Original Article
Hyalinizing Clear Cell Carcinoma Case Series and Comprehensive Review of the Literature Antonieta A. Solar, MD1,2, Brian L. Schmidt, DDS, MD, PhD3,4, and Richard C. K. Jordan, DDS, PhD, FRCPath1,4,5
BACKGROUND: Hyalinizing clear cell carcinoma (HCCC) is an uncommon malignant salivary gland tumor that was characterized only recently as a distinct entity. Because of its histologic similarity to several other primary and metastatic tumors and its purported favorable clinical outcome after local resection, it is important to recognize the features of this unusual tumor. METHODS: The authors present 8 new, fully characterized cases of HCCC and systematically reviewed 44 other cases of HCCC reported in the English language literature from 1980 to 2008. Historic cases were reviewed, and available data regarding morphology, special stains, demographics, clinical presentation, radiographic findings, management, and outcomes were extracted. Data from the current series were compared with the earlier published literature. RESULTS: To the best of the authors’ knowledge, this was the largest reviewed series of HCCC and included a total of 52 cases. The findings, which included key histologic features, clinical presentation, and outcome, generally were consistent with what was reported previously. However, the current review revealed that 25% of patients reported in the literature had metastases at initial presentation, including 10 of 44 patients who had metastases to regional lymph nodes and 1 patient who had metastasis to the lung. The authors were unable to identify any specific histologic features that would predict this behavior. CONCLUSIONS: The current results indicated that HCCC is less indolent than was believed previously; therefore, regional lymph node dissection should be considered in conjunction with wide local excision for patients with HCC. C 2008 American Cancer Society. Cancer 2009;115:75–83. V KEY WORDS: clear cell carcinoma, salivary gland, tumor, pathology, neoplasia.
Clear cell carcinomas or adenocarcinomas are rare neoplasms that account for less than 1% of all salivary gland tumors.1,2 Microscopically, these tumors contain a significant proportion of neoplastic cells with a clear cytoplasm and morphologically do not fit into other categories of salivary gland malignancy. Similar to many salivary gland tumors, clear cell carcinomas often occur on the palate and present as a small, painless mass that may be ulcerated. The microscopic diagnosis of clear cell carcinoma may be challenging, because the spectrum of microscopic features frequently overlaps with other salivary gland tumors that contain clear cells and, thus, it may be a diagnosis of exclusion. The differential diagnosis is wide and encompasses tumors with a range of clinical behavior, including clear cell oncocytoma, mucoepidermoid
Corresponding author: Richard C. K. Jordan, DDS, PhD, FRCPath, Department of Orofacial Sciences, University of California at San Francisco, S-512, 513 Parnassus Avenue, San Francisco, CA 94143-0424; Fax: (415) 476-6482;
[email protected] 1 Department of Orofacial Sciences, University of California at San Francisco, San Francisco, California; 2Department of Anatomic Pathology, Pontifica Universidad Cato´lica de Chile, Santiago, Chile; 3Department of Oral and Maxillofacial Surgery, University of California at San Francisco, San Francisco, California; 4Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California; 5Department of Pathology, University of California at San Francisco, San Francisco, California
Received: April 15, 2008; Revised: June 13, 2008; Accepted: July 28, 2008 C 2008 American Cancer Society Published online: November 17, 2008, V
DOI: 10.1002/cncr.23974, www.interscience.wiley.com
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Original Article
carcinoma, epithelial-myoepithelial carcinoma, clear cell myoepithelioma, myoepithelial carcinoma, acinic cell carcinoma, metastatic renal cell carcinoma, and balloon cell melanoma among others. In 1994, Milchgrub et al3 reported a series of 11 clear cell tumors of the salivary gland with distinctive histologic features that they called hyalinizing clear cell carcinoma (HCCC). Those authors described a tumor that occurred predominantly in the intraoral minor salivary glands, more commonly in middle-aged women. Microscopically, the tumor consisted of an infiltrative proliferation of clear and eosinophilic cells arranged as nests, trabeculae, sheets, and cords in a stroma that was hyalinized and resembled amyloid material but was positive for periodic acid–Schiff (PAS) stain and negative for Congo red (amyloid stain). The clinical behavior of HCCC currently is not well appreciated given the relative rarity of the lesion and the lack of analysis in published series. The conventional view is that HCCC is a low-grade malignancy with relatively indolent behavior.3-5 The objective of this report was to provide a comprehensive review of the histologic and clinical features of reported patients with HCCC in the English language literature along with another 8 patients from our archives.
