Carcinoma of unknown primary (CUP) accounts for 3-5% of all cancers. It is defined as a biopsy-proven malignancy without an identified primary site despite extensive evaluation. The median overall survival is typically 9 months. However, certain favorable subsets have been identified including women with peritoneal carcinomatosis or axillary lymph node metastases, men with skeletal metastases and elevated PSA, and extragonadal germ cell tumor syndrome patients. Molecular tumor profiling and next-generation sequencing can help identify targets for personalized treatment. While most CUP patients receive empirical platinum-based chemotherapy, evolving treatment options include targeted therapies, immunotherapy, and stereotactic radiotherapy for limited metastases. Identifying the primary site

1. CARCINOMA OF UNKNOWN
PRIMARY
Presenter: Dr Mohammad Masoom
Parwez
M.Ch Resident
Department of Surgical Oncology

2. OUTLINE
• Epidemiology
• Clinical Features
• Clinical / Pathologic Evaluation
• Gene Expression / Molecular Tumor Profiling
• Favourable subsets
• Chemotherapy
• Role of Radiation
• Evolving Treatment options
• Prognosis
• Future prospects
2

3. DEFINITION
Biopsy-proven malignancy without an identified
primary site of origin despite a comprehensive
evaluation (history, physical examination, imaging and
laboratory studies, and thorough histologic evaluation)
3

4. EPIDEMIOLOGY
• Heterogeneous group of malignancies with diverse biology
• 3 – 5% of all cancers
• Fourth most common cause of cancer related deaths
• Seventh most frequent malignancy
• 75% of tumors originate below the diaphragm
• Average age at onset is 60 years
• Potentially responsive to systemic treatment - 20% cases
• Primary site is found in 10-20% cases during lifetime, 50-75% at autopsy
• Poor prognosis
• Median OS is 9 months
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7. 7
Finding at autopsy

8. CLINICAL FEATURES
Multiple sites are involved in more than 50% of patients
 Pain (60%)
 Liver mass or other abdominal manifestations (40%)
 Lymphadenopathy (20%)
 Bone pain or pathologic fracture (15%)
 Respiratory symptoms (15%)
 Central nervous system abnormalities (5%)
 Weight loss (5%)
 Skin nodules (2%)
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10. MECHANISMS
• Excision or electrocautery may have removed unrecognized primary lesions
years before the appearance of metastatic lesions
• The primary cancer may have shed metastases and then undergone
spontaneous regression
• The primary tumor may be too small to be detected, even at autopsy
• The site of origin may be obscured by the extensiveness of metastases or by
the atypical pattern of dissemination
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12. CLINICAL EVALUATION

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16. PATHOLOGIC EVALUATION
16
CARCINOMA
• Pan-cytokeratin
• CK 7/20 : AdenoCA
• CK 5/6 , P63+ : SCC
LYMPHOMA
• CD 45
MELANOMA
• S 100
NET
• Synaptophysin
• Chromogranin
Standard
HPE and IHC

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18. HISTOPATHOLOGICAL SUBTYPES
70% • Adenocarcinoma
20-25% • Poorly differentiated carcinoma
5% • Squamous cell carcinoma
1-3% • Neuroendocrine tumors
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ACCURACY OF IHC: 64-67%

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22. Presentation title 22

23. GENE EXPRESSION–BASED TISSUE
OF ORIGIN TESTING/MOLECULAR
TUMOR PROFILING
• Metastatic tumors retain the gene expression profile of their site of origin
• even when they have lost predictive IHC markers
• MTP tests commercially available-
• Tissue of Origin (Cancer Genetics) - RNA expression-based test
• CancerTYPE ID (Biotheranostics) - 92-gene RT-PCR assay
• Cancer Origin (Rosetta Genomics) - 64-microRNA expression-level test
• Overall accuracy is 85% to 89%
• can provide additional information when IHC fails to provide a diagnosis
23

24. NEXT-GENERATION SEQUENCING
• Identification of driver mutations amenable to targeted therapy
• Targeted therapies may provide stability or shrinkage of disease along with
a survival benefit especially as additional resistance mechanisms are
identified and therapies become available
• Large cohort of patients with CUP (333) were evaluated at Memorial Sloan
Kettering Cancer Center
• January 2014 and June 2016
• (45%) underwent NGS using MSK-IMPACT - hybridization capture-
based assay encompassing 34 (later expanded to 410) cancer-
associated genes
• most frequent histology was adenocarcinoma
• OS of 13 months
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30. ADDITIONAL EVALUATION
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31. FAVOURABLE
SUBSETS

