Back node with known primary managementt
- 1. Dr HIMANSHU SONI Fellow in Head & Neck Surgical Oncology - FHNO Fellow in CranioMaxilloFacial Trauma – AOMSI Oral and Maxillofacial Surgeon
- 2. An unknown primary is defined as a squamous cell carcinoma (SCC) presenting in a lymph node or nodes in the neck with no primary index site in the head and neck having been identified. The term carcinoma of unknown primary (CUP) should be used if no evidence of primary tumor is found after adequate clinical examination fibreoptic endoscopy, imaging investigation which includes fluorine 18-labelled deoxyglucose positron emission tomograpgy ideally with CT fusion imaging biopsy of putative mucosal sites
- 3. • CUP accounts for 5%-10% of all tumours • 3–5% of head and neck cancers presented as cervical squamous cell carcinomas of unknown primary • Squamous cell carcinoma (SCC) is the most common histotype, followed by adenocarcinoma, undifferentiated carcinoma and other malignancies (for example, lymphoma and melanoma) Bell RB, Andersen PE, Fernandes RP. Oral, head and neck oncology and reconstructive surgery.2018
- 4. • About 1% of all head and neck malignancies are accounted for by metastasis from a remote primary site • most frequent identifiable sites include- • breast ,lung, gastrointestinal tract, genitourinary tract, and, uncommonly, the central nervous system • Breast - 2.3% to 4.3% • Lung - varies from 1.5 to 35% • Esophagus - 20% to 30% of esophageal carcinomas present with cervical node involvement López F, Rodrigo JP, Silver CE, Haigentz Jr M, Bishop JA, Strojan P, Hartl DM, Bradley PJ, Mendenhall WM, Suárez C,Takes RP. Cervical lymph node metastases from remote primary tumor sites. Head & neck. 2016 Apr;38(S1):E2374-85.
- 5. i) Slow growth rate ii) Spontaneous involution ( immunodestruction) iii) Small size iv) Hidden location ( tonsillar crypts)
- 6. Location of lymph nodes Lymphatic drainage of the region Possible location of the primary tumor (hidden sites) Histology of nodes Past history (relevant)
- 7. Profuse capillary lymphatic network present in Paranasal sinuses, middle ear and true vocal cords have sparse capillary lymphatics Nasopharynx & Pyriform sinus
- 8. In evaluating metastatic SCC to cervical lymph nodes, the occult primary is eventually detected in about half of the cohort.
- 10. Detailed history of symptomatology and habits Examination of neck Thorough clinical examination Level of nodal involvement
- 11. The mean interval between discovery of a cervical mass and diagnosis of CUP ranges from 2 to 5 months.
- 12. The lumps are usually located in level 2, followed by level 3, with bilateral involvement and other symptoms (i.e. pain and dysphagia) reported in less than 10 per cent. solid or cystic lesions solitary or multiple lumps. The usual clinical presentation is of a cervical mass with 3–4 weeks’ progression Neck lumps
- 13. The clinical N stage at presentation is usually N2a, N2b and N2c. The presence of cystic malignant metastases in level 2 is often considered to be a hallmark of human papilloma virus (HPV)-related squamous carcinoma, usually with subclinical primaries in the oropharynx. It should be also noted that patients presenting with supraclavicular lymphadenopathy may represent a different clinical entity, due to the potential for association with infraclavicular neoplasms, such as lung cancer.
- 14. If there is no obvious or highly suspicious lesion on out-patient assessment, then the patient should be regarded as having an unknown primary and should be evaluated further, this clinical entity being known as a ‘clinical’ unknown primary. Clinical examination nose post-nasal space oral cavity oropharynx larynx hypopharynx Including palpation of the oral cavity and tongue base The skin and scalp of the head and neck region should be examined to ensure that there are no significant cutaneous lesions. If there is an obvious lesion, or high suspicion of a lesion, then further management in the form of Imaging and Panendoscopy of that sub-site should be carried out.
- 18. Physical examination • Careful physical examination • Fiber-optic evaluation • Palpation of the oral cavity, oropharynx, and base of the tongue • Search for scars in the head and neck indicating previous surgery. • Examination of the neck, which includes site, size, mobility, and relationship of the node(s) to the adjacent structures. • Complete physical examination for abnormalities elsewhere: breast, axilla, groins, testicles, abdomen.
