274
Correspondence
An uncommon primary lung tumour: hyalinizing clear cell carcinoma, salivary gland-type DOI: 10.1111/his.12636 © 2014 John Wiley & Sons Ltd
Sir: Herein we report the first two cases in the literature of a hyalinizing clear cell carcinoma (HCCC), salivary gland-type, arising in the lung. HCCC is an uncommon salivary gland tumour that arises typically from the intra-oral minor salivary glands. It was first recognized as a distinct diagnostic entity by Milchgrub et al.1 in 1994. In the last several years, translocations involving EWSR1 have been found to be a defining molecular feature, being present in approximately 80% of these tumours.2,3 The first patient is a healthy, 32-year-old man who works in a coal mine. He is a non-smoker and underwent a screening computerized tomography (CT) scan as part of his employment. Imaging showed a 1.6-cm mass in the left lower lobe. A lobectomy was subsequently performed, and gross examination revealed a well-circumscribed, 1.8 9 1.7 9 1.7-cm, tan–white mass arising from a segmental bronchus (Figure 1). The second patient is a 39-year-old man who is also a non-smoker and underwent a CT scan in 2009 for a chest injury. He was noted to have a 2.0-cm mass in the right lower lobe. He was followed without intervention until July 2013, when a second chest CT scan showed a slight increase in the size of the
Figure 1. Gross image of case 1; the well-circumscribed, 2.0-cm, hyalinizing clear cell carcinoma of the right lower lobe.
mass. He subsequently underwent a right lower lobectomy, and gross examination showed a 2.6 9 2.6 9 2.0-cm firm, grey–white, well-circumscribed tumour with a whorled, fibrous cut surface, arising from the bronchial wall and abutting the pleura. Despite the gross circumscription of both lesions, microscopic examination showed infiltrative neoplasms composed of irregular nests, cords and trabeculae of polygonal tumour cells with clear to eosinophilic cytoplasm (Figure 2A). The tumour cells were monotonous, with irregular nuclear contours and inconspicuous nucleoli. Very rare intranuclear cytoplasmic inclusions were identified in the first patient’s tumour. The nests of tumour cells were embedded in a hyalinized stroma. Juxtaposed to the hyalinized areas were foci of prominent stromal desmoplasia (Figure 2B). Of note, both tumours were centred in the bronchus and protruded into the airway. Focally, they both appeared to be connected to the basal layer of the bronchial epithelium (Figure 2C). The normal bronchial wall architecture was replaced by both tumours. Small foci of tumour necrosis were present within the nests in the first patient’s tumour. The mitotic index for both tumours was low (2 per 50 highpower fields). A mild to moderate chronic inflammatory infiltrate was present at the edge of the tumours. A panel of immunohistochemical stains was performed for both cases, and collectively the tumour cells expressed pancytokeratin, cytokeratin 7 and p63 and did not express cytokeratin 20, CD10, paired box gene 8 (PAX8), chromogranin, synaptophysin, human melanoma black 45 (HMB45), thyroid transcription factor 1 (TTF-1), Napsin A, S100 and smooth muscle actin (SMA) (Figure 2C). Our foremost diagnostic considerations, based on the morphology together with pancytokeratin and p63 expression, were a squamous cell carcinoma with clear cell change and a low-grade mucoepidermoid carcinoma. The latter seemed less likely, given the monotony of the cell population and the lack of mucous cells. In addition, assessment of MAML2 by break-apart fluorescence in-situ hybridization, a highly sensitive and specific test for mucoepidermoid carcinoma, performed on the tumour from the second patient, was intact.4,5 Although we considered a squamous cell carcinoma, the tumours had only mild cytological atypia and lacked significant mitotic activity, which would be unusual for a primary squamous cell carcinoma of the lung. Additionally, there was Histopathology, 67, 267–276.
Correspondence
275
A
B Figure 2. A, The infiltrative hyalinizing clear cell carcinoma growing into the bronchial cartilage and submucosa and protruding into the airway (case 1, left; case 2, right) [haematoxylin and eosin (H&E)]. B, Nests of clear tumour cells are surrounded by hyalinization and desmoplasia (case 1, left; case 2, right) (H&E). C, The tumour cells are focally connected to the basal layer of the bronchial epithelium (left); the basal layer of the bronchial epithelium and the tumour cells demonstrate nuclear expression of p63 (right) (H&E).
