Oncology - Metastasis of unknown origin in neck

metastasis of unknown origin - neck

1. MUO NECK PRESENTER : DR. PANKAJ SHARMA MODERATOR: DR . ANERI MAM 1

2. 2

3. It accounts for 5-10% of cancers of head and neck Squamous cell carcinoma (SCC) of unknown primary accounts for 75%-90% of these cases True CUP 1-2 % of head neck cancers Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol. 2003 3

4. Important to know anatomic levels of neck, as well as primary sites draining to different levels. Cervical lymphadenopathy of unknown primary is most commonly seen at level 2, followed by level 3. Kinder et al PET Clin 2 • L 7 ess common for level 4

5. 5

6. 9 Points to be covered… Panendoscopy Role of PET , PET CT, CT/MRI Role of FNAC / biopsy IHC Role of tonsillectomies Role of TORS ( transoral robotic surgery) Role of surgery Role of RT/CTRT

7. 10 Role of panendoscopy… Panendoscopy with directed biopsies detected the primary site in 31%. sensitivity of PET/CT alone in detecting the primary site in HNSCC- UP is 73.1% (NPV 68.9%) Undetectable primary sites on PET CT identified by pan endoscopy.

8. Surgical panendoscopy is important workup in PET undetected unknown primaries If panendoscopy does not reveal any lesion, site directed biopsies of common sites should be obtained. Combination of Panendoscopy and Positron Emission Tomography/ Computed Tomography Increases Detection of Unknown Primary Head and Neck Carcinoma, the laryngoscope 2018 11

9. Role of PET Scan in CUP with SCC of neck PET detects 25 % more of primaries than cases in which PET was not done. PET detected additional met sites in 27 % cases. Disadvantage: cant detect lesions <8mm, waldeyar ring acute or chronic inflammation – false results ( 38% for PET , 39% for PET CT) DAHANCA 13 study : Head & Neck , 2008 ; 30 : 471 Rudmik L : Head & Neck 2011; 33 : 935 12

10. 13 PET after biopsy can contribute to false positives – thus timing of the PET prior to biopsy is important. PET- CT plus panendoscopy with directed biopsies with or without tonsillectomy allowed diagnosis in 59.6% of patients.

11. PET CT SCAN versus MRI/CT scan Prospective trial showing that PET- CT had sensitivity of 69% in detection the primary tumour versus contrast enhanced CT (16%) and contrast enhanced CT/MRI (41%) PET- CT detected the primary in 50% of false negative CT/MRI Kee et al Radiology 2015 14

12. 15 FNAC versus Biopsy FNAC is least invasive of options. USG guided FNAC preferable. Must prepare cell block so that IHC can be done if necessary. Core needle biopsy will provide greater tissue. Open biopsy only if necessary, avoid if possible. Incision must be planned taking into consideration future need for neck dissection.

13. Role of IHC Allow the differentiation of poorly differentiated tumours and greater diagnosis of squamous and adenocarcinomas. Chernock R, Lewis J Head Neck Pathol 2015 16

14. Cytokeratins in diagnosis 17

15. HPV & EBV Majority primary tumors that are identified are located in oropharynx ( tonsil 43% and tongue base 39%) More than 70% of oropharyngeal carcinoma is HPV positive. EBV genome sequence by PCR : nasopharyngeal carcinoma. 18

16. 19

17. Role of tonsillectomy… Occult primary mucosal lesions can be identified in a tonsillectomy specimen in upto 25- 30% of cases in ipsilateral tonsil. Mandenhall wm, SCC metastatic to the neck from an unknown head & neck primary site, Am J Otolaryngol.2001 Koch et al. demonstrated 10% tonsil SCC had contralateral metastases, advocating bilateral 20

18. Tonsillectomies …. In the absence of a visible or palpable lesion, a palatine tonsillectomy may improve the diagnostic yield compared to deep tonsil biopsies. 80–90 % of occult primary tumors are eventually localized in the palatine tonsil and tongue base, palatine and lingual tonsillectomies are important to the diagnostic workup of an unknown primary Adds little morbidity and eliminates uptake in post surveillance imaging : -mistaken for recurrence. Fu et al. Journal of Otolaryngology - Head and Neck Surgery (2016) 21

