ORIGINAL ARTICLE
Hyalinizing clear cell carcinoma of the head and neck: Case series and update W. Greer Albergotti, MD,1 Elizabeth A. Bilodeau, DMD, MD,2 J. Kenneth Byrd, MD,1 Mark M. Mims, BS,3 Stella Lee, MD,1 Seungwon Kim, MD1* 1
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 2Department of Diagnostic Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 3School of Medicine, University of Texas – Houston, Houston, Texas.
Accepted 24 October 2014 Published online 18 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23902
ABSTRACT: Background. Hyalinizing clear cell carcinoma (HCCC) is a rare neoplasm of salivary gland origin which is low-grade in nature. In this series, we report on 9 cases of HCCC and update the literature. Methods. A comprehensive literature search was performed. Our institutional database was queried for cases of HCCC. Pathology reports and slides were reviewed. Data was extracted, including demographics, staging, primary treatment, histopathologic findings, recurrence, and disease status. Statistical analysis was performed using a Pearson’s chi-square test. Results. One hundred thirty-six total cases were included for analysis. The overall recurrence rate was 19.8%. Necrosis was associated with
INTRODUCTION Hyalinizing clear cell carcinoma (HCCC) is a rare, typically indolent cancer of the minor salivary glands of the upper aerodigestive tract, which falls under an umbrella of other clear cell-containing neoplasms of the head and neck. It is most commonly seen in patients in their fifth and sixth decades of life with a slight female predominance.1,2 All told, clear cell-majority neoplasms account for 1/HPF were identified in 12 of 69 patients (17.4%). No clinical studies were identified that have commented upon EWSR1 translocation status.
FIGURE 4. Fluorescence in situ hybridization (FISH) dual-color break-apart probe demonstrating the absence of translocation of EWSR1 (22q12) in patient previously diagnosed with hyalinizing clear cell carcinoma (HCCC). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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TABLE 2. Locations of primary hyalinizing clear cell carcinoma reported within the literature. Location
No. of patients
Oral cavity Palate NOS Hard palate Floor of mouth Tongue Buccal mucosa Soft palate Lip Retromolar trigone Upper alveolus Oral cavity NOS Oropharynx BOT Tonsil Hypopharynx Uvula Oropharynx NOS Maxilla Parotid Nasopharynx Mandible Larynx Nasal cavity Sublingual Orbit/lacrimal gland Unknown
14 13 10 8 6 5 4 2 1 1 27 6 1 1 1 14 10 4 3 3 1 1 1 1
Abbreviations: NOS, not otherwise specified; BOT, base of tongue.
Of 111 patients of whom outcomes were known, there were 21 local recurrences. The average time to recurrence was 42.1 months (range 5 6–180 months). Three patients had locoregional recurrence with a mean time to recurrence of 42 months (range 5 6–84 months). Four patients had distant recurrence, all within the lung except for 1 patient who also had bony metastases. Mean time to distant recurrence was 16 months (range 5 3–48 months). Each of these patients also had local recurrence except for 1 patient who had an extremely aggressive tumor characterized by rapid growth.36 The overall risk of any recurrence was 22 of 111 patients (19.8%). Time to any recurrence is demonstrated within Figure 5. Of the patients with final outcomes reported, 72 of 84 (85.7%) had no evidence of disease at last known followup. Eight of 84 patients (9.8%) were alive with disease. Three of 84 patients (3.7%) died with disease and 1 of 84 (1.2%) died postoperatively. The average follow-up was 33.1 months (range 5 0–195 months). In an examination of factors predicting overall recurrence combining our patients with patients previously reported within the literature (Table 4), the presence of necrosis was found to be significantly associated with recurrence (p 5 .003). In those 5 patients with necrosis in their pathologic specimens and who had adequate followup, 4 (80%) had a documented recurrence. In those without necrosis, there was a 19% risk of recurrence. Margin status was also found to be significantly associated with risk of recurrence (50% vs 0%; p 5 .012), but this variable was inconsistently reported within the literature. The presence of lymph node metastasis at the time of 430
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presentation was significantly associated with recurrence (42.9% vs 8.5%; p 5 .046). Sex, size of primary, perineural invasion, ALI, and mitoses were not significantly associated with risk of overall recurrence.
