Clinical Review & Education
Clinical Problem Solving | PATHOLOGY
New-Onset Nasal Obstruction and Epistaxis of the Left Side of the Nose Yu-Hsuan Lin, MD; Szu-Pei Ho, MD; Yaoh-Shiang Lin, MD; Ming-Yee Lin, MD, PhD
A
B
D
C
Figure. A, Axial T1-weighted gadolinium-enhanced fat-suppressed magnetic resonance image of the neck. B-D, Histopathologic images (original magnifications ×400). B, Nests of small round to oval cells with scant cytoplasm, finely dispersed chromatin, nuclear molding, and inconspicuous nucleoli (hematoxylin-eosin). C, Cells positive for neural cell-adhesion molecule CD56 (CD56 immunostain). D, Dot-like staining pattern for pankeratin marker (pancytokeratin immunostain).
A woman in her 50s presented to our otolaryngology clinic with a 3-month history of persistent nasal obstruction of and occasional epistaxis from the left side of her nose. She denied having symptoms associated with aural or cranial nerve involveVideos at ment. However, a nontender, jamaotolaryngology.com firm, 3 × 4-cm mass fixed over the upper left side of her neck was detected. The patient was a nonsmoker, and her medical history was not remarkable. The flexible nasopharyngoscopy revealed an unclearly delineated fleshy mass obliterated the left side of the posterior choana (Video 1 and Video 2). Axial T1-weighted gadolinium-enhanced fat-suppressed magnetic resonance image revealed an expansile tumor originating from the posterolateral recess of the nasopharynx, with direct extension into the left sinonasal cavity (Figure, A). The patient then underwent an immediate biopsy. The histopathologic find-
jamaotolaryngology.com
ings revealed an image consisting of nests of small round to oval cells with scant cytoplasm, finely dispersed chromatin, nuclear molding, and inconspicuous nucleoli (Figure, B). Prominent mitotic activity and necrosis, cellular fragility with crushed artifact, and formation of pseudorosettes were readily identifiable. Use of immunohistochemical staining showed these cells to be positive for neural cell-adhesion molecule CD56 (Figure, C), with a dot-like staining pattern for pankeratin marker (clone: AE1/AE3) (Figure, D), but negative for thyroid transcription factor-1 (TTF-1), synaptophysin, chromogranin A, neuron-specific enolase, cytokeratin 20, CD99, and leukocyte common antigen. These cells also showed strong cytoplasmic expression of p16 but were negative for human papillomavirus (HPV) by in situ hybridization. Subsequent positron emission tomographic–computed tomographic scanning revealed no evidence of distant metastasis. What is your diagnosis?
JAMA Otolaryngology–Head & Neck Surgery November 2014 Volume 140, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
1079
Clinical Review & Education Clinical Problem Solving
Diagnosis Non-HPV–associated small cell carcinoma, neuroendocrine type of the nasopharynx
Discussion Extrapulmonary small-cell carcinoma (EPSCC), which is nowadays considered to be a type of high-grade neuroendocrine carcinoma,1,2 has been recognized as a distinct clinicopathological entity. Since the first description by Duguid and Kennedy in 1930, EPSCC has been reported throughout the whole human body.3 The most common primary sites are the gastrointestinal tract and genitourinary system.4,5 In terms of the head and neck regions, the frequency is greatest in the larynx, followed by the salivary glands and sinonasal regions.3 Occurrence in the nasopharynx is extremely rare.6 Clinically, EPSCC, neuroendocrine type (EPSCCNET) is typically found in patients in the fifth to seventh decades of life,4 with cases of limited disease being predominant and higher preponderance in males.4 Although most patients are heavy smokers, the correlation between tobacco use and development of EPSCCNET of the upper aerodigestive tract has not yet been conclusively established. The seventh edition of the American Joint Committee on Cancer has recommended a TNM staging classification for head and neck neuroendocrine tumors. However, it is advisable to use a modified version of the Veterans Affairs Lung Study Group staging system,4,5 designed for small cell lung carcinoma (SCLC). EPSCCNET has histopathological findings of confluent sheets of round to oval cells with typical cytomorphologic features, including scant cytoplasm, dispersed chromatin, and nuclear molding.1,3 Definite diagnosis is made on the basis of morphologic characteristics of hematoxylin-eosin–stained sections. Ancillary immunohistochemicalstainingforneuroendocrinemarkersandepithelialmarkerscanprovide further confirmation. Conversely, a negative result should not exclude the diagnosis if the histopathologic feature is diagnostic. Other malignant small, round, blue-cell tumors comprise a broad differential diagnostic entity. However, different ultrastructures and immunophenotypes provide particular diagnostic features. For example, like ARTICLE INFORMATION Author Affiliations: Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Y.-H. Lin); Department of Pathology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Ho); Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Y.-S. Lin, M.-Y. Lin); Department of Otolaryngology–Head and Neck Surgery, National Defense Medical Center, Taipei, Taiwan (Y.-S. Lin). Corresponding Author: Ming-Yee Lin, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Rd, Kaohsiung 813, Taiwan ([email protected]). Section Editor: Edward B. Stelow, MD. Published Online: October 2, 2014. doi:10.1001/jamaoto.2014.2245. Conflict of Interest Disclosures: None reported.