C
no evidence of squamous differentiation such as keratin pearl formation or keratinization in either of the cases. The most striking feature of the tumours was the stromal hyalinization together with the nests of clear cells. This morphology was highly distinctive, and is a typical feature of HCCCs that we have encountered in the salivary glands of the head and neck. Although HCCCs have not been reported in the lung we still considered this to be a diagnostic possibility, given the rare but well-known occurrence of primary salivary gland-type lung cancers.6 As this was a part of our diagnostic differential, we performed breakapart fluorescence in-situ hybridization for EWSR1, and both tumours demonstrated disrupted genes (Figure 3). In the context of a salivary gland-type tumour, the EWSR1 rearrangement is highly characteristic of HCCC and has not been found in mucoepidermoid carcinomas or other salivary gland tumours.3 The EWSR1 rearrangement has been documented in a subset of soft tissue-type myoepithelial tumours Histopathology, 67, 267–276.
Figure 3. Interphase nuclei demonstrating disrupted EWSR1 by fluorescence in-situ hybridization, case 1.
and in rare examples of such tumours occurring in the lung.7 Myoepithelial tumours, such as HCCC, can have clear cells with areas of sclerosis or desmoplasia.
276
Correspondence
However, the former usually has greater pleomorphism and, unlike HCCC, demonstrates true myoepithelial differentiation with expression of S100, SMA and/or calponin.7,8 We considered the possibility that these tumours represented metastases, as there have been rare case reports of HCCCs metastasizing to cervical lymph nodes and the lung.9 However, further clinical evaluation in both patients confirmed the lung to be the only tumour site. Thus, we conclude that both tumours represented primary HCCC, salivary glandtype, of the lung. As further evidence that these are primary tumours, at the time of this report both patients are free of any local recurrence, metastasis or appearance of a head and neck tumour after 1.5 years of follow-up despite receiving no additional therapy after surgery. In conclusion, to our knowledge, these are the first two reported cases of hyalinizing clear cell carcinoma, salivary gland-type, arising in the lung. Rare salivary gland tumours should be part of the differential diagnosis when lung tumours, particularly those arising in the bronchus and that have an unusual morphology, are encountered.
Conflicts of interest No conflicts of interest declared. Akeesha A Shah Mitra Mehrad1 Sarah M Kelting James S Lewis Jr1,2 Edward B Stelow2
Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA, 1Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA, and 2 Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine, St Louis, MO, USA 1. Milchgrub S, Gnepp DR, Vuitch F et al. Hyalinizing clear cell carcinoma of salivary gland. Am. J. Surg. Pathol. 1994; 18; 74–82. 2. Antonescu CR, Katabi N, Zhang L et al. EWSR1–ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosom. Cancer 2011; 50; 559–570. 3. Shah AA, LeGallo RD, van Zante A et al. EWSR1 genetic rearrangements in salivary gland tumors. Am. J. Surg. Pathol. 2013; 37; 571–578. 4. Martins C, Cavaco B, Tonon G et al. A study of MECT1– MAML2 in mucoepidermoid carcinoma and Warthin’s tumor of salivary glands. J. Mol. Diagn. 2004; 6; 205–210. 5. Behboudi A, Enlund F, Winnes M et al. Molecular classification of mucoepidermoid carcinomas – prognostic significance of the MECT1–MAML2 fusion oncogene. Genes Chromosom. Cancer 2006; 45; 470–481. 6. Molina JR, Aubry MC, Lewis JE et al. Primary salivary glandtype lung cancer. Cancer 2007; 110; 2253–2259. 7. Antonescu CR, Zhang L, Chang NE et al. EWSR1–POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosom. Cancer 2010; 49; 1114–1124. 8. Weinreb I. Hyalinizing clear cell carcinoma of salivary gland: a review and update. Head Neck Pathol. 2013; 7; S20–S29. 9. O’Sullivan-Mejia ED, Massey HD, Faquin WC et al. Hyalinizing clear cell carcinoma: report of eight cases and a review of literature. Head Neck Pathol. 2009; 3; 179–185.
Histopathology, 67, 267–276.