DISCUSSION In this series, we report on 6 patients who have not previously been reported in the literature with a diagnosis of HCCC and also provide a comprehensive literature review to yield 136 cases, which we believe represent all of the reported cases of HCCC. This is the largest report on this entity within the literature. Furthermore, much of the literature on HCCC focuses on the pathologic features rather than the clinical behavior. The diagnosis of clear cell tumors of the head and neck can be a challenge with the differential diagnosis being quite broad. For a comprehensive review of the differentiating histopathologic patterns of these tumors, see Weinreb1 (2013). In general, HCCC is characterized by nests or cords of polygonal or round cells with a clear or light pink cytoplasm (see Figure 1). The groups of cells are usually separated by a hyalinized stroma, but this may be variable.7,61 Immunohistochemically, clear cell carcinoma can generally be reliably differentiated from other etiologies by the presence of positivity for high molecular weight cytokeratins, p63, and periodic acid-Schiff (PAS) staining with diastase sensitivity and absence of staining for S-100, smooth muscle actin, glial fibrillary acidic protein, and vimentin.1,6,7 TABLE 3. Clinical features of patients with hyalinizing clear cell carcinoma reported within the literature. Characteristic
No. of patients
Sex ratio M:F 84:46 Mean age, y 57.2 Size at initial presentation, cm, (92 patients) 0–2 47 2–4 31 >4 7 Metastasis on presentation Nodal 7/57 Distant 2/46 Initial treatment (75 patients) Resection alone 50/75 Excision or enucleation 3/75 Resection with ND alone 10/75 Resection with adjuvant RT 5/75 Resection with ND and adjuvant RT 5/75 RT alone 1/75 Chemotherapy alone 1/75 Metastasis, late Nodal 3/105 (2 with local recurrence as well) Distant 4/92 (3 with local recurrence, other with positive margins) Local recurrence 21/111 Outcome Alive with NED 72/84 Alive with disease 8/84 Dead with disease 3/84 Dead other causes 1/84 Abbreviations: ND, neck dissection; RT, radiation therapy; NED, no evidence of disease.
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FIGURE 5. Time to recurrence among all published cases of hyalinizing clear cell carcinoma. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Recent reports by Antonescu et al11 and Bilodeau et al8 suggest that HCCC nearly always has an EWSR1-ATF1 rearrangement, which is specific to clear cell carcinoma and clear cell odontogenic carcinoma among clear cell variants in the head and neck. In total, the staining patterns and ultrastructural findings are suggestive of squamous differentiation.1,7,62 Although evidence suggests HCCC and clear cell odontogenic carcinoma are closely related, if not the same entity, we prefer to analyze the clinical behavior of HCCC independently because of the differences in anatomic location. Seven of 9 of our patients’ slides stained positively for an EWSR1 translocation. Two sets of slides were unable to be located. One patient who had been previously diagnosed with HCCC before the advent of EWSR1 staining was excluded after his EWSR1 staining was negative and review of his other immunohistochemical staining was not convincing for HCCC. His likely diagnosis after review of pathology was epithelial-myoepithelial carcinoma with clear cell features. This is the first clinical series to report on EWSR1 translocation status, and, given the varied histologic findings reported in the literature, TABLE 4. Analysis of factors related to any recurrence. Variables
Sex Size Lymph node status Margins PNI ALI Mitosis Necrosis
Any recurrence
p value
Men 5 5/34 (14.7%) Women 5 17/62 (27.4%) 0–2 cm 5 5/40 (12.5%) 2–4 cm 5 6/26 (23.1%) >4 cm 5 1/5 (20%) Positive 5 3/7 (42.9%) Negative 5 6/47 (8.5%) Positive 5 2/4 (50%) Negative 5 0/11 (0%) Positive 5 4/23 (17.4%) Negative 5 3/22 (13.6%) Positive 5 1/3 (33.0%) Negative 5 4/28 (14.3%) Positive 5 3/11 (27.3%) Negative 5 10/49 (20.4%) Positive 5 4/6 (66.7%) Negative 5 9/47 (19.1%)
.135
Abbreviations: PNI, perineural invasion; ALI, Angiolymphatic invasion. The figures in bold indicate statistical significance.