1080
SCLC, EPSCCNET cells often stain positive for TTF-1 but are negative for cytokeratin 20 (CK-20), except for those cells deriving from the salivary glands.1,6 Although Merkel cell carcinoma possesses morphologic characteristics akin to those of EPSCCNET, it consistently displays a characteristic punctate perinuclear CK-20 staining pattern but stains negative for TTF-1.1,3,6 Although several attempts have been made to identify candidate prognostic factors, prognosis of EPSCCNET remains far from well established. In terms of the head and neck region, the cumulative studies to date conclude that better outcomes are correlated with cases of limited disease, cases involving the salivary glands, and patients undergoing multimodality therapeutic approaches.2,7,8 Human papillomavirus (HPV) status is intriguing. Although routine HPV testing has expended the morphologic spectrum of HPV-related oropharyngeal carcinoma, HPV positivity confers a favorable prognosis.9 The exception is the HPV-related carcinoma harboring a small-cell phonotype, which still seems to behave in an aggressive manner.9 Current therapeutic modality was empirically extrapolated for trials designated for SCLC.3,4 The role of prophylactic cranial irradiation (PCI) in EPSCCNET remains open to debate. Walenkamp et al10 justified the addition of PCI as part of the standard treatment for limited-stage EPSCCNET originating from the head and neck, owing to this treatment being a statistically significant positive prognostic factor. In this case, the patient underwent 4 cycles of cisplatin- and etoposide-based concurrent chemoradiotherapy and subsequently achieved a clinical complete response. The tumor bed, along with the involved lymph nodes, was exposed to a dose equivalent to 70 Gy in 2-Gy fractions. Further addition of the PCI was delivered in 2-Gy daily fractions to a total of 24 Gy. Over the next 28 months, her status remained uneventful. In conclusion, we have described a case of non–HPV-related EPSCCNET originating from the nasopharynx. Additional experience is needed to elucidate the molecular alteration to characterize differences in clinical outcomes. At the very least, patients with this disease would best be treated with aggressive multimodal treatment strategies.
Correction: This article was corrected online November 20, 2014, for an error in punctuation. REFERENCES 1. Barnes L, Eveson J, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours: Pathology and Genetics. Head and Neck Tumours. Lyon, France: IARC Press; 2005:135-139. 2. Hatoum GF, Patton B, Takita C, et al. Small cell carcinoma of the head and neck: the University of Miami experience. Int J Radiat Oncol Biol Phys. 2009;74(2):477-481.
6. Lee LY, Chang KP, Hsu CL, Chen TC, Kuo TT. Small-cell neuroendocrine carcinoma of the nasopharynx: report of a rare case lacking association with Epstein-Barr virus. Int J Surg Pathol. 2011;19(2):199-202. 7. Likhacheva A, Rosenthal DI, Hanna E, Kupferman M, Demonte F, El-Naggar AK. Sinonasal neuroendocrine carcinoma: impact of differentiation status on response and outcome. Head Neck Oncol. 2011;3(3):32.
3. Renner G. Small cell carcinoma of the head and neck: a review. Semin Oncol. 2007;34(1):3-14.
8. Barker JL Jr, Glisson BS, Garden AS, et al. Management of nonsinonasal neuroendocrine carcinomas of the head and neck. Cancer. 2003;98 (11):2322-2328.
4. Haider K, Shahid RK, Finch D, et al. Extrapulmonary small cell cancer: a Canadian province’s experience. Cancer. 2006;107(9):22622269.
9. Kraft S, Faquin WC, Krane JF. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol. 2012;36(3):321-330.
5. Lin YL, Chung CY, Chang CS, et al. Prognostic factors in extrapulmonary small cell carcinomas: a large retrospective study. Oncology. 2007;72(34):181-187.
