Hyalinizing clear cell carcinoma

Case series and comprehensive review of the literature


  • Antonieta A. Solar MD,

    1. Department of Orofacial Sciences, University of California at San Francisco, San Francisco, California
    2. Department of Anatomic Pathology, Pontifica Universidad Católica de Chile, Santiago, Chile
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  • Brian L. Schmidt DDS, MD, PhD,

    1. Department of Oral and Maxillofacial Surgery, University of California at San Francisco, San Francisco, California
    2. Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California
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  • Richard C. K. Jordan DDS, PhD, FRCPath

    Corresponding author
    1. Department of Orofacial Sciences, University of California at San Francisco, San Francisco, California
    2. Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California
    3. Department of Pathology, University of California at San Francisco, San Francisco, California
    • Department of Orofacial Sciences, University of California at San Francisco, S-512, 513 Parnassus Avenue, San Francisco, CA 94143-0424===

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    • Fax: (415) 476-6482



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.


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.


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 metastatases 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.


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. Cancer 2009. © 2008 American Cancer Society.

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 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.


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


Immunohistochemistry was performed on unstained sections using selected antibodies (Table 1) Briefly, 5-micron-thick sections were cut and mounted on adherent 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.

Table 1. Clinical Findings of the Patients
Patient No.Age, ySexClinical DescriptionDuration, moLocationSize, cmTreatmentFollow-Up, moOutcomePASPASDMucicarmineCytokeratin A1/A3SMAS-100
  1. PAS indicates periodic acid-Schiff stain; PASD, PAS stain with diastase digestion; SMA, smooth muscle actin; +, positive; −, negative; HIV, human immunodeficiency virus positive; HCV, hepatitis C virus positive.

134ManPainless firm massHard palate1Wide excision131 Recurrence++
249WomanPainless firm massBuccal mucosa3Wide excision and radiotherapy1142 Recurrences++
352WomanUlcerated tender mass; patient was HIV+ and HCVHard palateWide excision++
465WomanPainless firm massFloor of mouth3Wide excision++
530ManPainless firm mass, history of radiation9Hard palate1.5++
685WomanPainful, ulcerated, locally aggressive mass with loss of palatal bone, eroding into sinusRight maxilla1.2Wide excision151 Recurrence++
765WomanPainless ulcerated mass, occasional bleeding2Left maxilla, alveolar process1++
860WomanPainless massMaxillary vestibule++

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, glycogen-rich, 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.


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, 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 immunohistochemical 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.

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).

Table 2. Tumor Characteristics
Site of OccurrenceNo. of Patients (% of 52)
  • *

    Three patients from the current series.

  • One patient from the current series.

  • One patient from the current series.

  • §

    Two patients from the current series.

  • One patient from the current series.

Tongue15 (28)
Palate11 (21)*
Floor of mouth6 (11)
Buccal mucosa4 (7)
Parotid gland3 (6)
Maxillary gingival3 (6)§
Retromolar area2 (4)
Maxilla1 (2)
Maxillary vestibule1 (2)
Subglottic larynx1 (2)
Nasopharynx1 (2)
Jaw (unspecified)1 (2)
Hypopharynx1 (2)
Tonsillar region1 (2)
Salivary gland (unspecified)1 (2)

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 35tumors, 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 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.

Table 3. Clinical and Pathologic Features of the 44 Published Cases of Hyalinizing Clear Cell Carcinoma Identified Through Review of the Literature
ReferenceNo. of PatientsAge, ySex (Men:Women)Clinical DescriptionDuration, moSize, cmTreatmentMetastasisFollow-up, moOutcome
  • 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.

  • In studies in which there was a series of patients, the ratio was used.

Chaundry 198361*46ManSwelling22Wide excision72NED
Simpson 1990252*701:1Painless swelling1742.5Wide excisionNo69Both NED
Rajab 199471*31WomanPainless swelling43Wide excision + RTLocal lymph nodesNED
Orden 1994241*24WomanPainless swelling2Wide excisionNo24NED
Milchgrub 1994311553:8Painless swelling1.9Wide excision in 11 patients, + RT in 2 patients, + RND in 1 patient2/11 Local lymph nodes441 DPO, 10 NED
Tang 19958165WomanObstructing tumorIncomplete excisionNo144Multiple disease recurrences
Urban 19969130ManPainless swelling92Wide excisionNo12NED
Berho & Huvos 1999102660:2Painless swelling32Wide excisionNo15.5Both NED
Rinaldo 1999113420:31 with painless swelling, 1 with foreign body sensation, and 1 with a painful throat13Wide excision in 1 patient, ND in 2 patients1 With local lymph nodes58.61 MET, 1 disease recurrence, 1 NED
Ereno 200012153ManPainless swelling2IncisionLung10NED
Milchgrub 2000134442:2Painless swelling2.2Wide excision3/4 With local lymph nodes601 MET, 1 disease recurrence
Boccato 200123157ManPainless swelling33.2Wide excisionLocal lymph nodes
Grenevicki 200114153WomanNasal bleeding95ChemotherapyLung and local lymph nodes36MET
Manoharan 20025140WomanPainful ulcerated swelling244.5Wide excisionNo22NED
Balakrishnan 20021135ManPainless foreign body sensation, dysphonia123Wide excisionNo12NED
Browne & Holland 200216174ManWide excisionNo19NED
Felix 200215348WomanPainless swelling40Wide excisionNo27.5NED
Chao 20044142WomanSevere pain, anesthesia, rash362.5Wide excisionNo8NED
O'Regan 200417157WomanPainless swelling44Wide excisionLocal lymph nodes, lung, and vertebra10DOD
Sun 200518148WomanPainless swelling24Wide excisionNo12NED
Suzuki 200619166WomanPainless swelling, dysphagia14Wide excisionNo21NED
Pujary 200820157ManPainless foreign body sensation13Wide excision + RTNo18NED
Uzochukwo 200721147WomanDysphagia, sore throat, hemoptysis54Complete excisionNo8NED
Meer & Altini 2007221
Angiero & Stefani 200726157WomanPainless swelling2Wide excisionNo12NED

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 immunohistochemical 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.

Table 4. Special Stains and Immunohistochemical Findings in the Reported Literature
Stain/MarkerPublished Cases/Positive Results (%)
  • 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.

  • Seven cases were reported that presented few droplets and were consider negative if none of the other features of mucoepidermoid carcinoma were present.

PAS39/38 (97.4)*
PASD29/2 (6.9)
Congo red9/0
CAM 5.219/19 (100)
Cytokeratin A1/A336/36 (100)
EMA20/15 (75)
CEA20/8 (40)
HMFG2/2 (100)
NSE2/2 (100)


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 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 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 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 gland-type 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.