.524 .046 .012 .728 .394 .617 .003
we believe EWSR1 translocation status should be reported with any diagnosis of HCCC. Although the EWSR1 translocation is seen in clear cell odontogenic carcinoma and other diverse sets of tumors, this translocation is highly sensitive for the diagnosis of HCCC. Although EWSR1ATF translocation is likely more specific to HCCC, testing for any EWSR1 translocation should be enough to confirm the diagnosis of HCCC when combined with expected histologic findings. Our analysis reveals that HCCC typically affects middle-aged adults, with women affected more often than men. It is typically a neoplasm with origin within the minor salivary glands with base of tongue being the most common primary location. Our patient’s primaries were similar to those reported in the literature, although 1 patient in our series had an unknown primary, which has not previously been reported. It is possible that his tonsillar cancer treated 15 years prior with radiotherapy was the primary site, although this is unlikely given the length of time elapsed between diagnoses. Although HCCC is considered a low-grade, indolent carcinoma with only rare ability to metastasize, we have found 4 cases that developed distant metastatic spread and 3 reports of patients who died of disease.27,36,50 Interestingly, 2 of these cases reported frequent mitoses on histology as well as focal necrosis, both of which are unusual findings in the reported cases. Our analysis shows that the presence of necrosis is significantly associated with risk of recurrence (80.0% vs 19.1%; p 5 .003), although the presence of mitoses were not (27.3% vs 20.4%; p 5 .617). Two other patients have presented with distant metastases at the time of diagnosis, but, unfortunately, the mitotic index and presence of necrosis is not reported in these patients.19,24 Lymph node metastases have been reported in just 7 patients at the time of presentation.5,19,36,40 Three additional patients developed locoregional recurrence.33 Our analysis does reveal preoperative lymph node status to be significantly and positively associated with overall recurrence (42.9% vs 8.5% recurrence; p 5 .046). Of interest, none of the patients without clinical lymphadenopathy undergoing lymph node dissection at the time of initial therapy was found to have locoregional disease. This suggests that selective neck dissection may be avoided unless there is clinical evidence for positive lymph nodes at the time of presentation or other worrisome clinical or histopathologic features. HEAD & NECK—DOI 10.1002/HED
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The ideal management of HCCC should be resection with negative margins. At our institution, our pathologists consider positive margins to be tumor involving the inked margin. We consider tumor within 2 mm of the inked margin to be close but not positive. For patients with positive margins, re-resection should be attempted to obtain negative margins or, if this is unfeasible, adjuvant radiotherapy should be considered. In our analysis, margin positivity was associated with overall recurrence (50.0% vs 0.0%; p 5 .012). Unfortunately, as with many of the potential predictors of recurrence analyzed, margin status is incompletely reported within the literature and is a confounding factor within the analysis. Patients treated with resection without documented positive margins and without evidence of metastasis at the time of resection had a 10 in 49 (20.4%) risk of any recurrence, and only 1 patient died with disease. PNI and ALI are relatively frequent findings among patients with HCCC, but do not seem to provide prognostic value as they occur in similar frequencies both in patients with well-controlled local disease and patients with diffuse metastasis. Any recurrence occurs in 17.4% of patients with PNI and 13.6% without PNI (p 5 .728). Similarly in patients with ALI, recurrence is found in 33% versus 14.3% in those without ALI (p 5 .394). This analysis was limited by the lack of reporting of clinical and pathologic features within various case reports in the literature. This limits the conclusions that can be drawn from our analysis. Despite this limitation, as with most malignant tumors within the head and neck, margin status, lymph node status, and worrisome histopathologic findings, such as necrosis, portend a higher risk of recurrence. The findings in this analysis suggest that this is also the case for HCCC.