10. Walenkamp AM, Sonke GS, Sleijfer DT. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat Rev. 2009;35(3):228236.
JAMA Otolaryngology–Head & Neck Surgery November 2014 Volume 140, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
jamaotolaryngology.com
Clinical Problem Solving | PATHOLOGY
New-Onset Nasal Obstruction and Epistaxis of the Left Side of the Nose Yu-Hsuan Lin, MD; Szu-Pei Ho, MD; Yaoh-Shiang Lin, MD; Ming-Yee Lin, MD, PhD
A
B
D
C
Figure. A, Axial T1-weighted gadolinium-enhanced fat-suppressed magnetic resonance image of the neck. B-D, Histopathologic images (original magnifications ×400). B, Nests of small round to oval cells with scant cytoplasm, finely dispersed chromatin, nuclear molding, and inconspicuous nucleoli (hematoxylin-eosin). C, Cells positive for neural cell-adhesion molecule CD56 (CD56 immunostain). D, Dot-like staining pattern for pankeratin marker (pancytokeratin immunostain).
A woman in her 50s presented to our otolaryngology clinic with a 3-month history of persistent nasal obstruction of and occasional epistaxis from the left side of her nose. She denied having symptoms associated with aural or cranial nerve involveVideos at ment. However, a nontender, jamaotolaryngology.com firm, 3 × 4-cm mass fixed over the upper left side of her neck was detected. The patient was a nonsmoker, and her medical history was not remarkable. The flexible nasopharyngoscopy revealed an unclearly delineated fleshy mass obliterated the left side of the posterior choana (Video 1 and Video 2). Axial T1-weighted gadolinium-enhanced fat-suppressed magnetic resonance image revealed an expansile tumor originating from the posterolateral recess of the nasopharynx, with direct extension into the left sinonasal cavity (Figure, A). The patient then underwent an immediate biopsy. The histopathologic find-
jamaotolaryngology.com
ings revealed an image consisting of nests of small round to oval cells with scant cytoplasm, finely dispersed chromatin, nuclear molding, and inconspicuous nucleoli (Figure, B). Prominent mitotic activity and necrosis, cellular fragility with crushed artifact, and formation of pseudorosettes were readily identifiable. Use of immunohistochemical staining showed these cells to be positive for neural cell-adhesion molecule CD56 (Figure, C), with a dot-like staining pattern for pankeratin marker (clone: AE1/AE3) (Figure, D), but negative for thyroid transcription factor-1 (TTF-1), synaptophysin, chromogranin A, neuron-specific enolase, cytokeratin 20, CD99, and leukocyte common antigen. These cells also showed strong cytoplasmic expression of p16 but were negative for human papillomavirus (HPV) by in situ hybridization. Subsequent positron emission tomographic–computed tomographic scanning revealed no evidence of distant metastasis. What is your diagnosis?
JAMA Otolaryngology–Head & Neck Surgery November 2014 Volume 140, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
1079
Clinical Review & Education Clinical Problem Solving
Diagnosis Non-HPV–associated small cell carcinoma, neuroendocrine type of the nasopharynx
Discussion Extrapulmonary small-cell carcinoma (EPSCC), which is nowadays considered to be a type of high-grade neuroendocrine carcinoma,1,2 has been recognized as a distinct clinicopathological entity. Since the first description by Duguid and Kennedy in 1930, EPSCC has been reported throughout the whole human body.3 The most common primary sites are the gastrointestinal tract and genitourinary system.4,5 In terms of the head and neck regions, the frequency is greatest in the larynx, followed by the salivary glands and sinonasal regions.3 Occurrence in the nasopharynx is extremely rare.6 Clinically, EPSCC, neuroendocrine type (EPSCCNET) is typically found in patients in the fifth to seventh decades of life,4 with cases of limited disease being predominant and higher preponderance in males.4 Although most patients are heavy smokers, the correlation between tobacco use and development of EPSCCNET of the upper aerodigestive tract has not yet been conclusively established. The seventh edition of the American Joint Committee on Cancer has recommended a TNM staging classification for head and neck neuroendocrine tumors. However, it is advisable to use a modified version of the Veterans Affairs Lung Study Group staging system,4,5 designed for small cell lung carcinoma (SCLC). EPSCCNET has histopathological findings of confluent sheets of round to oval cells with typical cytomorphologic features, including scant cytoplasm, dispersed chromatin, and nuclear molding.1,3 Definite diagnosis is made on the basis of morphologic characteristics of hematoxylin-eosin–stained sections. Ancillary immunohistochemicalstainingforneuroendocrinemarkersandepithelialmarkerscanprovide further confirmation. Conversely, a negative result should not exclude the diagnosis if the histopathologic feature is diagnostic. Other malignant small, round, blue-cell tumors comprise a broad differential diagnostic entity. However, different ultrastructures and immunophenotypes provide particular diagnostic features. For example, like ARTICLE INFORMATION Author Affiliations: Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Y.-H. Lin); Department of Pathology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Ho); Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Y.-S. Lin, M.-Y. Lin); Department of Otolaryngology–Head and Neck Surgery, National Defense Medical Center, Taipei, Taiwan (Y.-S. Lin). Corresponding Author: Ming-Yee Lin, MD, PhD, Department of Otolaryngology–Head and Neck Surgery, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Rd, Kaohsiung 813, Taiwan ([email protected]). Section Editor: Edward B. Stelow, MD. Published Online: October 2, 2014. doi:10.1001/jamaoto.2014.2245. Conflict of Interest Disclosures: None reported.
