STEP 3: Diagnosis, assessment and treatment planning

Step 3 outlines the process for confirming the diagnosis and planning subsequent treatment. The guiding principle is that interaction between appropriate MDT members should determine the treatment plan.

Diagnosis for CUP is continually evolving in all areas, including imaging, pathology and genetics. Every effort should be made to use current best practice evidence when confirming a diagnosis of CUP.

Optimal diagnostic workup should be quickly applied. It should aim to identify the primary tumours where possible. However, it is important that the risk of over-investigation is minimised in patients with poor performance status where exhaustive testing is unlikely to improve outcome. This needs to be balanced against the risk of missing treatable cancers.

Diagnostic workup for patients with metastatic disease should include all of the following investigations in order to confirm a diagnosis of CUP (adapted from Fizazi et al. 2015):

  • a thorough medical history and physical examination including breast exam and rectal exam where clinically appropriate
  • basic blood and biochemical analyses (full blood examination; LDH; electrolytes, urea, creatinine; liver function tests) – it is not of proven value to order tumour markers indiscriminately in the work-up of CUP; however, specific tumour markers may be of value depending on the clinical presentation
  • contrast-enhanced CT scans of thorax, abdomen and pelvis
  • adequate tissue sample from one site of disease for histopathology and IHC.

Additional investigations for identified CUP subsets:

  • female patients –> mammography
  • females with axillary adenocarcinoma without a breast primary on mammogram or breast ultrasound –> breast magnetic resonance imaging (MRI)
  • people with midline metastatic disease –> serum α-fetoprotein and human chorionic gonadotropin
  • signs and symptoms or laboratory abnormalities suggestive of a gastrointestinal primary –> endoscopies, carcinoembryonic antigen and CA19.9
  • neuroendocrine tumours –> dotatate gallium / positron emission tomography (PET) scan and plasma chromogranin A
  • squamous cell carcinoma restricted to neck nodes –> head and neck PET/CT scan, fibre optic nasendoscopy
  • men with bone metastases –> serum PSA
  • based on signs and symptoms or laboratory abnormalities –> additional diagnostic pathology such as specific tumour markers as directed by the clinical pattern of disease.

Note: The role of PET/CT in extracervical CUP is controversial. The literature suggests that a primary may be identified in 30–40 per cent of patients, but the impact on patient outcomes with the routine use of PET in CUP cases is unclear (Burglin et al. 2017), and there is currently no specific Medicare rebate available for PET/CT in CUP. However, the use of PET/CT may be appropriate in patients with apparent localised CUP who are being considered for treatment with curative intent.

In patients with a significant family or personal history of cancer (see eviQ guidelines), consideration should be given to referral for genetic testing.

Biopsy material should be examined by an anatomical pathologist with expertise in this area, and may require referral for a second opinion. The use of specific IHC panels is promising in assigning a likely primary site of origin (Park et al. 2007). The choice of which IHC stains or ancillary pathology investigations to perform is highly dependent on the clinical setting, the morphology of the malignant cells and the available material in biopsy specimens. Therefore, no one set of IHC stains or ancillary tests is appropriate for all patients. The 20 cytokeratin (CK) subtypes are typically expressed in carcinomas. A CK7 plus CK20 staining pattern may lead to additional IHC staining and specific clinical tests, so these should be considered for all CUPs (Losa et al. 2018).

Important principles to consider in selecting the appropriate ancillary testing to perform on tissue include the following:

  • Tissue biopsy is usually better than FNA because it provides more tissue for ancillary testing, including IHC.
  • It is important to identify highly treatable non-epithelial malignancies such as lymphoma, melanoma and germ cell tumour.
  • The need to optimally classify CUP with extensive ancillary testing that may exhaust tissue needs to be balanced against the limited tissue available; therefore, some testing may need to be triaged.

Examples where ancillary molecular testing may be appropriate include in patients where there is a strong clinical suspicion of a specific tumour type, where standard molecular profiling to look for actionable genomic abnormalities for that tumour type should occur. For example, patients with TTF-1 adenocarcinoma thought most likely to be lung cancer (even in the absence of an identifiable lung primary) should have testing for epidermal growth factor receptor mutations and, if this is negative, anaplastic lymphoma kinase re-arrangements.

The optimal role of molecular profiling tests to determine the tissue of origin is the subject of ongoing research. Existing guidelines do not recommend the use of gene-expression-based profiling to identify primary tumours. However, where this is available via CUP research projects, it may be helpful.