CONCLUSION
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25.
Patients who present with HCCC can be reasonably assured that they have a good prognosis when adequate resection has been performed and margins are clear. Locoregional disease is unusual but those with clinical lymphadenopathy should be offered a selective neck dissection. Tumors with the presence of necrosis or those with lymph node disease or positive margins should be monitored closely for evidence of recurrence. It is important that pathologists be aware of this disease entity and should strongly consider EWSR1 translocation testing when considering a diagnosis of HCCC.
26. 27.
28.
29. 30.
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HYALINIZING 38. Ponniah I, SureshKumar P, Karunakaran K. Clear cell carcinoma of minor salivary gland–case report. Ann Acad Med Singapore 2007;36:857–860. 39. Pujary K, Rangarajan S, Nayak DR, Balakrishnan R, Ramakrishnan V. Hyalinizing clear cell carcinoma of the base of tongue. Int J Oral Maxillofac Surg 2008;37:93–96. 40. Rajab E, Akmal SN, Nasir A.M. Glycogen-rich clear cell carcinoma in the tongue. J Laryngol Otol 1994;108:716–718. 41. Rezende RB, Drachenberg CB, Kumar D, et al. Differential diagnosis between monomorphic clear cell adenocarcinoma of salivary glands and renal (clear) cell carcinoma. Am J Surg Pathol 1999;23:1532–1538. 42. Rinaldo A, McLaren KM, Boccato P, Maran AG. Hyalinizing clear cell carcinoma of the oral cavity and of the parotid gland. ORL J Otorhinolaryngol Relat Spec 1999;61:48–51. 43. Saleh KA, Nurishmah MI, Firouzeh GN, Goh BS. Primary clear cell carcinoma of minor salivary gland of the soft palate: a case report. Med J Malaysia 2012;67:335–336. 44. Sicurella F, Gregorio A, Stival P, Brenna A. Clear cell carcinoma of minor salivary gland of the tongue. Acta Otorhinolaryngol Ital 2004;24:157–160. 45. Suzuki H, Katoh A, Udaka T, et al. Hyalinizing clear cell carcinoma arising from the base of the tongue. Acta Otolaryngol 2006;126:653–656. 46. Tang SK, Wan SK, Chan JK. Hyalinizing clear cell carcinoma of salivary gland: report of a case with multiple recurrences over 12 years. Am J Surg Pathol 1995;19:240–241. 47. Urban SD, Keith DA, Goodman M. Hyalinizing clear cell carcinoma: report of a case. J Oral Pathol Med 1996;25:562–564. 48. Uzochukwu NO, Shrier DA, Lapoint RJ. Clear cell carcinoma of the base of the tongue: MR imaging findings. AJNR Am J Neuroradiol 2007;28:127–128. 49. Wang B, Brandwein M, Gordon R, Robinson R, Urken M, Zarbo RJ. Primary salivary clear cell tumors–a diagnostic approach: a clinicopathologic and immunohistochemical study of 20 patients with clear cell carcinoma, clear cell myoepithelial carcinoma, and epithelial-myoepithelial carcinoma. Arch Pathol Lab Med 2002;126:676–685. 50. Yang S, Zhang J, Chen X, Wang L, Xie F. Clear cell carcinoma, not otherwise specified, of salivary glands: a clinicopathologic study of 4 cases and
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Hyalinizing clear cell carcinoma of the head and neck: Case series and update W. Greer Albergotti, MD,1 Elizabeth A. Bilodeau, DMD, MD,2 J. Kenneth Byrd, MD,1 Mark M. Mims, BS,3 Stella Lee, MD,1 Seungwon Kim, MD1* 1
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 2Department of Diagnostic Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 3School of Medicine, University of Texas – Houston, Houston, Texas.
