Basaloid neoplasms of the head and neck Richard Jordan DDS PhD FRCPath Professor & Director UCSF Oral Pathology Laboratory University of California San Francisco Basaloid Tumors Head and Neck Basaloid SCC (HPV-) Non-keratinizing carcinoma (HPV+) Basal cell adenocarcinoma Adenoid cystic carcinoma PLGA NPC including EBV-/HPV+ NPC SNUC Neuroendocrine carcinoma Basaloid SCC Wain 1986; often misclassified before that Similar tumors at other sites: anus, thymus, esophagus Hypopharynx, supraglottic larynx, base of tongue and palatine tonsils Nest & cords of densely packed pleomorphic basaloid cells Cribriform areas can be confused with ACC Intracytoplasmic mucins are negative Comedo necrosis in larger areas; Mitotic activity frequent Tumor cells have hyperchromatic nuclei with eosinophilic cytoplasms Look for squamous differentiation. Connection to overlying mucosa Clinico-pathologic features HPV posi)ve HPV nega)ve Site Tonsil, base of tongue Any Histology Basaloid Kera;nizing Age Younger Older Gender 3:1 male 3:1 male Socio- economic status High Low Risk factors Sexual behavior Alcohol, tobacco Survival >80% at 3 years 50% at 3 years Incidence Increasing Decreasing 1
Common HPV Types and Effects Low- Risk High- Risk HPV Types HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Lead to: Benign cervical changes Genital warts Precancer cervical changes Cervical cancer Anal and other cancers 1. Cox. Baillière s Clin Obstet Gynaecol. 1995;9:1. 2. Munoz et al. N Engl J Med. 2003;348:518. 7 From Marur et al. Lancet Oncol 2010 HPV-16 & HNSCC Associations Sexual Transmission of HPV in oropharyngeal cancer Tonsil OR: 15.1, 95% CI: 6.8-33.7 Oropharynx OR: 4.3, 95% CI: 2.1-8.9 Oral OR 2.0, 95% CI: 1.2-3.4 Larynx OR =2.0 95% CI 1.0-4.2 Variability based on detection method ELISA showed greatest variability PCR showed least variability Methods: Case-control study of 100 pts with new OP SCC 200 control patients Results: High # of vaginal sex partners (>26) associated with OP SCC Odds Ratio = 3.1 High # of oral sex partners (>6) associated with OP SCC Odds Ratio = 3.4 OP SCC significantly associated with HPV-16 infection Odds Ratio = 14.6 Hobbs CG et al. Clin Otolaryngol. 2006 Aug;31(4):259-66. D Souza et al. 2007 HPV detection methods In situ hybridization: Dako GenPoint: HPV 16/18, 6/11 Ventana Inform HPV PCR: Home made assays Roche Linear Array and Amplicor Immunohistochemistry: HPV common antigens p16 surrogate Ventana Inform HPV Slide based, nonamplified ISH using chromogenic detection Uses Ventana Benchmark machine Cocktail and single type HPV 16 probes available 2
p16 Immunohistochemistry Surrogate marker of HPV Diffuse, strong nuclear or nuclear + cytoplasmic > 70% cells Correlates with HPV DNA integration into host Uncoupling cell cycle machinery at G1/S Small proportion (~7-12%) of cases p16+ but HPV16 Differences due to non-hpv 16 strains, impaired prb Does basaloid morphology predict HPV in SCC? Does basaloid morphology predict HPV in SCC? Basaloid Squamous Cell Carcinoma of the Head and Neck is a Mixed Variant That Can be Further Resolved by HPV Status. Begum & Westra American Journal of Surgical Pathology. 32(7): 1044-1050, July 2008. Basaloid Squamous Cell Carcinoma of the Head and Neck is a Mixed Variant That Can be Further Resolved by HPV Status. Begum & Westra American Journal of Surgical Pathology. 32(7): 1044-1050, July 2008. Why test for HPV? p16 HPV16 ISH Predict clinical outcome: 56% Localize primary tumor: 21% Establish tumor classification: 9% Eligibility for vaccine trial: 8% Patient curiosity: 5% N = 256 cases p16 HPV16 ISH Basaloid Squamous Cell Carcinoma of the Head and Neck is a Mixed Variant That Can be Further Resolved by HPV Status. Begum & Westra American Journal of Surgical Pathology. 32(7):1044-1050, July 2008. 3
