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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 30-34

Carcinoma of unknown primary with N1 neck node: A case-specific short review

1 Department of Radiation Oncology, Patel Hospital, Jalandhar, Punjab, India
2 Department of Head and Neck and Microvascular Reconstructive Surgery, Patel Hospital, Jalandhar, Punjab, India

Date of Submission10-Apr-2021
Date of Acceptance18-May-2021
Date of Web Publication31-Jul-2021

Correspondence Address:
Dr. Sajal Goel
Department of Radiation Oncology, Patel Hospital, Behind Skylark Hotel, Civil Lines, Jalandhar 144001, Punjab.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_4_21

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Carcinoma of unknown primary (CUP) with N1 neck node is rare, and management of patients generates interest as well as poses challenges. It can also be a topic of debate between radiation oncologists and surgeons. Both radiation and surgery can be used for management, but in some cases, treatment can be multimodality especially if the surgeon is unsure of the microscopic disease, a small ulcer, or a node with microscopic extracapsular extension. We hereby discuss and review an interesting case on CUP with a N1 neck node that was managed using multimodality treatment.

Keywords: Carcinoma of unknown primary, multimodality management, NI neck node

How to cite this article:
Goel S, Aggarwal A, Chawla S, Alekchander C, Chopra S, Kumar B. Carcinoma of unknown primary with N1 neck node: A case-specific short review. J Curr Oncol 2021;4:30-4

How to cite this URL:
Goel S, Aggarwal A, Chawla S, Alekchander C, Chopra S, Kumar B. Carcinoma of unknown primary with N1 neck node: A case-specific short review. J Curr Oncol [serial online] 2021 [cited 2022 Nov 30];4:30-4. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2021/4/1/30/322894

  Key Messages: Top

Carcinoma of unknown primary with N1 node may need multimodality management in exceptional cases if surgeon is unsure of microscopic disease, a small ulcer, or a node with microscopic extracapsular extension.

  Introduction Top

Carcinoma of unknown primary (CUP) represents a heterogeneous group of malignancies presenting with lymph node or distant metastases, for which diagnostic work-up fails to identify the site of origin.[1] CUP accounts for 5-10% of all tumors, and as a result of recent improvement in imaging procedures, its number is decreasing.[1],[2],[3] The overall age-standardized incidence is 4–19 cases per lakh persons per year.[4] The incidence of advanced nodal disease (cN2/N3) is more common than that of clinical N1 disease.[5] Very few patients of CUP develop primary tumor later in life. Hence, prospective data are sparse.

  Case History Top

A 60-year-old male, chronic smoker was evaluated for complaints of lump in the right side of the neck of 2 months duration. On local examination, a single level II lymph node of 2 × 2 cm size was palpable in the right submandibular region. Oral cavity, nose, endo-larynx and bilateral ears were normal. Fine needle aspiration cytology from the swelling revealed metastatic carcinomatous deposits, possibly squamous cell carcinoma (SCC). CT scan face and neck done outside showed multiple lymph nodes in the right submandibular region with the largest one of size 17 × 15 mm. Panendoscopy revealed no abnormality in nasopharynx, oropharynx, supraglottis, glottis, hypopharynx, bilateral pyriform fossae, esophagus, and bilateral bronchi till third to fourth generations. Whole body PET-CT scan [Figure 1] showed few enlarged right level II lymph nodes with increased fluorodeoxyglucose (FDG) uptake, largest measuring approximately 18 × 15 mm (SUV max 8.85). Few small level II and V lymph nodes were noted in the left side of the neck with no significant FDG uptake (SUV max 2.91). No other FDG avid lesion was seen in rest of the body to suggest mitotic pathology. He underwent diagnostic transoral robot-assisted base of tongue mucosectomy along with bilateral tonsillectomy and right-sided neck dissection of level I–V lymph nodes. Histopathological examination [Figure 2] revealed 27 lymph nodes (level Ib 0/2, level II 1/4, level III 0/5, level IV 0/1, level Va 0/12, level Vb 0/3), and one of them had deposits of SCC. Extranodal extension was not identified. Size of the positive node was 2.5 cm. One lymph node that recovered from level Ia was free of tumor. Bilateral tonsils showed chronic tonsillitis. Immunohistochemistry (IHC) [Figure 3]A–D was reported as metastatic SCC with positivity for CK5/6 (EP 24/EP 67) and P40 (polyclonal) and negativity for Epstein–Barr virus (EBV) (CS 1–4) and p16 (G175–405). He was finally staged as CUP pT0 pN1 cM0. He was referred to us for adjuvant treatment.
Figure 1: An axial PET-CT image showing enlarged right level II lymph nodes with an increased FDG uptake (SUV max 8.85) (courtesy: Dr Rajesh Sachdeva, Department of Nuclear Medicine, Patel Hospital)

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Figure 2: Section examined shows nodal parenchyma infiltrated by sheets and strips of moderately differentiated squamous cell carcinoma (courtesy: Dr Mayurakshi Das and Dr Lata Kini, Core Diagnostics)