Accepted 24 October 2014 Published online 18 June 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23902
ABSTRACT: Background. Hyalinizing clear cell carcinoma (HCCC) is a rare neoplasm of salivary gland origin which is low-grade in nature. In this series, we report on 9 cases of HCCC and update the literature. Methods. A comprehensive literature search was performed. Our institutional database was queried for cases of HCCC. Pathology reports and slides were reviewed. Data was extracted, including demographics, staging, primary treatment, histopathologic findings, recurrence, and disease status. Statistical analysis was performed using a Pearson’s chi-square test. Results. One hundred thirty-six total cases were included for analysis. The overall recurrence rate was 19.8%. Necrosis was associated with
INTRODUCTION Hyalinizing clear cell carcinoma (HCCC) is a rare, typically indolent cancer of the minor salivary glands of the upper aerodigestive tract, which falls under an umbrella of other clear cell-containing neoplasms of the head and neck. It is most commonly seen in patients in their fifth and sixth decades of life with a slight female predominance.1,2 All told, clear cell-majority neoplasms account for 1/HPF were identified in 12 of 69 patients (17.4%). No clinical studies were identified that have commented upon EWSR1 translocation status.
FIGURE 4. Fluorescence in situ hybridization (FISH) dual-color break-apart probe demonstrating the absence of translocation of EWSR1 (22q12) in patient previously diagnosed with hyalinizing clear cell carcinoma (HCCC). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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TABLE 2. Locations of primary hyalinizing clear cell carcinoma reported within the literature. Location
No. of patients
Oral cavity Palate NOS Hard palate Floor of mouth Tongue Buccal mucosa Soft palate Lip Retromolar trigone Upper alveolus Oral cavity NOS Oropharynx BOT Tonsil Hypopharynx Uvula Oropharynx NOS Maxilla Parotid Nasopharynx Mandible Larynx Nasal cavity Sublingual Orbit/lacrimal gland Unknown
14 13 10 8 6 5 4 2 1 1 27 6 1 1 1 14 10 4 3 3 1 1 1 1
Abbreviations: NOS, not otherwise specified; BOT, base of tongue.
Of 111 patients of whom outcomes were known, there were 21 local recurrences. The average time to recurrence was 42.1 months (range 5 6–180 months). Three patients had locoregional recurrence with a mean time to recurrence of 42 months (range 5 6–84 months). Four patients had distant recurrence, all within the lung except for 1 patient who also had bony metastases. Mean time to distant recurrence was 16 months (range 5 3–48 months). Each of these patients also had local recurrence except for 1 patient who had an extremely aggressive tumor characterized by rapid growth.36 The overall risk of any recurrence was 22 of 111 patients (19.8%). Time to any recurrence is demonstrated within Figure 5. Of the patients with final outcomes reported, 72 of 84 (85.7%) had no evidence of disease at last known followup. Eight of 84 patients (9.8%) were alive with disease. Three of 84 patients (3.7%) died with disease and 1 of 84 (1.2%) died postoperatively. The average follow-up was 33.1 months (range 5 0–195 months). In an examination of factors predicting overall recurrence combining our patients with patients previously reported within the literature (Table 4), the presence of necrosis was found to be significantly associated with recurrence (p 5 .003). In those 5 patients with necrosis in their pathologic specimens and who had adequate followup, 4 (80%) had a documented recurrence. In those without necrosis, there was a 19% risk of recurrence. Margin status was also found to be significantly associated with risk of recurrence (50% vs 0%; p 5 .012), but this variable was inconsistently reported within the literature. The presence of lymph node metastasis at the time of 430
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presentation was significantly associated with recurrence (42.9% vs 8.5%; p 5 .046). Sex, size of primary, perineural invasion, ALI, and mitoses were not significantly associated with risk of overall recurrence.