MATERIALS AND METHODS Case Series The databases of the University of California at San Francisco Oral Pathology Biopsy Service and Department of Pathology were searched systematically for all salivary gland tumors that contained clear cells over the 25 years encompassing 1982 through 2007. All slides and case reports were retrieved and reviewed. New sections were cut and stained when the original section quality was judged to be poor. Sections were assessed independently by the authors, and the patients who fulfilled previously reported criteria for HCCC were included.3
glass slides, dewaxed in xylene, and rehydrated in graded ethanols. Endogenous peroxidase activity was blocked by immersion in 0.3% aqueous peroxide for 15 minutes followed by 2 washes in 1 phosphate-buffered saline (PBS) for 5 minutes each. Slides were treated with 0.6 M sodium citrate buffer and heated in a microwave at 100 C. Endogenous proteins were blocked by incubating in a 2% solution of bovine serum albumen in PBS for 20 minutes. Then, the sections were incubated for 1 hour at room temperature with the primary antibody diluted in PBS. This was followed by 2 washes in PBS and incubation with a hapten/peroxidase secondary antibody complex (Envision Plus; Dako Corp., Carpinteria, Calif) for 30 minutes. The bound complexes were observed by the application of either aminoethylcarbazole or diaminobenzadine (Sigma Chemical Company, St. Louis, Mo) containing 0.3 hydrogen peroxide as a substrate. After incubation, the sections were washed, then lightly counterstained with hematoxylin, and coverslipped. Negative controls consisted of omission of the primary antibody in selected sections. Literature Review We conducted a comprehensive computer search of the English language literature in the National Institutes of Health PubMed database using combinations of components of the terms hyalinizing clear cell carcinoma, clear cell carcinoma, clear cell adenocarcinoma, clear cell, glycogenrich, and salivary gland tumor to search studies that were published between 1980 and December 2007. After a careful review of each published case, tumors were selected for inclusion if they were either diagnosed as HCCC and/or if they showed the morphologic, clinical, histochemical, and immunohistochemical features typical of HCCC.3 Then, data were extracted regarding demographics, clinical presentation, radiographic findings, management, and outcomes.
RESULTS Immunohistochemistry Immunohistochemistry was performed on unstained sections using selected antibodies (Table 1) Briefly, 5micron-thick sections were cut and mounted on adherent 76
From our files, we were able to identify 8 patients who fulfilled the criteria for HCCC. The clinical findings for these patients are summarized in Table 1. Six tumors occurred in women, and 2 tumors occurred in men. The mean age at presentation was 55 years (range, Cancer
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52
65
30
85
65
60
3
4
5
6
7
8
Maxillary vestibule
Left maxilla, alveolar process
2
—
Right maxilla
Hard palate
—
9
Floor of mouth
Hard palate
—
—
Buccal mucosa
—
Wide excision
—
—
1
—
—
Wide excision
Wide excision and radiotherapy Wide excision
Wide excision
1.2
1.5
3
—
3
1
Size, cm Treatment
—
—
15
—
—
—
114
13
—
—
1 Recurrence
—
—
—
2 Recurrences
1 Recurrence
Follow-Up, mo Outcome
þ þ
þ
þ þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
Cytokeratin PAS PASD Mucicarmine A1/A3 SMA S-100
PAS indicates periodic acid-Schiff stain; PASD, PAS stain with diastase digestion; SMA, smooth muscle actin; þ, positive; , negative; HIVþ, human immunodeficiency virus positive; HCVþ, hepatitis C virus positive.
Woman
Woman
Woman
Man
Woman
Woman
Woman
Ulcerated tender mass; patient was HIVþ and HCVþ Painless firm mass Painless firm mass, history of radiation Painful, ulcerated, locally aggressive mass with loss of palatal bone, eroding into sinus Painless ulcerated mass, occasional bleeding Painless mass
49
Hard palate
2
—
Painless firm mass Painless firm mass
34
1
Man
Clinical Duration, Description mo Location
Patient Age, No. y Sex
Table 1. Clinical Findings of the Patients
Hyalinizing Clear Cell CA Review / Solar et al
77
Original Article Table 2. Tumor Characteristics
Site of Occurrence
No. of Patients (% of 52)
Tongue Palate Floor of mouth Buccal mucosa Parotid gland Maxillary gingival Retromolar area Maxilla Maxillary vestibule Subglottic larynx Nasopharynx Jaw (unspecified) Hypopharynx Tonsillar region Salivary gland (unspecified)
15 11 6 4 3 3 2 1 1 1 1 1 1 1 1
(28) (21)* (11)y (7)z (6) (6)§ (4) (2)k (2) (2) (2) (2) (2) (2) (2)
* Three patients from the current series. y One patient from the current series. z One patient from the current series. § Two patients from the current series. kOne patient from the current series.