- 19. • FNAC • Imaging • Endoscopy • Molecular assays • Examination under General Anaesthesia
- 20. FNAC: To confirm the presence and type of malignancy Core biopsy: If repeated FNAC negative Image guided FNAC/Biopsy: If repeated FNAC negative and in case of a cystic metastasis to get an aspirate from the wall of the cyst IHC For undifferentiated neoplasms EBV detection: If high probability of nasopharyngeal carcinoma is suspected in view of ethnicity, bilateral nodes and undifferentiated histology
- 21. Lymph-node fine-needle aspiration, preferably under ultra-sound control, is the first-line examination. Core biopsy The advantage of a core biopsy over FNA cytology is that a clearer HISTOLOGICAL PICTURE can be determined. Although this is generally used to differentiate between squamous, thyroid, salivary, breast or bronchial origins, it may be possible from the cell architecture to suggest the potential origin of the index primary. Immuno- histochemical techniques May not be able to suggest the TUMOUR ORIGIN they may, however, potentially exclude sites, e.g. by the use of lung or thyroid markers. More specific investigations such as identification of Epstein-Barr virus (EBV) may correlate highly with a nasopharyngeal site. Allow detection of the primary in more than 50% of patients
- 22. Do not rule out metastatic lymph nodes, especially in case of cystic presentation, where the false-negative rate may be as high as 42% . A simple means of confirming differentiated thyroid cancer is to assay thyroglobulin. Even in the absence of tumor cells, elevated thyroglobulin confirms neoplasia of thyroid origin Trocar biopsy may be considered in case ofnegative findings; the risk of dissemination is no more than 0.001%[ Partial lymph-node resection is not recommended due to riskof local complications and systemic dissemination
- 23. • Head and Neck- CT, MRI • CECT Thorax – Trachea – Oesophagus – Lungs • CECT Abdomen – Liver – Ovary – Testes – Prostate
- 24. All patients should have computed tomography (CT) imaging from skull base to diaphragm as part of the assessment of a newly diagnosed SCC of the head and neck. If the disease presents in a level 2/3 lymph node magnetic resonance imaging (MRI) of the oropharynx, and in particular the tongue base, tonsil and tonsil lingual angle, should be carried out.
- 25. • With negative routine clinical examination, CT, and MRI, PET scan allows detection of primary tumours in 5-43% of patients. • Overall staging accuracy -69-78% • Higher rates of primary tumour detection-non-head and-neck CUP or histologies other than SCC
- 26. Positron emission tomography-computed tomography scanning is the recognised investigation of choice in the assessment of the unknown primary and has been shown to be superior to CT scanning alone. Recent meta-analysis reported an identification rate of 44 per cent, a sensitivity of 97 per cent and a specificity of 68 percent. Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and metaanalysis. Eur Radiol 2009;19:731–44 Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomography–computed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol 2013;22:190–94
- 27. According to Miller, PET-CT detects 29% of primaries when CT and MRI proved negative; linking PET-CT to panendoscopy gave a detection rate of 45%. Miller FR, Hussey D, Beeram M, EngT, McGuff HS, Otto RA. Positronemission tomography in the management of unknown primary headand neck carcinoma. Arch Otolaryngol Head Neck Surg 2005;131:626–9,http://dx.doi.org/10.1001/archotol.131.7.626. PET coupled to CT (PET-CT) shows better diagnostic efficiency than PET alone, and is now the reference technique
- 28. • The resolution of the PET scan limited to 5 mm • Tumours of the supraglottic region and Waldeyer’ s tonsillar ring-most difficult to be diagnosed with FDG-PET – low tumour volume in small, superficial lesions – the presence of normal lymphoid tissues • Ideally, biopsies should be performed after PET scan – Avoids false positive PET-scans at biopsy site.
- 29. Following each of the clinical and radiological assessments it is necessary to carry out panendoscopy of the upper aerodigestive tract under general anaesthesia. Timing
- 30. vallecula posterior pharyngeal wall
- 31. Palpation of oral cavity and tongue base should also be carried out. In any of these areas if there is any suspicion of ulceration, change in colour, asymmetry or fullness, then the area should be photographed and appropriate deep biopsies taken.