DISCUSSION In this series, we report on 6 patients who have not previously been reported in the literature with a diagnosis of HCCC and also provide a comprehensive literature review to yield 136 cases, which we believe represent all of the reported cases of HCCC. This is the largest report on this entity within the literature. Furthermore, much of the literature on HCCC focuses on the pathologic features rather than the clinical behavior. The diagnosis of clear cell tumors of the head and neck can be a challenge with the differential diagnosis being quite broad. For a comprehensive review of the differentiating histopathologic patterns of these tumors, see Weinreb1 (2013). In general, HCCC is characterized by nests or cords of polygonal or round cells with a clear or light pink cytoplasm (see Figure 1). The groups of cells are usually separated by a hyalinized stroma, but this may be variable.7,61 Immunohistochemically, clear cell carcinoma can generally be reliably differentiated from other etiologies by the presence of positivity for high molecular weight cytokeratins, p63, and periodic acid-Schiff (PAS) staining with diastase sensitivity and absence of staining for S-100, smooth muscle actin, glial fibrillary acidic protein, and vimentin.1,6,7 TABLE 3. Clinical features of patients with hyalinizing clear cell carcinoma reported within the literature. Characteristic
No. of patients
Sex ratio M:F 84:46 Mean age, y 57.2 Size at initial presentation, cm, (92 patients) 0–2 47 2–4 31 >4 7 Metastasis on presentation Nodal 7/57 Distant 2/46 Initial treatment (75 patients) Resection alone 50/75 Excision or enucleation 3/75 Resection with ND alone 10/75 Resection with adjuvant RT 5/75 Resection with ND and adjuvant RT 5/75 RT alone 1/75 Chemotherapy alone 1/75 Metastasis, late Nodal 3/105 (2 with local recurrence as well) Distant 4/92 (3 with local recurrence, other with positive margins) Local recurrence 21/111 Outcome Alive with NED 72/84 Alive with disease 8/84 Dead with disease 3/84 Dead other causes 1/84 Abbreviations: ND, neck dissection; RT, radiation therapy; NED, no evidence of disease.
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FIGURE 5. Time to recurrence among all published cases of hyalinizing clear cell carcinoma. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Recent reports by Antonescu et al11 and Bilodeau et al8 suggest that HCCC nearly always has an EWSR1-ATF1 rearrangement, which is specific to clear cell carcinoma and clear cell odontogenic carcinoma among clear cell variants in the head and neck. In total, the staining patterns and ultrastructural findings are suggestive of squamous differentiation.1,7,62 Although evidence suggests HCCC and clear cell odontogenic carcinoma are closely related, if not the same entity, we prefer to analyze the clinical behavior of HCCC independently because of the differences in anatomic location. Seven of 9 of our patients’ slides stained positively for an EWSR1 translocation. Two sets of slides were unable to be located. One patient who had been previously diagnosed with HCCC before the advent of EWSR1 staining was excluded after his EWSR1 staining was negative and review of his other immunohistochemical staining was not convincing for HCCC. His likely diagnosis after review of pathology was epithelial-myoepithelial carcinoma with clear cell features. This is the first clinical series to report on EWSR1 translocation status, and, given the varied histologic findings reported in the literature, TABLE 4. Analysis of factors related to any recurrence. Variables
Sex Size Lymph node status Margins PNI ALI Mitosis Necrosis
Any recurrence
p value
Men 5 5/34 (14.7%) Women 5 17/62 (27.4%) 0–2 cm 5 5/40 (12.5%) 2–4 cm 5 6/26 (23.1%) >4 cm 5 1/5 (20%) Positive 5 3/7 (42.9%) Negative 5 6/47 (8.5%) Positive 5 2/4 (50%) Negative 5 0/11 (0%) Positive 5 4/23 (17.4%) Negative 5 3/22 (13.6%) Positive 5 1/3 (33.0%) Negative 5 4/28 (14.3%) Positive 5 3/11 (27.3%) Negative 5 10/49 (20.4%) Positive 5 4/6 (66.7%) Negative 5 9/47 (19.1%)
.135
Abbreviations: PNI, perineural invasion; ALI, Angiolymphatic invasion. The figures in bold indicate statistical significance.
