncommon entity to avoid misdiagnosis and patient mismanagement.

References 1. Michal M, Skalova A, Simpson RH, et al. Cribriform adenocarcinoma of the tongue: A hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue. Histopathology 1999;35:495–501. 2. Skalova A, Sima R, Kaspirkova-Nemcova J, et al. Cribriform adenocarcinoma of minor salivary gland origin principally affecting the tongue: Characterization of new entity. Am J Surg Pathol 2011;35: 1168–1176. 3. Laco J, Kamaradova K, Vıtkova P, et al. Cribriform adenocarcinoma of minor salivary glands may express galectin-3, cytokeratin 19, and HBME-1 and contains polymorphisms of RET and H-RAS proto-oncogenes. Virchows Arch 2012;461:531–540. 4. Borowski-Borowy P, Dyduch G, Papla B, et al. Cribriform adenocarcinoma of the tongue. Pol J Pathol 2011;62:168–171. 5. Prasad KC, Kaniyur V, Pai RR, et al. Pedunculated cribriform adenocarcinoma of the base of the tongue. Ear Nose Throat J 2004;83:62–64. 6. Cocˇek A, Hronkova K, Voldanova J, et al. Cribriform adenocarcinoma of the base of the tongue and low-grade, polymorphic adenocarcinomas of the salivary glands. Oncol Lett 2011;2:135–138. 7. Perez-Ordonez B, Linkov I, Huvos AG. Polymorphous low-grade adenocarcinoma of minor salivary glands: A study of 17 cases with emphasis on cell differentiation. Histopathology 1998;32:521–529. 8. Seethala RR, Johnson JT, Barnes EL, et al. Polymorphous low grade adenocarcinoma: The University of Pittsburgh experience. Arch Otolaryngol Head Neck Surg 2010;136:385–392. 9. Colmenero CM, Patron M, Burgue~ no M, et al. Polymorphous lowgrade adenocarcinoma of the oral cavity: A report of 14 cases. J Oral Maxillofac Surg 1992;50:595–600. 10. Crocker TP, Kreutner A, Jr, Othersen HB, Jr, Garvin AJ. Papillary adenocarcinoma of minor salivary gland origin in a child. Arch Otolaryngol 1983;109:827–831. 11. Yajima M, Yamazaki T, Minemura T, Kotani A. Tubular adenocarcinoma of the apex of the tongue. J Oral Maxillofac Surg 1989;47: 86–88.

Cribriform adenocarcinoma of minor salivary gland: a report of two cases with an emphasis on cytology.

Cribriform adenocarcinoma of minor salivary gland (CAMSG) is a recently characterized low grade salivary gland malignancy that most commonly presents ...
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