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Figure 3: A. CK5/6 (EP 24/EP 67)-positive (courtesy: Dr Mayurakshi Das and Dr Lata Kini, Core Diagnostics). B. P40 (polyclonal)-positive (courtesy: Dr Mayurakshi Das and Dr Lata Kini, Core Diagnostics). C. EBV (CS-1–4)-negative (courtesy: Dr Mayurakshi Das and Dr Lata Kini, Core Diagnostics). D. P16 (G175-405)-positive (courtesy: Dr Mayurakshi Das and Dr Lata Kini, Core Diagnostics)

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After discussion in the tumor board, the patient was planned for external beam radiation by image-guided radiotherapy (IGRT) technique on TrueBeam Linear Accelerator. He was prescribed a dose of 60 Gy in 30 fractions at the rate of 2 Gy per fraction to high-risk planning target volume (HRPTV), i.e., ipsilateral neck, and 54 Gy in 27 fractions at the rate of 2 Gy per fraction to low-risk planning target volume (LRPTV) (contralateral neck and naso-oropharyngeal mucosa) [Figure 4]. The dose achieved by various targets and organs at risk is shown in [Table 1]. During the treatment, the patient developed grade II-III mucositis and grade I-II dermatitis. He underwent nasogastric tube insertion for difficulty in swallowing. Overall, the radiation treatment was completed in 43 days. Thereafter, he remained on close follow-up and was found to have treatment-induced changes in the local area. The patient had spent 18 months after treatment and he is clinically and radiologically normal.
Figure 4: Dose wash of the area radiated by IGRT [red: PTV 60, orange: PTV 54, green: larynx, blue: dysphagia and aspiration-related structures (DARS), dark purple: spinal cord, purple: oral cavity oropharynx (OCOP)]

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Table 1: Doses prescribed and achieved by targets and organs at risk

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  Discussion Top

Of the total 154 head and neck cancer patients radiated at our center since 2018, only 5 patients had CUP that needed adjuvant radiation. Out of those five, only one had N1 disease. The median age at diagnosis is 60 years with a male predilection, as in this case.[6] The primary is mostly confined to head and neck in cases presenting with upper and/or middle cervical lymph nodes and presumably in lung in patients with lower cervical or supraclavicular lymph nodes involvement.[7] This patient presented with level II node, very likely from the head and neck region. This was the sole disease that was detected after best investigative workup. Detection of the EBV with the use of in situ hybridization in metastatic lymph nodes may suggest nasopharyngeal tumor.[8] Human papillomavirus detected by polymerase chain reaction may indicate oropharyngeal cancer.[9] The IHC tests for both viruses were negative in this case.

The nodal staging decides the course of management in CUP. Patients with N1 disease may need surgery followed by radiotherapy with or without chemotherapy.[7] Surgery is also the first treatment as per NCCN Guidelines.[10] This patient underwent neck dissection of level I-V lymph nodes. A neck dissection is often considered sufficient for patients with a single positive lymph node <3 cm unless there is extra-capsular spread of disease.[11] Alternately, radiation alone is sufficient for patients with N1 (up to 2 cm) disease as long as the fraction size (2 Gy) and the total dose are sufficient.[11] The size of the positive right level II node in this case was 2.5 cm. There was a debate in our tumor board as to whether adjuvant treatment is to be offered to this patient or not.

The surgeon believed that a microscopic disease, small ulcer, or microscopic extracapsular extension could be missed on diagnostic procedures at unknown sites in head and neck-like hypopharynx. After surgery, he wants to give local control to ipsilateral neck bearing the disease; pharyngeal mucosa that does not have visible disease and contralateral neck, which may be at the risk of recurrence. Now it was left to the wisdom of radiation oncologist whether radiation was to be delivered or not. If yes, then how much neck and mucosa was to be radiated.

The existing literature was extensively reviewed, and it was found insufficient in the light of rarity of disease and absence of randomized trials. Colletier et al.[12] recommended radiation to the neck and pharyngeal axis for patients suspected of having residual microscopic disease following surgery for squamous cell carcinoma metastatic to the neck from an unknown primary site. Radiation could be added for control of subclinical disease in the contralateral side of the neck.[11] Galloway and Ridge opined that routine bilateral neck radiation produces gratifying oncologic results. In today’s time, the disease mostly recurs distally.[5] With these ideas in mind, the patient was offered adjuvant radiotherapy.

The patient underwent immobilization in an Orfit cast and planning contrast CT scan with slice thickness 3 mm from air to mid-chest. However while contouring, the views between two radiation oncologists at the same center differed. The first wanted to radiate HRPTV I/L neck and pharyngeal mucosa as a single volume to a dose of 60 Gy/30 fractions and LRPTV C/L neck to a dose of 54 Gy/30 fractions. The pharyngeal mucosa included standard nasopharynx, oropharynx, hypopharynx, and larynx. The standard comprehensive radiotherapy portals used in this case would have been over-treatment and same as we treat N2/N3 disease.[13] However, larynx- and hypopharynx-sparing radiotherapy is feasible.[14],[15] Individualized reduction of PTVs can be done in IMRT treatment of cervical lymph nodes of CUP.[16] Patients have good treatment tolerance and local control.[16] The larynx and hypopharynx can often be omitted from the target volumes in view of high treatment-associated morbidity.[17] The second oncologist treated HRPTV I/L neck to a dose of 60 Gy/30 fractions and naso-oropharyngeal mucosa along with LRPTV C/L neck to a dose of 54 Gy/27 fractions. This was assumed to be specific to this case. This was interesting as hypopharynx that was believed to have microscopic disease was spared from radiation treatment.