- 32. Oropharyngeal LymphoidTissue Resection Excision Or SamplingThe LingualTonsil RANDOM biopsies ?????
- 33. Most current groups would suggest that PET–CT imaging conjunction with panendoscopy directed biopsy as appropriate and bilateral tonsillectomy offer the greatest chance of identifying the occult primary tumour in the routine clinical setting. The role of tongue base mucosectomy by transoral laser or robotic approach, with or without PET–CT or HPV positivity needs prospective evaluation. Following detailed clinical, radiological and operative assessment, if an index primary site is identified then treatment should be according to the guidelines for that site with nodal metastasis. If each of these investigations is negative, then this should be regarded as a ‘true’ unknown primary and the treatment considered as such.
- 34. Sequential panendoscopy-tonsillectomy-biopsy is used for squamous cell CUP. Head and neck panendoscopy including nasopharyngeal endoscopy under general anesthesia is systematic. It screens for sometimes millimeter-sized submucosal lesions, notably in the tonsillar and tongue-base regions, with the help of finger palpation. If panendoscopy and PET-CT fail to guide biopsy, palatine tonsillectomy ipsilateral to the metastatic lymph node coupled to tongue-base biopsy is performed. The aim is to detect submucosal cancer or cancer in the palatine and lingual tonsil lymphoepithelial crypts; these sites account for up to 90% of unknown primaries emerging during follow-up.
- 35. Tonsillectomy ipsilateral to the metastatic lymph node provides between18% and 44.6% detection of primaries The diagnostic efficiency of palatine tonsillectomy is greater than that of deep biopsy: 29.5% versus 3.2% (P = 0.0002) A recent technique consists in trans oral robotic-assisted or laser resection of tongue-base lympho epithelial tissue.
- 36. A literature review reported 80% primary detection when trans oral palatine tonsillectomy was associated to lingual tonsillectomy; primaries were located in the lingual tonsils in 56% of cases. The usefulness of bilateral palatine tonsillectomy is a subject of discussion. Two studies reported respectively10% (4/41) and 23% (5/22) primary detection in the contralateral palatine tonsil. Bilateral palatine tonsillectomy has other interests: morbidity is low; it resolves clinicians’ doubts in case of contralateral tonsillar fixation on follow-up PET-CT; and serendipitous discovery of synchronous primaries has been reported.
- 37. Epstein-Barr virus (EBV) -nasopharyngeal tumour. Human Papilloma virus (HPV) - oropharyngeal cancer
- 38. • Mandatory • Biopsies taken from all sites suspicious at the clinical and imaging evaluation • Or blindly from the sites of possible origin of the primary o base of tongue o tonsil or tonsillar fossa o pyriform sinus o nasopharynx on the lesion side
- 39. • Another option is open biopsy • Increased risk of distant metastases following this procedure has been suggested • Detection rate – CT scan -15-20% – Panendoscopy with biopsies -up to 65%
- 40. • The most common sites of primary (82%) – Tonsil – Base of tongue • Bilateral Tonsillectomy, in the absence of suspicious lesions- up to 25% of primary tumours are detected in this site • 10% rate of contralateral spread from occult tonsil lesions - justifies bilateral diagnostic tonsillectomy
- 41. The neck is staged as set out elsewhere in this supplement. It should be noted that the correct T stage for an unknown primary is T0 and not TX.
- 42. SUMMARY
- 44. Management • Surgery • Radiation • Chemotherapy • Combination • The choice of the treatment schedule depends on the histology and on the stage of the disease.
- 45. Most treatment regimens will therefore involve combined modality treatment, but on occasions, radiotherapy (RT), and even more rarely surgery, will be used as single modality treatment. The rate of emergence of the primary tumour is approximately 3 per cent per year, which is equivalent to the development of second carcinomas in the head and neck, lung and oesophagus. Therefore the primary aim of treatment is locoregional control.. Curative with the least morbidity to the upper aerodigestive tract possible.