The use of gene panel DNA sequencing to identify actionable mutations is still under investigation. It appears that, in a minority of patients, potentially actionable mutations may be found (Gatalica et al. 2014, Ross et al. 2015, Tothill et al. 2013, Varghese et al. 2017). In addition, other findings such as mutational signatures indicating tobacco or UV exposure may assist in diagnosing the primary site (Tothill et al. 2013, Varghese et al. 2017). The use of immunotherapy may be effective in some patients, especially those with high tumour mutation burden (Gröschel et al. 2016). Panel testing may also identify germline risk alleles. There is currently a lack of evidence as to whether patients receiving this panel testing have an outcome benefit. However, where this is available via CUP research projects, it may be helpful.

Timeframe for obtaining a diagnosis

Timeframes for diagnosis should be informed by evidence-based guidelines (where they exist) while recognising that shorter timelines for appropriate consultations and treatment can reduce patient distress.

Investigations should be completed within two weeks.

People with CUP have a malignancy that has already spread; therefore, by definition it is a metastatic cancer. There is no definite staging classification used for patients with CUP; however, disease can be classified as localised or disseminated disease.

CUP is a very heterogeneous disease. There is a specific CUP subset of patients who have a pattern of disease similar to known cancers types that may respond well to standard disease-specific treatment. The remaining patients are considered within the non-specific subset of CUP, with their prognosis and suitability for treatment dependent on their ECOG performance status and LDH level.

Between 2010 and 2014, people with CUP had a 14 per cent chance of surviving for five years when compared with the age- and sex-matched general Australian population (AIHW 2018).

Patients in the specific-CUP subset should be discussed at the MDT meetings of the tumour stream most closely related to the person’s CUP.

Patients who appear to fall into a non-specific CUP subset should be referred to a CUP-specific oncology service or else to the general medical oncology service, which can then triage them into the most appropriate clinic for ongoing care depending on the jurisdiction. Since most centres do not have a specific CUP clinic this may include the patient being seen in a general oncology clinic or a disease-specific clinic depending on the presentation and suspected diagnosis.

The complex nature of CUP, along with the advantages gained from multidisciplinary collaboration in this situation, argue strongly for establishing dedicated MDT services for this group, even if convened via tele- or video-conferencing. However, where CUP MDTs do not exist, an MDT with members who have expertise in managing CUP should discuss the patient.

The responsibilities of the MDT are to:

  • nominate a team member to coordinate patient care and identify this person to the patient
  • nominate a team member to be the lead clinician (the lead clinician may change over time depending on the stage of the care pathway and where care is being provided) and identify this person to the patient (if different from the care coordinator)
  • develop and document an agreed treatment plan at the MDT meeting
  • communicate/circulate the agreed MDT treatment plan to relevant team members, including the patient’s GP.

The general or primary medical practitioner who made the referral is responsible for the patient until care is passed to another practitioner.

The general or primary medical practitioner may play a number of roles in all stages of the cancer pathway including diagnosis, referral, treatment and coordination and continuity of care as well as providing information and support to the patient and their family.

The care coordinator is responsible for ensuring there is continuity throughout the care process and for coordinating all necessary care for a particular phase. The care coordinator may change over the course of the pathway.

The lead clinician is responsible for overseeing the activity of the team.

The MDT should comprise the core disciplines that are integral to providing good care. Team membership will vary according to cancer type but should reflect both clinical and psychosocial aspects of care. Additional expertise or specialist services may be required for some patients (Department of Health 2007a).

Team members may include a:

  • care coordinator (as determined by MDT members)*
  • medical oncologist*
  • pathologist*
  • radiologist*
  • surgeon*
  • nurse (with appropriate expertise)*
  • radiation oncologist*
  • social worker*
  • clinical trials coordinator
  • dietitian
  • GP
  • psychologist
  • nuclear medicine physician
  • occupational therapist
  • specialist palliative care team member(s)
  • pharmacist
  • physiotherapist
  • psychiatrist
  • rehabilitation physician
  • speech therapist.

* Core members of the MDT are expected to attend most MDT meetings either in person or remotely.

Treatment options for all newly diagnosed patients should be discussed in an MDT meeting before beginning treatment. The level of discussion may vary depending on both the clinical and psychosocial factors.

There may also need to be a review of existing treatment plans for patients who have been discussed previously.

Results of all relevant tests and imaging should be available for the MDT discussion. The care coordinator or treating clinician should also present information about the patient’s concerns, preferences and social circumstances at the meeting (Department of Health 2007a).

Participation in research and/or clinical trials should be encouraged where available and appropriate.