34-85 years). All tumors occurred in the oral cavity at the following sites (see Table 2): palate (3 tumors), maxilla (2 tumors), floor of mouth (1 tumor), buccal mucosa (1 tumor), and maxillary vestibule (1 tumor). A painless, nonulcerated mass was the presenting symptom in 6 patients; and 2 patients presented with an ulcerated painful mass, both with extension to the adjacent bone and 1 with erosion into the maxillary sinus. The tumors were described as dome-shaped or sessile, white or red, firm, and with a mean greatest dimension of 1.8 mm (range, 10-30 mm). Microscopically, the normal architecture in all 8 tumors showed infiltration of the oral submucosa by trabeculae, cords, nests, and solid sheets of neoplastic epithelial cells with infiltrative margins (Fig. 1a). All tumors demonstrated fibrous and hyalinized stroma (Fig. 1b). Six tumors showed foci of loose, mixoid stroma. The predominant cell was round to polygonal with abundant and clear cytoplasm (Fig. 1b), which was positive for PAS staining (Fig. 1c), sensitive to diastase treatment (indicating glycogen) (Fig. 1d), and negative for mucin (mucicarmine). Seven tumors contained smaller, polygonal cells with eosinophilic cytoplasm admixed with the clear cells (Fig. 1b). In 4 tumors, rare mitoses were observed; and 1 tumor had 4 mitotic figures per 10 high-power fields. Perineural invasion was identified in 3 tumors, and focal necrosis was identified in 3 tumors, but no tumors had lymphovascular invasion. A summary of the immuno78
FIGURE 1. (a) Anastomosing trabeculae and nests of clear cells among hyalinized stroma (hematoxylin and eosin [H&E] stain, original magnification 100). (b) Nests and cords of a bipopulation with clear cells (arrowhead) and eosinophilic cells (arrow) (H&E stain, original magnification 200). (c) Strongly positive periodic acid–Schiff (PAS) stain without diastase highlighting the abundant cytoplasmic glycogen (original magnification 200). (d) Negative PAS stain with diastase digestion (original magnification 200).
histochemical findings is presented in Table 1. The cytokeratin was diffusely and strongly positive in all tumors; however, by contrast, the myoepithelial markers S-100 protein and smooth muscle actin (SMA) were absent in all tumors. The clinical and pathologic features of the 44 published patients with HCCC who we identified in our review of the literature are summarized in Table 3.1,3-26 Thirty-one tumors (72%) occurred in women, 12 tumors (28%) occurred in men, and, in 1 tumor, the sex of the patient was not stated. The reported mean age at presentation was 51.7 years (range, 24-78 years). The primary location (Table 2) was the minor salivary glands of the oral cavity in 35 tumors, intraosseous in 2 tumors, parotid in 3 tumors, nasopharynx in 1 tumor, hypopharynx in 1 tumor, and larynx in 1 tumor. The initial symptom at presentation was a painless swelling in 29 patients. Ten of 44 patients (23%) had documented spread of tumor to local lymph nodes at the time of diagnosis, including 1 patient with an additional metastasis to the lung and another patient with metastases to the lung and vertebra. One patient had an isolated metastasis to lung at presentation without involvement of regional lymph nodes. The duration of the symptoms before presentation ranged from 1 Cancer
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1* 11
Cancer
1
1 2 3
1 4
1
1
1 1
1 3 1 1
1 1 1
1
1 1
Tang 19958
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Urban 19969 Berho & Huvos 199910 Rinaldo 199911
Ereno 200012 Milchgrub 200013
Boccato 200123
Grenevicki 200114
Manoharan 20025 Balakrishnan 20021
Browne & Holland 200216 Felix 200215 Chao 20044 O’Regan 200417
Sun 200518 Suzuki 200619 Pujary 200820
Uzochukwo 200721
Meer & Altini 200722 Angiero & Stefani 200726 — Woman
Woman
Woman Woman Man
Man Woman Woman Woman
Woman Man
Woman