Correspondence
An uncommon primary lung tumour: hyalinizing clear cell carcinoma, salivary gland-type DOI: 10.1111/his.12636 © 2014 John Wiley & Sons Ltd
Sir: Herein we report the first two cases in the literature of a hyalinizing clear cell carcinoma (HCCC), salivary gland-type, arising in the lung. HCCC is an uncommon salivary gland tumour that arises typically from the intra-oral minor salivary glands. It was first recognized as a distinct diagnostic entity by Milchgrub et al.1 in 1994. In the last several years, translocations involving EWSR1 have been found to be a defining molecular feature, being present in approximately 80% of these tumours.2,3 The first patient is a healthy, 32-year-old man who works in a coal mine. He is a non-smoker and underwent a screening computerized tomography (CT) scan as part of his employment. Imaging showed a 1.6-cm mass in the left lower lobe. A lobectomy was subsequently performed, and gross examination revealed a well-circumscribed, 1.8 9 1.7 9 1.7-cm, tan–white mass arising from a segmental bronchus (Figure 1). The second patient is a 39-year-old man who is also a non-smoker and underwent a CT scan in 2009 for a chest injury. He was noted to have a 2.0-cm mass in the right lower lobe. He was followed without intervention until July 2013, when a second chest CT scan showed a slight increase in the size of the
Figure 1. Gross image of case 1; the well-circumscribed, 2.0-cm, hyalinizing clear cell carcinoma of the right lower lobe.
mass. He subsequently underwent a right lower lobectomy, and gross examination showed a 2.6 9 2.6 9 2.0-cm firm, grey–white, well-circumscribed tumour with a whorled, fibrous cut surface, arising from the bronchial wall and abutting the pleura. Despite the gross circumscription of both lesions, microscopic examination showed infiltrative neoplasms composed of irregular nests, cords and trabeculae of polygonal tumour cells with clear to eosinophilic cytoplasm (Figure 2A). The tumour cells were monotonous, with irregular nuclear contours and inconspicuous nucleoli. Very rare intranuclear cytoplasmic inclusions were identified in the first patient’s tumour. The nests of tumour cells were embedded in a hyalinized stroma. Juxtaposed to the hyalinized areas were foci of prominent stromal desmoplasia (Figure 2B). Of note, both tumours were centred in the bronchus and protruded into the airway. Focally, they both appeared to be connected to the basal layer of the bronchial epithelium (Figure 2C). The normal bronchial wall architecture was replaced by both tumours. Small foci of tumour necrosis were present within the nests in the first patient’s tumour. The mitotic index for both tumours was low (2 per 50 highpower fields). A mild to moderate chronic inflammatory infiltrate was present at the edge of the tumours. A panel of immunohistochemical stains was performed for both cases, and collectively the tumour cells expressed pancytokeratin, cytokeratin 7 and p63 and did not express cytokeratin 20, CD10, paired box gene 8 (PAX8), chromogranin, synaptophysin, human melanoma black 45 (HMB45), thyroid transcription factor 1 (TTF-1), Napsin A, S100 and smooth muscle actin (SMA) (Figure 2C). Our foremost diagnostic considerations, based on the morphology together with pancytokeratin and p63 expression, were a squamous cell carcinoma with clear cell change and a low-grade mucoepidermoid carcinoma. The latter seemed less likely, given the monotony of the cell population and the lack of mucous cells. In addition, assessment of MAML2 by break-apart fluorescence in-situ hybridization, a highly sensitive and specific test for mucoepidermoid carcinoma, performed on the tumour from the second patient, was intact.4,5 Although we considered a squamous cell carcinoma, the tumours had only mild cytological atypia and lacked significant mitotic activity, which would be unusual for a primary squamous cell carcinoma of the lung. Additionally, there was Histopathology, 67, 267–276.
Correspondence
275
A
B Figure 2. A, The infiltrative hyalinizing clear cell carcinoma growing into the bronchial cartilage and submucosa and protruding into the airway (case 1, left; case 2, right) [haematoxylin and eosin (H&E)]. B, Nests of clear tumour cells are surrounded by hyalinization and desmoplasia (case 1, left; case 2, right) (H&E). C, The tumour cells are focally connected to the basal layer of the bronchial epithelium (left); the basal layer of the bronchial epithelium and the tumour cells demonstrate nuclear expression of p63 (right) (H&E).