  • Australian Cancer Trials is a national clinical trials database. It provides information on the latest clinical trials in cancer care, including trials that are recruiting new participants. For more information visit the Australian Cancer Trials website.

Cancer prehabilitation uses a multidisciplinary approach combining exercise, nutrition and psychological strategies to prepare patients for the challenges of cancer treatment such as chemotherapy, immunotherapy and radiation therapy.

Evidence indicates that prehabilitation of newly diagnosed cancer patients prior to starting treatment can be beneficial. This may include conducting a physical and psychological assessment to establish a baseline function level, identifying impairments and providing targeted interventions to improve the patient’s health, thereby reducing the incidence and severity of current and future impairments related to cancer and its treatment (Silver & Baima 2013).

Medications should be reviewed at this point to ensure optimisation and to improve adherence to medicines used for comorbid conditions.

Where appropriate, fertility issues should be reviewed with the patient.

Screening with a validated screening tool (such as the National Comprehensive Cancer Network Distress Thermometer and Problem Checklist), assessment and referral to appropriate health professionals or organisations is required to meet the identified needs of the patient, their carer(s) and family.

In addition to the other common issues outlined in the Appendix, specific needs that may arise at this time include the following:


  • Fatigue/change in functional abilities is a common symptom, and patients may benefit from referral to occupational therapy.


  • Many patients with CUP find the uncertainty surrounding their disease and the limited treatment options difficult and would welcome the opportunity to ask questions and learn about others’ experiences (Boyland & Davis 2008).
  • Many patients with CUP and their clinicians have a poor understanding of their illness, difficulty in explaining their illness to others, and a sense of frustration in health professionals not having the answers (Boyland & Davis 2008, Karapetis et al. 2017).
  • Depressive symptoms are higher in people with CUP when compared with people with cancer of a known origin, so they require more psychosocial support and specific interventions (Hyphantis et al. 2013).
  • Information about genomic profiling available via CUP research projects should be provided to patients.
  • GPs play an important role in coordinating care for patients, including assisting with side effects and offering support when questions or worries arise. For most patients, simultaneous care provided by their GP is very important (Lang et al. 2017).
  • Patients may require help with psychological and emotional distress while adjusting to the diagnosis, treatment phobias, existential concerns, stress, difficulties making treatment decisions, anxiety/depression, loss of previous life roles including driving, and interpersonal problems.


  • Patients may need support to attend appointments.
  • Patients may need guidance about financial and employment issues (such as loss of income and having to deal with travel and accommodation requirements for rural patients and caring arrangements for other family members).


  • Patients with CUP will most likely undergo extensive testing, and support and information should be provided to assist with any distress while undergoing these tests (Wagland et al. 2017).
  • CUP patients are more likely to want more written information about their type of cancer and tests received but less likely to understand explanations of their condition (Wagland et al. 2017).
  • Patients from culturally and linguistically diverse backgrounds may need information provided in other formats.
  • Patients may need advice about safe driving.

Spiritual needs

  • Lead clinicians should have access to suitably qualified, authorised and appointed spiritual caregivers who can act as a resource for patients, carers and staff.
  • Patients and their families should have access to spiritual support appropriate to their needs throughout the cancer journey.

The lead clinician should:

  • ensure the patient understands that they have been diagnosed with CUP and that they understand the ramifications of this diagnosis
  • assist the patient in explaining their diagnosis to their family; audio recordings may be a helpful resource for patients (Pitkethly et al. 2008)
  • establish if the patient has a regular or preferred GP
  • discuss a timeframe for diagnosis and treatment with the patient and carer
  • discuss the benefits of multidisciplinary care and make the patient aware that their health information will be available to the team for discussion at the MDT meeting
  • offer individualised CUP information that meets the needs of the patient and carer (this may involve advice from health professionals as well as written and visual resources)
  • offer advice on how to access information and support from websites, community and national cancer services and support groups for both patients and carers
  • use a professionally trained interpreter to communicate with people from culturally or linguistically diverse backgrounds.

The lead clinician should:

  • ensure regular and timely (within a week) communication with the person’s GP regarding the treatment plan and recommendations from MDT meetings
  • notify the GP and family/carer if the person does not attend clinic appointments
  • gather information from the GP including their perspective on the person (psychological issues, social issues and comorbidities) and locally available support services
  • ask the person’s GP to contribute to developing a chronic disease and mental healthcare plan as required
  • discuss management of shared care with the person’s GP
  • invite the GP to participate in MDT meetings (consider using video or teleconferencing).