OP HNSCC: HPV in lymph nodes 94% (15/16) of patients with HPV +ve tonsillar SCC had HPV in LNs Pts with HPV +ve Tonsillar SCC without metastatic disease had no evidence of HPV in their lymphatic tissue (8 patients) Use to detect possible primary HPV Status and Prognosis Stroma et al., 2002 Survival difference by HPV-16 status Oropharyngeal SCC Study Year # Patients TX type Survival HPV + % (years) Survival HPV - % (years) Lassen 2009 156 RT 62 (5) 26 (5) Hafkamp 2008 77 NS 69 (5) 31 (5) Reimers 2007 97 S, RT, CRT 73 (5) 63 (5) Fakry 2008 62 CRT 78 (5) 50 (5) Weinberger 2006 107 RT 79 (5) 20 (5) Kumar 2008 50 CRT 80 (5) 40 (5) Chung 2009 46 CRT 86 (5) 35 (5) Nichols 2009 44 CRT 89 (3) 69 (3) S = surgery, RT = Radiotherapy, CRT = chemoradiation, NS = not specified Ang K et al. N Engl J Med 2010;10.1056/NEJMoa0912217 Basaloid Tumors Head and Neck Basaloid SCC (HPV-) Non-keratinizing carcinoma (HPV+) Basal cell adenocarcinoma Adenoid cystic carcinoma PLGA NPC including EBV-/HPV+ NPC SNUC Neuroendocrine carcinoma 4
Basal cell adenocarcinoma (BCAC) Clinical features Malignant counterpart basal cell adenoma (BCA); lots of synonyms May arise de novo (75%) or from BCA (25%) 1.6% of all salivary gland tumors, 90% parotid Wide age range; in infants: sialoblastoma Slowly growing, long standing mass Basal cell adenocarcinoma (BCAC) Histology Mimics BCA: solid, membraneous, trabecular, tubular patterns Low power infiltration Basaloid cells with little pleomorphism PNI and LVI common (25%) Mitoses > 4-5/ 10 HPF IHC: keratin, S100 (focal), EMA, CEA Adenoid cystic carcinoma Clinical Features 4-7 th decades, F:M 3:2, 3 rd most common SGT Slowly growing, widely infiltrative tumor Can occur in major and minor glands Perineural invasion is classical feature 80-90% pts dies of disease in 15-20 years Recurrence rates 16-85% Distant mets: 25-55% Only 20% pts with distant mets survival > 5 years Adenoid cystic carcinoma Histology Tubular, cribriform, solid patterns Bipopulation: myoepithelial & ductal Bland basophilic cells with angulated nuclei & condensed chromatin >30% solid areas = solid type Necrosis only in solid form Take care with small biopsies or no evidence of invasion CD117 may not be helpful SMA, S-100, p63 stain myoepithelial cells 5
p63 SMA Polymorphous Low-grade Adenocarcinoma PLGA CK CD117 Minor salivary gland only Presents as asymptomatic submucosal mass Polymorphous microscopic pattern Most cases show nerve invasion, but no effect on prognosis Wide excision Recurrence rate ~10% Occasional metastasis Regional nodes ~10% Rare to lungs PLGA Misdiagnosis Mono adenoma 11 ACC 10 Carcinoma ex 9 Adenoca NOS 7 Mixed tumor 5 42/204 PLGA vs ACC PLGA ACC Site Intraoral Any Metastases 9-17% 25-55% Morphology Diverse Tubular/cribriform/solid Population One cell Bipopulation Nuclei Uniform, vesicular Angulate, dark PNI + small nerves +++ any Blue goo - +++ Muscle antigens Varies Myoepithelial Keratin Varies Ductal cells Ki-67 <5% >10% C-kit May be + Usually always + Sinonasal undifferentiated carcinoma (SNUC) Rare, older patients Dismal prognosis despite aggressive therapy Difficult to differentiate from basaloid SCC, NPC, NE carcinoma Grows in sheets, nests, ribbons. Mitoses, apoptotic cells, necrosis common Focal squamous differentiation is not helpful but large areas rule out SNUC Range of cell sizes, larger than basaloid SCC, eosinophilic cytoplasm, prominent nucleoli p63 interpretation with care. Usually only focal 6
5/5/11 Neuroendocrine carcinoma NEC vs. SNUC vs. basaloid SCC challenging Squamous differentiation should be focal No connection with overlying mucosa No stromal mucin & pseudoglandular structures NEC positive for synaptophysin, chromogranin, CD56 NSE no value Perinuclear punctate staining with cytokeratin valuable Kera;n Synaptophysin Neuroendocrine carcinoma Kera;n Chromogranin Nasopharyngeal carcinoma 3 forms: Kera;n Chromogranin A Synaptophysin keratinizing (type 1) non-keratinizing (type 2) lymphoepithelioma (type 3) Asians, peak in 2nd to 4th decades Lymph node mets common at dx Nuclei are vesicular and large compared to basaloid SCC where they are denser and more atypical ISH for EBV important CD56 7
kera;n Nasopharyngeal carcinoma EBV ISH EBER EBV- HPV+ Nasopharyngeal CA Rare <5% of NPC are HPV16+/p16+ Nonkeratinizing type or keratinizing type More common in North American populations Prognosis not established p16 EBV ISH EBER 8