C
no evidence of squamous differentiation such as keratin pearl formation or keratinization in either of the cases. The most striking feature of the tumours was the stromal hyalinization together with the nests of clear cells. This morphology was highly distinctive, and is a typical feature of HCCCs that we have encountered in the salivary glands of the head and neck. Although HCCCs have not been reported in the lung we still considered this to be a diagnostic possibility, given the rare but well-known occurrence of primary salivary gland-type lung cancers.6 As this was a part of our diagnostic differential, we performed breakapart fluorescence in-situ hybridization for EWSR1, and both tumours demonstrated disrupted genes (Figure 3). In the context of a salivary gland-type tumour, the EWSR1 rearrangement is highly characteristic of HCCC and has not been found in mucoepidermoid carcinomas or other salivary gland tumours.3 The EWSR1 rearrangement has been documented in a subset of soft tissue-type myoepithelial tumours Histopathology, 67, 267–276.
Figure 3. Interphase nuclei demonstrating disrupted EWSR1 by fluorescence in-situ hybridization, case 1.
and in rare examples of such tumours occurring in the lung.7 Myoepithelial tumours, such as HCCC, can have clear cells with areas of sclerosis or desmoplasia.
276
Correspondence
However, the former usually has greater pleomorphism and, unlike HCCC, demonstrates true myoepithelial differentiation with expression of S100, SMA and/or calponin.7,8 We considered the possibility that these tumours represented metastases, as there have been rare case reports of HCCCs metastasizing to cervical lymph nodes and the lung.9 However, further clinical evaluation in both patients confirmed the lung to be the only tumour site. Thus, we conclude that both tumours represented primary HCCC, salivary glandtype, of the lung. As further evidence that these are primary tumours, at the time of this report both patients are free of any local recurrence, metastasis or appearance of a head and neck tumour after 1.5 years of follow-up despite receiving no additional therapy after surgery. In conclusion, to our knowledge, these are the first two reported cases of hyalinizing clear cell carcinoma, salivary gland-type, arising in the lung. Rare salivary gland tumours should be part of the differential diagnosis when lung tumours, particularly those arising in the bronchus and that have an unusual morphology, are encountered.
Conflicts of interest No conflicts of interest declared. Akeesha A Shah Mitra Mehrad1 Sarah M Kelting James S Lewis Jr1,2 Edward B Stelow2
Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA, 1Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA, and 2 Department of Otolaryngology Head and Neck Surgery, Washington University School of Medicine, St Louis, MO, USA 1. Milchgrub S, Gnepp DR, Vuitch F et al. Hyalinizing clear cell carcinoma of salivary gland. Am. J. Surg. Pathol. 1994; 18; 74–82. 2. Antonescu CR, Katabi N, Zhang L et al. EWSR1–ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland. Genes Chromosom. Cancer 2011; 50; 559–570. 3. Shah AA, LeGallo RD, van Zante A et al. EWSR1 genetic rearrangements in salivary gland tumors. Am. J. Surg. Pathol. 2013; 37; 571–578. 4. Martins C, Cavaco B, Tonon G et al. A study of MECT1– MAML2 in mucoepidermoid carcinoma and Warthin’s tumor of salivary glands. J. Mol. Diagn. 2004; 6; 205–210. 5. Behboudi A, Enlund F, Winnes M et al. Molecular classification of mucoepidermoid carcinomas – prognostic significance of the MECT1–MAML2 fusion oncogene. Genes Chromosom. Cancer 2006; 45; 470–481. 6. Molina JR, Aubry MC, Lewis JE et al. Primary salivary glandtype lung cancer. Cancer 2007; 110; 2253–2259. 7. Antonescu CR, Zhang L, Chang NE et al. EWSR1–POU5F1 fusion in soft tissue myoepithelial tumors. A molecular analysis of sixty-six cases, including soft tissue, bone, and visceral lesions, showing common involvement of the EWSR1 gene. Genes Chromosom. Cancer 2010; 49; 1114–1124. 8. Weinreb I. Hyalinizing clear cell carcinoma of salivary gland: a review and update. Head Neck Pathol. 2013; 7; S20–S29. 9. O’Sullivan-Mejia ED, Massey HD, Faquin WC et al. Hyalinizing clear cell carcinoma: report of eight cases and a review of literature. Head Neck Pathol. 2009; 3; 179–185.
Histopathology, 67, 267–276.