19. Role of Transoral Robotic Surgery in Head & Neck CUP ? 22

20. Role of TORS May identify a primary in tonsil during lingual tonsillectomy. Mehta et al : 10 cases of CUP with neck nodes after PET/pan endoscopy/ pallatine tonsillectomy underwent TORS with lingual tonsillectomy. Primary found in 9/10 cases after TORS in lingual tonsils. Laryngoscope. 2013; 123: 146 - 151 23

21. Laryngoscope. 2013; 123: 146 - 151 24

22. Head & Neck 2014; 36 25

23. TORS and primary site identification 26 JAMA Laryngol Head & Neck . 2013; 139:

24. TORS and primary site identification Tumor site identified in 34 of 47 pts ( 72 % ): Base of tongue – 20 ( 58 % ) Pallatine tonsils – 13 ( 38 % ) In 18 out of 47 pts ( 38 % ) ,preop radiology and physical examination did not identify the primary. - in 13 of these 18 pts ( 72 % ) , primary could be identified. JAMA Laryngol Head & Neck . 2013; 139: 1203 27

25. Caris MI: a multiplatform test 30

26. HPV +ve SCC with UNKNOWN PRIMARY NECK .

27. Principles of treatment of CUP with neck nodes 31

28. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion a H&P should include documentation and quantification (pack years smoked) of tobacco use history, as well as alcohol use and counseling. All patients who currently smoke should be advised to quit smoking, and those who formerly smoked should be advised to remain abstinent from smoking. For additional cessation support, refer to the Smoking Cessation and Treatment Resources in the NCCN Guidelines for Smoking Cessation . b Screen for depression ( NCCN Guidelines for Distress Management ) . c Repeat FNA, core, or open biopsy may be necessary for uncertain or non- diagnostic histologies. Patient should be prepared for neck dissection at time of open biopsy, if indicated. d Determined with appropriate immunohistochemical stains. PRESENTATION PATHOLOGY WORKUP Neck mass H&P a,b Complete head and neck exam with attention to skin; palpation of the oropharynx; mirror and fiberoptic examination as clinically indicated to examine nasopharynx, oro pharynx, hypopha rynx, and larynx FNA c Squamous cell carcinoma, adenocarcinoma, and anaplastic/ undifferentiated epithelial tumors d Lymphoma Thyroid Melanoma CT with contrast or MRI with and without contrast (skull base through thoracic inlet) e FDG-PET/CT as indicated (before EUA) e Chest CT with contrast (if PET/CT not done) e HPV, EBV testing for squamous cell or undifferentiated histology f,g Thyroglobulin, calcitonin, PAX8, and/or thyroid transcription factor (TTF) staining for a denocarcinoma and anaplastic/ undifferent iated tumors As clinically indicated:  Dental evaluation h  Nutrition, speech and swallowing evaluation/therapy i  Smoking cessation counseling a  Fertility/reproductive counseling j  Screening for hepatitis B NCCN Guidelines for B-Cell Lymphomas and NCCN Guidelines for T- Cell Lymphomas NCCN Guidelines for Thyroid Carcinoma Workup and treatment per NCCN Guidelines for Melanoma: Cutaneous Skin exam, note regressing lesions Workup for Mucosal Melanoma (MM- 1) Primary Therapy for Mucosal Melanoma (MM- 4) Primary found T0 and p16 (HPV)- positive T0 and EBV+ or EBER+ Treat as oropharyngeal cancer (ORPH- 1) Treat as nasopharyngeal cancer (NASO- 1) Treat as appropriate (NCCN Guidelines Index) Workup and Treatment (OCC- 2) Primary not found k e Principles of Imaging (IMG- A) . f Whether HPV or EBV positive status may help to define the radiation fields is being investigated [see Principles of Radiation Therapy (OCC-A) and Discussion ]. g p16+ unknown primary disease should only be considered HPV- positive with HPV- specific testing. h Principles of Oral/Dental Evaluation and Management (DENT- A) . i Principles of Nutrition: Management and Supportive Care (NUTR- A) . j See fertility and reproductive endocrine considerations in the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology . k Strongly consider referral to a high-volume, multidisciplinary cancer center. Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved. Note: All recommendations are category 2A unless otherwise indicated. OCC- 1 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

29. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion l Image-guided (US or CT) needle biopsy of cystic neck nodes may offer better diagnostic yield than FNA by palpation alone for initial diagnosis in this setting. For unresectable or metastatic disease where there is a plan for systemic therapy, a core biopsy would allow for ancillary immune-genomic testing. m Principles of Imaging (IMG- A) . PATHOLOGIC FINDINGS WORKUP DEFINITIVE TREATMENT Node level I, II, III, upper V Node level IV, lower V EUA Palpation and inspection Biopsy l of areas of clinical concern and tonsillectomy ± lingual tonsillectomy Direct laryngoscopy and nasopharynx survey EUA including direct laryngoscopy, esophagoscopy, bronchoscopy Chest/abdomen/ pelvis CT with contrast (or FDG-PET/CT if not previously performed) m Primary found Treat as appropriate (NCCN Guidelines Index) Adenocarcinoma of neck node, thyroglobulin negative, calcitonin negative Poorly differentiated or nonkeratinizin g squamous cell or Not otherwise specified (NOS) or Anaplastic (not thyroid) of neck node or Squamous cell carcinoma of neck node n Definitive Treatment (OCC- 3) Levels I–III Levels IV, V Neck dissection + parotidectomy, if indicated o Evaluate for infraclavicular primary RT p to neck ± parotid bed Neck dissection, o if indicated ± adjuvant treatment if indicated ( OCC- 4 ) Follow- up ( FOLL-A, 1 of 2 ) Primary not found Post Systemic Therapy/RT or RT Neck Evaluation (FOLL-A, 2 of 2) M1 disease at initial presentation ADV- 2 Unresectable nodal disease or unfit for surgery ADV- 1 n HPV and EBV testing are suggested if not yet done. o Principles of Surgery (SURG- A) . p Principles of Radiation Therapy (OCC- A) . Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved. Note: All recommendations are category 2A unless otherwise indicated. OCC- 2 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

30. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion o Principles of Surgery (SURG- A) . p Principles of Radiation Therapy (OCC- A) . q Treatment for nasopharyngeal (NASO-2) and p16-positive oropharyngeal cancers ( ORPHPV-3 and ORPHPV-4 ) to guide management of EBV- positive and p16- positive occult primary tumors. r Principles of Systemic Therapy for Non-Nasopharyngeal Cancers (SYST- A) . HISTOLOGY DEFINITIVE TREATMENT q Poorly differentiated or nonkeratinizing squamous cell or NOS or anaplastic (not thyroid) or Squamous cell carcinoma q Neck dissection o or Concurrent systemic therapy/RT p,r (category 2B) or Induction chemotherapy r,s (category 3) followed by systemic therapy/RT p,r or RT p Neck dissection o or RT p (category 2B) OCC- 4 OCC- 4 Recurrent or persistent disease ( ADV- 3 ) Recurrent or persistent disease ( ADV- 3 ) N1 N2–3 Post Systemic Therapy/ RT or RT Neck Evaluation (FOLL-A, 2 of 2) Post Systemic Therapy/ RT or RT Neck Evaluation (FOLL-A, 2 of 2) Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved. s See Discussion on induction chemotherapy. Note: All recommendations are category 2A unless otherwise indicated. OCC- 3 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

31. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion f Whether HPV or EBV positive status may help to define the radiation fields is being investigated [see Principles of Radiation Therapy (OCC-A) and Discussion ]. q Treatment for nasopharyngeal (NASO-2) and p16-positive oropharyngeal cancers ( ORPHPV-3 and ORPHPV-4 ) to guide management of EBV- positive and p16- positive occult primary tumors. Post neck dissection N1 without extranodal extension RT (target volume determined by tumor size, nodal station, and HPV and EBV status) f,q or Observe TREATMENT N2,N3 without extranodal extension Extranodal extension f,r RT (target volume determined by tumor size, nodal station, and HPV and EBV status) f,q or Consider systemic therapy/RT (category 2B) Systemic therapy/RT f,r (category 1) or RT (target volume determined by tumor size, nodal station, and HPV and EBV status) f,q Follow- up ( FOLL-A, 1 of 2 ) Recurrent or persistent disease ( ADV- 3 ) Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved. r Principles of Systemic Therapy for Non-Nasopharyngeal Cancers (SYST- A) . Note: All recommendations are category 2A unless otherwise indicated. OCC- 4 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

32. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion IMRT (preferred) is recommended when targeting the pharyngeal axis to minimize the dose to critical structures. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy, or when photon-based therapy causes compromise of standard radiation dosing to tumor or postoperative volumes. a For squamous cell carcinoma, adenocarcinoma, and poorly differentiated carcinoma. b See Principles of Radiation Techniques (RAD-A) and Discussion . c For doses >70 Gy, some clinicians feel that the fractionation should be slightly modified (eg, <2.0 Gy/fraction for at least some of the treatment) to minimize toxicity. An additional 2–3 doses can be added depending on clinical circumstances. d Suggest 44–50 Gy in sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). e Principles of Systemic Therapy for Non-Nasopharyngeal Cancers (SYST- A) . f Based on published data, concurrent systemic therapy/RT most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m 2 ; 2–3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0129) (Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24-35). When carboplatin and 5-FU are used, the recommended regimen is standard fractionation plus 3 cycles of chemotherapy [Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 2012;13:145-153]. Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, or altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent systemic therapy/RT carries a high toxicity burden; multiagent chemotherapy will likely further increase the toxicity burden. For any systemic therapy/RT approach, close attention should be paid to published reports for the specific chemotherapy agent, dose, and schedule of administration. Systemic therapy/RT should be performed by an experienced DEFINITIVE : RT Alone PTV  High risk: Involved lymph nodes [this includes possible local subclinical infiltration at the high-risk level lymph node(s)] Fractionation: – 66 Gy (2.2 Gy/fraction) to 70 Gy (2.0 Gy/fraction); daily Monday–Friday in 6–7 weeks c – Mucosal dosing: 50–66 Gy (2.0 Gy/fraction) to putative mucosal sites, depending on field size. Consider higher dose to 60–66 Gy to particularly suspicious areas  Low to intermediate risk: Sites of suspected subclinical spread 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction) d PRINCIPLES OF RADIATION THERAPY a,b CONCURRENT SYSTEMIC THERAPY/RT : e,f PTV  High risk: Typically 70 Gy (2.0 Gy/fraction)  Mucosal dosing: 50–60 Gy (2.0 Gy/fraction) to putative mucosal primary sites, depending on field size and use of chemotherapy. Consider higher dose to 60–66 Gy to particularly suspicious areas  Low to intermediate risk: 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction) c Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved. team and should include substantial supportive care. Note: All recommendations are category 2A unless otherwise indicated. OCC- A 1 OF 2 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

33. NCCN Guidelines Version 5.2025 Occult Primary NCCN Guidelines Index Table of Contents Discussion Oncol 2020;38:2570- 2596. Note: All recommendations are category 2A unless otherwise indicated. OCC- A 2 OF 2 Version 5.2025, 08/12/2025 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN. a For squamous cell carcinoma, adenocarcinoma, and poorly differentiated carcinoma. b See Principles of Radiation Techniques (RAD-A) and Discussion . d Suggest 44–50 Gy in sequentially planned IMRT or 54–63 Gy with IMRT dose painting technique (dependent on dose per fraction). e Principles of Systemic Therapy for Non-Nasopharyngeal Cancers (SYST- A) . 1 Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945- 1952. 2 Cooper JS, Pajak TF, Forastiere AA, 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- 1944. 3 Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843- 850. 4 Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198- 1205. 5 Maghami E, Ismaila N, Alvarez A, et al. Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO Guideline. J Clin PRINCIPLES OF RADIATION THERAPY a,b POSTOPERATIVE : RT or Concurrent Systemic Therapy/RT e,1- 4 Preferred interval between resection and postoperative RT is ≤6 weeks PTV  High risk: Adverse pathologic features such as extranodal extension ( OCC- 4 ) Mucosal dose: 50–66 Gy (2.0 Gy/fraction) to putative mucosal sites, depending on field size has historically been used. 5 Consider higher dose to 60–66 Gy to particularly suspicious areas  Low to intermediate risk: Sites of suspected subclinical spread 44–50 Gy (2.0 Gy/fraction) to 54–63 Gy (1.6–1.8 Gy/fraction) d IMRT (preferred) is recommended when targeting the pharyngeal axis to minimize the dose to critical structures. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy, or when photon-based therapy causes compromise of standard radiation dosing to tumor or postoperative volumes. Printed by Pankaj Sharma on 17/08/2025 12:46:45 pm. For personal use only. Not approved for distribution. Copyright 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.

34. 37

35. 38 Role of Surgery in H & N CUP N1 disease without extracap spread: Single modality : RT or Surgery alone For high volume N2a : Post op RT For extracapsular extension : CTRT. For N2b or higher : concurrent CT + RT

36. 39 Post op Radiotherapy

37. 43

38. ASCO GUIDELINES

39. 76 THANK YOU…