- 46. Surgery on its own may be sufficient treatment for N1 necks demonstrating no extracapsular spread, but in all other scenarios, needs to be supplemented by adjuvant (chemo) radiation For more advanced neck disease intensive combined treatment is required. This could be either a combination of neck dissection and RT or initial (chemo)- radiotherapy followed by planned neck dissection if a complete response is not evident on imaging. Both of these approaches appear to be equally effective.
- 47. May be treated with surgery alone provided the surgery has been comprehensive. This has been shown to be as effective as RT and clearly avoids the potential side effects of RT. There are no randomiseddata to support MRND over selective neck dissection(SND).13 RT to at least the involved nodal levels is necessary, although it is more usual to irradiate the entire ipsilateral post-operative neck, and boost the involved levels. There are also some reports that locoregional tumour control is up to 40 per cent higher with surgery and radiation therapy compared with radiation alone, meaning radiation alone, even for N1 disease, must remain an option only for those who are inoperable on medical grounds or where it is considered appropriate for those who are HPV positive. T0N1 – no extracapsular spread T0N1 – with extracapsular spread.
- 48. For each of these stages comprehensive clearance of the involved lymph node levels is usually required in the form of MRND or SND with possible contralateral SND or MRND. Radical RT to one or both sides of the neck should be considered, even for pN2a disease, as in one of the largest series of occult primary head and neck cancer in 136 patients from the MD Anderson Centre, combined surgery and post-operative radiation was associated with lower rates of locoregional relapse and higher disease-free survival. This radiation may be given with or without concomitant chemotherapy as described above. While there remains no randomised data to support the use of chemotherapy for pN2 disease from an occult head and neck primary, there are two case series both demonstrating excellent progression- free survival (PFS) and overall survival (OS) rates. The chemotherapy protocols used were heterogeneous, and included concomitant cisplatin, concomitant 5- fluorouracil (5-FU) and hydroxyurea, as well as paclitaxel.
- 49. It may not be possible to have a curative aim in patients with this staging. For curative intent a radical neck dissection or Type I MRND with postoperative chemoradiotherapy will usually be necessary.
- 50. Primary treatment. For N1 disease with extracapsular spread, N2 and N3 disease, initial chemoradiation with planned neck dissection only for those patients not achieving a clinical or metabolic complete response on post-treatment imaging is a valid management strategy. The extent of the RT fields to be treated is controversial In the absence of high-level evidence, the practice of radiation therapy in this setting includes involved field only or bilateral neck and TMI. The latter is practiced commonly in the UK.
- 53. Post-operative neck: 60 Gy in 30 fractions or equivalent Post-operative neck with extracapsular spread: 64–66 Gy in 32–33 fractions or equivalent Gross macroscopic disease still present: 70 Gy in 30 fractions or equivalent Putative mucosal sites and the uninvolved neck: 50 Gy in 25 fractions or equivalent.
- 54. There is a lack of consensus on the RT target volumes that should be treated after neck dissection. Treatment of the ipsilateral hemi-neck alone is of considerably lower toxicity and has been shown to achieve local control rates in the cervical nodes of 90 per cent with contralateral relapse rates as low as 4.7 per cent, provided treatment strategies are determined using PET–CT. However, total mucosal and bilateral neck irradiation of the head and neck region is a common practice with the aim of eradicating the primary and the microscopic neck disease. With the addition of cisplatin to primary RT for the treatment of head and neck cancer, an absolute survival benefit of 6.5 per cent is seen at five years.
- 55. Investigating concomitant chemoradiation in the postoperative setting, the Radiation Therapy Oncology Group (RTOG) demonstrated a 10 per cent improvement in locoregional control rate, and a 22 per cent risk reduction of disease recurrence and death at two years, while the European Organisation for Research and Treatment of Cancer (EORTC) group showed a 13 per cent improvement in locoregional control, 25 per cent risk reduction of disease progression, and 30 per cent risk reduction of death at five years. These findings were based on the concomitant use of cisplatin 100 mg/m2 on days 1, 22 and 43,whichmust therefore remain the gold standard. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52 Cooper JS, PajakTF, ForastiereAA, Jacobs J, Campbell BH, Saxman SB et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44
- 56. This remains a controversial issue. In the largest series to date, no patient developed a metachronous primary in the follow-up period, and so would have experienced only toxicity rather than benefit from TMI. Some groups have recommended bilateral neck and TMI for occult primary head and neck cancer patients, claiming improved local control, but no OS benefit. There is no conclusive evidence to support the routine use of TMI.