Man
Man 2:2y
Man 0:2y 0:3y
Woman
Woman 3:8y
Painless swelling Painless swelling, dysphagia Painless foreign body sensation Dysphagia, sore throat, hemoptysis — Painless swelling
Painful ulcerated swelling Painless foreign body sensation, dysphonia — Painless swelling Severe pain, anesthesia, rash Painless swelling
Nasal bleeding
Painless swelling
Painless swelling Painless swelling 1 with painless swelling, 1 with foreign body sensation, and 1 with a painful throat Painless swelling Painless swelling
Obstructing tumor
Painless swelling Painless swelling
— —
5
24 1 1
— 40 36 4
24 12
9
3
— —
9 3 13
—
— —
2 174 4
— 2
4
— 4 3
— — 2.5 4
4.5 3
5
3.2
2 2.2
2 2 —
—
2 1.9
2 2.5 3
excision excision excision excision
— Wide excision
Complete excision
Wide excision Wide excision Wide excision þ RT
Wide Wide Wide Wide
Wide excision Wide excision
Chemotherapy
Wide excision
Incision Wide excision
Wide excision Wide excision Wide excision in 1 patient, ND in 2 patients
Wide excision Wide excision in 11 patients, þ RT in 2 patients, þ RND in 1 patient Incomplete excision
Wide excision Wide excision Wide excision þ RT
Duration, Size, mo cm Treatment
— No
No
No No No Local lymph nodes, lung, and vertebra No No No
Lung 3/4 With local lymph nodes Local lymph nodes Lung and local lymph nodes No No
No No 1 With local lymph nodes
No
— No Local lymph nodes No 2/11 Local lymph nodes
— 12
8
12 21 18
19 27.5 8 10
22 12
36
—
10 60
12 15.5 58.6
144
24 44
72 69 –
— NED
NED
NED NED NED
NED NED NED DOD
NED NED
MET
NED 1 MET, 1 disease recurrence —
Multiple disease recurrences NED Both NED 1 MET, 1 disease recurrence, 1 NED
NED 1 DPO, 10 NED
NED Both NED NED
Follow-up, Metastasis mo Outcome
HCCC indicates hyalinizing clear cell carcinoma; NED, no evidence of disease; RND, radical neck dissection; RT, radiotherapy; DPO, died postoperatively; ND, NED dissection; MET, metastasis; DOD, died of disease. * Reported cases were not diagnosed as HCCC but were included because the clinical, morphologic, and immunohistochemical features noted in the photographs and reported in the study were consistent with those of HCCC. y In studies in which there was a series of patients, the ratio was used.
— 57
47
48 66 57
74 48 42 57
40 35
53
57
53 44
30 66 42
65
24 55
Swelling Painless swelling Painless swelling
Orden 199424 Milchgrub 19943
Man 1:1y Woman
1* 2* 1*
Chaundry 19836 Simpson 199025 Rajab 19947 46 70 31
No. of Age, Sex (Men: Clinical Patients y Women) Description
Reference
Table 3. Clinical and Pathologic Features of the 44 Published Cases of Hyalinizing Clear Cell Carcinoma Identified Through Review of the Literature
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Original Article Table 4. Special Stains and Immunohistochemical Findings in the Reported Literature
Stain/Marker
Published Cases/Positive Results (%)
PAS PASD Mucicarmine Fat PTAH Congo red CAM 5.2 Cytokeratin A1/A3 SMA MSA S-100 EMA CEA Vimentin Calponin CD10 TTF-1 GFAP CD68 HMB-45 HMFG NSE Thyroglobulin Desmin Myosin
39/38 (97.4)* 29/2 (6.9) 38/0y 1/0 1/0 9/0 19/19 (100) 36/36 (100) 38/0 15/0 39/0 20/15 (75) 20/8 (40) 10/0 1/0 2/0 1/0 3/0 1/0 1/0 2/2 (100) 2/2 (100) 2/0 2/0 2/0
PAS indicates periodic acid-Schiff stain; PASD, PAS stain with diastase digestion; PTAH, phosphotungstic acid hematoxiline; SMA, smooth muscle actin; MSA, muscle-specific actin; EMA, epithelial membrane antigen; CEA, carcinoembryonic antigen; TTF-1, thyroid transcription factor-1; GFAP, glial fibrillary acidic protein; HMFG, human milk fat globule; NSE, neuron-specific enolase. * The negative case was included, because the remaining stains, the morphology, and the clinical presentation were consistent with those of hyalinizing clear cell carcinoma. y Seven cases were reported that presented few droplets and were consider negative if none of the other features of mucoepidermoid carcinoma were present.