The radiation toxicity data in CUP are sparse as most of the studies were retrospective. The plan evaluation for this case showed that doses to organs at risks like parotids were beyond limits with ipsilateral and contralateral receiving a mean dose of 44 and 35 Gy, respectively. Mandible received a maximum dose of slightly less than 63 Gy. This let us introspect whether we were giving unnecessary toxicity while over treating the case. However, the outcome of treatment that was offered was fairly good in terms of tolerance and overall survival.

It was further thought that the outcomes could be different if this case was treated with upfront concurrent chemoradiation. The addition of chemotherapy increased both acute and late radiation toxicities.[18] However, considering deintensification of treatment in N1 disease, concurrent chemoradiation did not appear to be a good option. Probably, more data needs to be generated to have concise answers to all those questions that we faced while treating this case.


The authors wish to acknowledge the efforts of Dr Rajesh Sachdeva, Dr Simarpreet Kaur, Mr Osho Sai, and Ms Rajwinder Kaur for their help in data collection. The authors also acknowledge Dr Ruchika Goel’s efforts in editing and reviewing the final version.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

ESMO Guidelines Task Force. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP). Ann Oncol 2001;12:1057-8.  Back to cited text no. 1
Daugaard G. Unknown primary tumours. Cancer Treat Rev 1994;20:119-47.  Back to cited text no. 2
Saghatchian M, Fizazi K, Borel C, Ducreux M, Ruffié P, Le Chevalier T, et al. Carcinoma of an unknown primary site: A chemotherapy strategy based on histological differentiation—Results of a prospective study. Ann Oncol 2001;12:535-40.  Back to cited text no. 3
Pavlidis N, Khaled H, Gaafar R. A mini review on cancer of unknown primary site: A clinical puzzle for the oncologists. J Adv Res 2015;6:375-82.  Back to cited text no. 4
Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site J Clin Oncol 2015;33:3328-37.  Back to cited text no. 5
Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012;379:1428-35.  Back to cited text no. 6
Rajeev LK, Asati V, Lokesh KN, Rudresh AH, Babu S, Jacob LA, et al. Cancer of unknown primary: Opportunities and challenges. Indian J Med Paediatr Oncol 2018;39:219-26.  Back to cited text no. 7
  [Full text]  
Lee WY, Hsiao JR, Jin YT, Tsai ST. Epstein–Barr virus detection in neck metastases by in-situ hybridization in fine-needle aspiration cytologic studies: An aid for differentiating the primary site. Head Neck 2000;22:336-40.  Back to cited text no. 8
Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709-20.  Back to cited text no. 9
National Comprehensive Cancer Network. Head and Neck Cancer (Version 2.2020). Available from: http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed October 2, 2020.  Back to cited text no. 10
Mendenhall WM, Million RR, Bova FJ. Analysis of time-dose factors in clinically positive neck nodes treated with irradiation alone in squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1984;10:639-43.  Back to cited text no. 11
Colletier PJ, Garden AS, Morrison WH, Goepfert H, Geara F, Kian Ang K. Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: Outcomes and patterns of failure. Head Neck 1998; 20: 674-81  Back to cited text no. 12
Reddy SP, Marks JE. Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: Results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys 1997;37:797-802.  Back to cited text no. 13
Wallace A, Richards GM, Harari PM, Kirwan JM, Morris CG, Katakam H, et al. Head and neck squamous cell carcinoma from an unknown primary site. Am J Otolaryngol 2011;32: 286-90.  Back to cited text no. 14
Barker CA, Morris CG, Mendenhall WM. Larynx-sparing radiotherapy for squamous cell carcinoma from an unknown head and neck primary site. Am J Clin Oncol 2005;28: 445-8.  Back to cited text no. 15
Janssen S, Glanzmann C, Huber G, Studer G. Individualized IMRT treatment approach for cervical lymph node metastases of unknown primary. Strahlenther Onkol 2014;190: 386-93.  Back to cited text no. 16
Amdur RJ, Li JG, Liu C, Hinerman RW, Mendenhall WM. Unnecessary laryngeal irradiation in the IMRT era. Head Neck 2004;26:257-63; discussion 263-4.  Back to cited text no. 17
Chen AM, Farwell DG, Lau DH, Li BQ, Luu Q, Donald PJ. Radiation therapy in the management of head-and-neck cancer of unknown primary origin: How does the addition of concurrent chemotherapy affect the therapeutic ratio? Int J Radiat Oncol Biol Phys 2011;81:346-52.  Back to cited text no. 18


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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