- 57. Frank SJ, Rosenthal DI, Petsuksiri J, Ang KK, MorrisonWH,Weber RS et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head and- neck primary site: M. D. Anderson cancer center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010;78:1005–10 MD Anderson group 5 year locoregional control of 94 per cent OS of 89 per cent. Four centres have reported their experience of using IMRT to deliver TMI for unknown primaries, with excellent two-year locoregional control (85–88 per cent) and OS (74–85 per cent).
- 58. The chemotherapy regimen used is at the discretion of the treating clinician, but will usually be platinum-based, single-agent cisplatin or carboplatin or cetuximab in patients with suboptimal renal function
- 59. While the meta-analysis of chemotherapy in head and neck cancer (MACHNC) failed to demonstrate a significant benefit for the use of induction chemotherapy, many of the historical trials included pre-dated the use of taxanes. Both the EORTC 24971 and TAX 323 studies and the TAX 324 trial found that the addition of docetaxel (T) to cisplatin (P) and 5-FU resulted in improved PFS, OS and response rate and yet lower associated toxicity. In the context of gross unresectable neck disease, it therefore seems reasonable to consider the use of such induction chemotherapy, particularly for patients with excellent performance status, as a cytoreductive measure prior to definitive concomitant chemoradiation, even for occult primary disease.
- 60. Adjuvant chemotherapy. There are no convincing data that chemotherapy given after radiation or surgery is of benefit in terms of either disease-free or OS for patients with detectable primaries. This approach cannot therefore be recommended for patients with occult primary head and neck cancer.
- 61. • Platinum based chemotheraptic agents are used. • Cisplatin at 100 mg/m2, and 5-fluorouracil(5- FU) at 400 mg/m2. • Chemoradiation conducted with high-dose cisplatin at 100 mg/m2 once per three weeks during the period of radiotherapy HungYH, Liu SA, Wang CC, Wang CP, Jiang RS, Wu SH.Treatment outcomes of unknown primary squamous cell carcinoma of the head and neck. PloS one. 2018;13(10). Chemotherapy regimen
- 62. 1)Stage N1/N2-N3 2) Level of LN I/II-III-upper V/IV/lower level V 3)Presence of extracapsular extension If present chemotherapy to be added
- 67. By using IMRT the degree of toxicity can be reduced compared with conventional methods. High OS, DFS, and nodal control can be achieved for patients with T0N1 or T0N2a disease without extracapsular spread. Patients with extracapsular spread or bulky T0N2b–c or T0N3 disease have a worse prognosis and may benefit from the addition of more cytotoxic chemotherapy,molecular targeted therapy, and/or accelerated radiation regimens. Kamal M, MohamedAS, Fuller CD, Sturgis EM, Johnson FM, MorrisonWH, GunnGB, Hutcheson KA, Phan J,Volpe S, Ng SP. Outcomes of patients diagnosed with carcinoma metastatic to the neck from an unknown primary source and treated with intensity‐modulated radiation therapy. Cancer. 2018 Apr 1;124(7):1415-27.
- 68. All patients presenting with confirmed cervical lymph node metastatic squamous cell carcinoma and no apparent primary site should undergo: ○ Positron emission tomography-computed tomography whole-body scan. (R) ○ Panendoscopy and directed biopsies. (R) ○ Bilateral tonsillectomy. (R) Tongue base mucosectomy can be offered if facilities and expertise exists. (G)
- 69. Concomitant chemotherapy with radiation should be considered in patients with an unknown primary. (R) Concomitant chemotherapy with radiation should be offered to suitable patients in the post-operative setting, where indicated. Neo-adjuvant chemotherapy can be used in gross ‘unresectable’ disease. (R) Patients should be followed up at least two months in the first two years and three to six months in the subsequent years. (G) Patients should be followed up to a minimum of five years with a prolonged follow up for selected patients. (G) Positron emission tomography–computed tomography scan at three to four months after treatment is a useful follow-up strategy for patients treated by chemoradiation therapy. (R)
- 70. Thank you