1080
SCLC, EPSCCNET cells often stain positive for TTF-1 but are negative for cytokeratin 20 (CK-20), except for those cells deriving from the salivary glands.1,6 Although Merkel cell carcinoma possesses morphologic characteristics akin to those of EPSCCNET, it consistently displays a characteristic punctate perinuclear CK-20 staining pattern but stains negative for TTF-1.1,3,6 Although several attempts have been made to identify candidate prognostic factors, prognosis of EPSCCNET remains far from well established. In terms of the head and neck region, the cumulative studies to date conclude that better outcomes are correlated with cases of limited disease, cases involving the salivary glands, and patients undergoing multimodality therapeutic approaches.2,7,8 Human papillomavirus (HPV) status is intriguing. Although routine HPV testing has expended the morphologic spectrum of HPV-related oropharyngeal carcinoma, HPV positivity confers a favorable prognosis.9 The exception is the HPV-related carcinoma harboring a small-cell phonotype, which still seems to behave in an aggressive manner.9 Current therapeutic modality was empirically extrapolated for trials designated for SCLC.3,4 The role of prophylactic cranial irradiation (PCI) in EPSCCNET remains open to debate. Walenkamp et al10 justified the addition of PCI as part of the standard treatment for limited-stage EPSCCNET originating from the head and neck, owing to this treatment being a statistically significant positive prognostic factor. In this case, the patient underwent 4 cycles of cisplatin- and etoposide-based concurrent chemoradiotherapy and subsequently achieved a clinical complete response. The tumor bed, along with the involved lymph nodes, was exposed to a dose equivalent to 70 Gy in 2-Gy fractions. Further addition of the PCI was delivered in 2-Gy daily fractions to a total of 24 Gy. Over the next 28 months, her status remained uneventful. In conclusion, we have described a case of non–HPV-related EPSCCNET originating from the nasopharynx. Additional experience is needed to elucidate the molecular alteration to characterize differences in clinical outcomes. At the very least, patients with this disease would best be treated with aggressive multimodal treatment strategies.
Correction: This article was corrected online November 20, 2014, for an error in punctuation. REFERENCES 1. Barnes L, Eveson J, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours: Pathology and Genetics. Head and Neck Tumours. Lyon, France: IARC Press; 2005:135-139. 2. Hatoum GF, Patton B, Takita C, et al. Small cell carcinoma of the head and neck: the University of Miami experience. Int J Radiat Oncol Biol Phys. 2009;74(2):477-481.
6. Lee LY, Chang KP, Hsu CL, Chen TC, Kuo TT. Small-cell neuroendocrine carcinoma of the nasopharynx: report of a rare case lacking association with Epstein-Barr virus. Int J Surg Pathol. 2011;19(2):199-202. 7. Likhacheva A, Rosenthal DI, Hanna E, Kupferman M, Demonte F, El-Naggar AK. Sinonasal neuroendocrine carcinoma: impact of differentiation status on response and outcome. Head Neck Oncol. 2011;3(3):32.
3. Renner G. Small cell carcinoma of the head and neck: a review. Semin Oncol. 2007;34(1):3-14.
8. Barker JL Jr, Glisson BS, Garden AS, et al. Management of nonsinonasal neuroendocrine carcinomas of the head and neck. Cancer. 2003;98 (11):2322-2328.
4. Haider K, Shahid RK, Finch D, et al. Extrapulmonary small cell cancer: a Canadian province’s experience. Cancer. 2006;107(9):22622269.
9. Kraft S, Faquin WC, Krane JF. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol. 2012;36(3):321-330.
5. Lin YL, Chung CY, Chang CS, et al. Prognostic factors in extrapulmonary small cell carcinomas: a large retrospective study. Oncology. 2007;72(34):181-187.
10. Walenkamp AM, Sonke GS, Sleijfer DT. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat Rev. 2009;35(3):228236.
JAMA Otolaryngology–Head & Neck Surgery November 2014 Volume 140, Number 11
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a Nanyang Technological University User on 05/25/2015
jamaotolaryngology.com