month to 15 years. All patients were treated with wide local excision. Three patients received additional radiotherapy, and 1 patient received chemotherapy. Clinical follow-up ranged from 5 months to 13 years: Thirty-one patients had no evidence of metastatic disease, 3 patients developed local recurrences (including 1 patient who had multiple recurrences), and 1 patient developed widespread metastasis and died of disease. The pathologic findings from the reported patients all were consistent with HCCC. Focal necrosis was reported in 1 patient, and perineural invasion was reported in 15 patients. There was no significant correlation between morphologic features and tumor behavior. Results of the reported histochemical and immunohisto80
chemical studies are summarized in Table 4. Thirty-eight tumors reportedly were positive for PAS in the cytoplasm, and 29 tumors were sensitive to PAS diastase (PAS-D) (glycogen). The presence of mucin was analyzed in 38 tumors, and all 38 tumors reportedly were negative. Thirty-eight tumors were studied for the expression of cytokeratin A1/A3 protein by immunohistochemistry, and all tumors were strongly positive. Low-molecular-weight keratin expression was present in all 19 tumors that were examined, epithelial membrane antigen was present in 15 of 20 tumors, and 8 of 20 tumors were positive for carcinoembryonic antigen. The presence of neoplastic myoepithelial cells was assessed by determining the expression S100 protein, SMA, and muscle-specific actin in 39 tumors, 38 tumors, and 15 tumors, respectively, all of which were negative.
DISCUSSION To the best of our knowledge, this is the largest reviewed series of HCCC (52 patients, including 8 new patients from our archives) that has been reported to date in the English literature. The analysis of the demographic and pathology findings in our 8 patients generally was consistent with those reported previously in patients with HCCC. According to our review of the literature, approximately 71% of HCCCs occurred in women, and most commonly in middle-aged women. In 42 patients (80.7%) the primary tumor location was within the oral cavity, affecting the minor salivary glands; and the most frequent site of occurrence was the tongue and palate, which accounted for >50% of tumors. Other less common sites included the parotid gland, subglottic larynx, nasopharynx, and hypopharynx. The most common symptom shared by almost all patients was a slowly growing, painless swelling. Other presenting symptoms included foreign body sensation, dysphonia, dysphagia, bleeding, obstruction, and tenderness. In our series, ulceration was a common clinical finding and was present in 3 of 8 patients. By contrast, pain as a presenting symptom was unusual and was observed in only 2 of 8 patients. The diagnosis of clear cell carcinoma can be a challenge. Clear cell tumors of the oral mucosa, jaws, and salivary glands constitute a heterogeneous group of lesions that may be either odontogenic, salivary gland, or metastatic in origin. Clear cells can be found in a range of Cancer
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Hyalinizing Clear Cell CA Review / Solar et al
salivary gland tumors, including benign tumors, such as clear cell oncocytoma and clear cell myoepithelioma; malignant tumors, including mucoepidermoid carcinoma, epithelial myoepithelial carcinoma, myoepithelial carcinoma, and acinic cell carcinoma; and some nonsalivary gland tumors, such as metastatic renal cell carcinoma. Our review suggests that the presence of clusters of clear cells associated with hyalinization of the adjacent stroma is the most important finding that raises the suspicion of HCCC. In addition to histochemical staining to identify the glycogen content of tumor cells, careful attention to exclude features of other morphologically similar tumors is important. For example, although mucoepidermoid carcinomas may contain clear cells, the distinction from HCCC is possible by demonstrating the presence of intracytoplasmic mucin in mucoepidermoid carcinoma and by the finding of some cystic spaces and islands of epidermoid, intermediate, and columnar mucinous cells, all of which should not be present in HCCC. Moreover, the trabecular arrangement characteristic of HCCC generally is not observed in mucoepidermoid carcinoma. Calcifying epithelial odontogenic tumor (CEOT) is usually an intraosseous lesion but has been reported in extraosseous locations27,28 and rarely may have a prominent clear cell component.28,29 Two cases of HCCC from our review of the literature were reported to be in an intraosseous location.10 Consequently, CEOT must be included in the differential diagnosis. CEOT has polyhedral epithelial cells with distinct cellular outlines and intercellular bridges, the nuclei may show considerable pleomorphism, and often present are large areas of amyloid-like extracellular material and concentric calcifications.30,31 Metastasis to the salivary glands from other carcinomas with clear cells, such as renal cell carcinoma, also should be considered among the differential diagnosis. An accurate medical history; the presence of prominent sinusoids, hemorrhage, and hemosiderin deposition; some glandular structures; and the coexpression of cytokeratin and vimentin all support a diagnosis of renal cell carcinoma. In addition renal cell carcinoma expresses both CD10 and an antigen found in the renal proximal tubular brush border, the RCC antigen, both of which would assist with establishing this diagnosis.32 Clear cell oncocytomas correspond to 11% of oncocytomas33 and consists of sheets or trabeculae of clear cells Cancer