.524 .046 .012 .728 .394 .617 .003
we believe EWSR1 translocation status should be reported with any diagnosis of HCCC. Although the EWSR1 translocation is seen in clear cell odontogenic carcinoma and other diverse sets of tumors, this translocation is highly sensitive for the diagnosis of HCCC. Although EWSR1ATF translocation is likely more specific to HCCC, testing for any EWSR1 translocation should be enough to confirm the diagnosis of HCCC when combined with expected histologic findings. Our analysis reveals that HCCC typically affects middle-aged adults, with women affected more often than men. It is typically a neoplasm with origin within the minor salivary glands with base of tongue being the most common primary location. Our patient’s primaries were similar to those reported in the literature, although 1 patient in our series had an unknown primary, which has not previously been reported. It is possible that his tonsillar cancer treated 15 years prior with radiotherapy was the primary site, although this is unlikely given the length of time elapsed between diagnoses. Although HCCC is considered a low-grade, indolent carcinoma with only rare ability to metastasize, we have found 4 cases that developed distant metastatic spread and 3 reports of patients who died of disease.27,36,50 Interestingly, 2 of these cases reported frequent mitoses on histology as well as focal necrosis, both of which are unusual findings in the reported cases. Our analysis shows that the presence of necrosis is significantly associated with risk of recurrence (80.0% vs 19.1%; p 5 .003), although the presence of mitoses were not (27.3% vs 20.4%; p 5 .617). Two other patients have presented with distant metastases at the time of diagnosis, but, unfortunately, the mitotic index and presence of necrosis is not reported in these patients.19,24 Lymph node metastases have been reported in just 7 patients at the time of presentation.5,19,36,40 Three additional patients developed locoregional recurrence.33 Our analysis does reveal preoperative lymph node status to be significantly and positively associated with overall recurrence (42.9% vs 8.5% recurrence; p 5 .046). Of interest, none of the patients without clinical lymphadenopathy undergoing lymph node dissection at the time of initial therapy was found to have locoregional disease. This suggests that selective neck dissection may be avoided unless there is clinical evidence for positive lymph nodes at the time of presentation or other worrisome clinical or histopathologic features. HEAD & NECK—DOI 10.1002/HED
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The ideal management of HCCC should be resection with negative margins. At our institution, our pathologists consider positive margins to be tumor involving the inked margin. We consider tumor within 2 mm of the inked margin to be close but not positive. For patients with positive margins, re-resection should be attempted to obtain negative margins or, if this is unfeasible, adjuvant radiotherapy should be considered. In our analysis, margin positivity was associated with overall recurrence (50.0% vs 0.0%; p 5 .012). Unfortunately, as with many of the potential predictors of recurrence analyzed, margin status is incompletely reported within the literature and is a confounding factor within the analysis. Patients treated with resection without documented positive margins and without evidence of metastasis at the time of resection had a 10 in 49 (20.4%) risk of any recurrence, and only 1 patient died with disease. PNI and ALI are relatively frequent findings among patients with HCCC, but do not seem to provide prognostic value as they occur in similar frequencies both in patients with well-controlled local disease and patients with diffuse metastasis. Any recurrence occurs in 17.4% of patients with PNI and 13.6% without PNI (p 5 .728). Similarly in patients with ALI, recurrence is found in 33% versus 14.3% in those without ALI (p 5 .394). This analysis was limited by the lack of reporting of clinical and pathologic features within various case reports in the literature. This limits the conclusions that can be drawn from our analysis. Despite this limitation, as with most malignant tumors within the head and neck, margin status, lymph node status, and worrisome histopathologic findings, such as necrosis, portend a higher risk of recurrence. The findings in this analysis suggest that this is also the case for HCCC.
CONCLUSION
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25.
Patients who present with HCCC can be reasonably assured that they have a good prognosis when adequate resection has been performed and margins are clear. Locoregional disease is unusual but those with clinical lymphadenopathy should be offered a selective neck dissection. Tumors with the presence of necrosis or those with lymph node disease or positive margins should be monitored closely for evidence of recurrence. It is important that pathologists be aware of this disease entity and should strongly consider EWSR1 translocation testing when considering a diagnosis of HCCC.
26. 27.
28.
29. 30.
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