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that which show a PAS-positive and PAS-D–negative cytoplasm. Unlike HCCC, it is encapsulated or circumscribed, and the clear cells have a marginal rim of cytoplasm that maintains eosinophilic granules. Tumor cells also stain positive with phosphotungstic acid hematoxylin and show strong expression for mitochondria by immunohistochemistry. Clear cells may appear in several other salivary gland malignancies, including epithelial–myoepithelial carcinoma, clear cell myoepithelioma, and clear cell myoepithelial carcinoma. Immunohistochemistry to demonstrate the expression of actin, a finding that is absent in HCCC, is helpful to achieve the diagnosis. We reviewed the available histologic features in the published literature and in the current series and were unable to identify specific features that would be predictive of the behavior of HCCC. The patient who had multiple distant metastases had foci with mitotic activity, necrosis, and mild-to-moderate pleomorphism17; however, in the remaining patients, the presence of necrosis, mitosis, or pleomorphism was focal, rare, and mild, respectively; and, in most patients, was associated with indolent behavior. Perineural invasion is a frequent finding, but it does not help to predict tumor behavior, because this finding was present in approximately in 43% of the patients in the current study, including those with and without metastasis or recurrence. The conventional view of the clinical behavior of HCCC has been that it is an indolent, low-grade salivary gland malignancy that rarely metastasizes.3-5 This view of indolent clinical behavior has shaped the recommended management of the disease, which generally has been wide local excision. However, the current review suggests that the tumor may display more aggressive local and distant behavior. We observed that 11.5% of the combined patients from the literature and our series developed recurrent disease: Two patients developed recurrences within 1 year of follow-up, 1 patient developed a recurrence after 7 years, and 1 patient had multiple recurrences after >12 years. In our current series of 8 patients, 3 patients had follow-up information available, and all 3 had known recurrences (2 patients after 1 year and 1 patient after 7 years and after 10 years). None of the 8 patients presented with cervical lymph node metastasis at the time of diagnosis. We also observed that 11 of 44 patients (25%) reported in the literature had evidence 81
Original Article
of metastatic disease at presentation, including 9 patients who had spread to regional lymph nodes, 1 patient who had spread to the lung, and 1 patient who had spread to regional lymph nodes and lungs plus vertebral metastasis; the latter patient died of disease within 1 year. Although HCCC is rare, we accept the possibility that the metastatic rate may have been artificially elevated in the current study because of publication bias. Moreover, it is important to acknowledge the limitations of extracting, analyzing, and drawing conclusions from a narrow number of small studies and case reports on an admittedly rare tumor. Despite the widely held view that local excision is the treatment of choice, the current data suggest that a careful assessment of regional lymph nodes is necessary when managing these patients. Traditionally, a neck dissection has not been proposed as part of the management for salivary gland malignancies. However, the results of the current review suggest that there potentially is a role for neck dissection in the management of HCCC. A commonly cited study in the management of head and neck squamous cell carcinoma is the decision tree analysis by Weiss et al,34 which proposes that a 20% risk of occult metastasis should be the threshold for treatment of the neck. With such a high rate of cervical metastasis for HCCC, careful evaluation of the neck should be performed, and the removal of regional lymphatics should be strongly considered. If the neck is not going to be addressed at the time of resection, then careful follow-up with clinical examination and appropriate radiology studies would be indicated. In summary, we analyzed 44 reported patients with HCCC from the English language literature and added another 8 patients from our archives. The clinical and morphologic findings generally were consistent with those from previously reported cases. The most significant finding of the current study was the high rate of cervical lymph node metastasis, which implied that HCCC is less indolent than was believed previously. Therefore, we recommended performing a careful evaluation of the neck, and we believe that such patients should be considered for regional lymph node dissection. For pathologists, it is important to recognize this unusual variant of salivary glandtype neoplasm and to avoid confusing it with other primary and metastatic clear cell tumors, which require alternative management and have a correspondingly different natural history. 82
Conflict of Interest Disclosures Supported by National Institutes of Health grants CA095231 (to R.C.K.J.) and CA113833 (to B.L.S.) and by grant T32DE017249 (to R.C.K.J.).
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