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33. WOMEN WITH PERITONEAL
CARCINOMATOSIS
• Many of these carcinomas arise from the ovary or peritoneal surface of the
fallopian tube
• Occur more frequently in women with BRCA mutations
• BRCA1 mutation – risk factor
• Histologic features typical of ovarian carcinoma, such as papillary configuration or
psammoma bodies
• This syndrome has been termed “multifocal extraovarian serous carcinoma” or
“peritoneal papillary serous carcinoma”
• Consider surgical cytoreduction + chemotherapy if there is bulky disease
• Treat with chemotherapy if extra-abdominal metastases (response rates
39-66%)
33

34. WOMEN WITH AXILLARY LYMPH NODE
METASTASES
• Approach as if they have stage II breast cancer
• Biopsy of the axillary adenopathy and IHC for (ER), (PR), (HER2), CEA,
CK7, CK20, mammaglobin, and (TTF1)
• Positive staining for CEA, CK7, ER/PR, and mammaglobin with negative
staining for CK20 and TTF1 : favours breast primary
• In case of a negative mammogram, breast MRI should be performed
• MRI can detect an occult breast malignancy in 72% of such women with no
tumor in the breast detected by physical examination, mammography, or
ultrasound
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35. WOMEN WITH AXILLARY LYMPH NODE
METASTASES
• Complete staging with a chest/abdomen/pelvis CT ; bone scan (if
symptoms / elevated ALP)
• Axillary lymph node dissection and local therapy to the ipsilateral breast :
localized disease
• Breast-preserving therapy with whole-breast radiation is an option
• Stage II breast cancer with a non-occult primary - should undergo systemic
adjuvant therapy
• Women with metastatic sites in addition should receive a trial of systemic
therapy using guidelines for the treatment of metastatic breast cancer
35

36. MEN WITH SKELETAL METASTASES
• Serum PSA levels should be measured in all men
• Elevated serum PSA levels (or positive tumor staining with PSA) should be
treated according to guidelines for metastatic prostate cancer
• Osteoblastic bone metastases are also an indication for a trial of prostate
cancer treatment
• even in the context of atypical clinical features, a significantly elevated
serum PSA is a reason for trial of androgen- deprivation therapy
36

37. EXTRAGONADAL GERM CELL TUMOR
SYNDROME
• Young man with a poorly differentiated carcinoma whose primary tumor is
in the mediastinum or retroperitoneum
• These patients have improved prognosis if treated with site-specific therapy
• Marked elevation of serum hCG or AFP levels,
• Presence of 12p chromosomal gain (isochromosome 12p),
• IHC staining for octamer-binding transcription factor 4
• should receive treatment for extragonadal germ cell tumor with four cycles
of cisplatin-based chemotherapy followed by resection of residual tumor
masses
37

38. SINGLE SITE OF NEOPLASM
• e.g., isolated brain metastases, isolated node involvement, or isolated skin
involvement
• should be evaluated for more widespread disease
• PET scan - to identify unsuspected additional sites
• Exclude Merkel cell tumors, skin adnexal tumors (such as apocrine,
eccrine, and sebaceous carcinomas), sarcomas, melanomas, or
lymphomas
• localized disease should be treated with aggressive local therapy - long-
term disease-free survival if all clinically evident disease can be removed
• Adjuvant therapy can be considered on a case-by-case basis
38

39. SQUAMOUS CELL IN CERVICAL OR
SUPRACLAVICULAR LYMPH NODES
• Typically treated similarly to patients with head/neck squamous cell
carcinoma of known primary (85%)
• Location of adenopathy
• Isolated supraclavicular lymphadenopathy typically originates from a
primary site beneath the clavicle
• Initial evaluation: nasopharyngolaryngoscopy, CT and/or MRI of the
head/neck, and a PET scan
• Treatment typically involves a combination of surgery and/or radiation
and/or chemotherapy
• Patients with low cervical or supraclavicular lymph nodes are more likely
to have a primary lung cancer, and treatment results are inferior
39

40. SQUAMOUS CELL IN INGUINAL LYMPH
NODES
• Careful examination of the anogenital region, including anoscopy
• In patients with no primary detected, an inguinal lymph node dissection with
or without adjuvant radiation is recommended
• Adjuvant chemotherapy can be considered on a case-by-case basis
• may test positive for p16 expression, which could indicate a human
papillomavirus (HPV)-related malignancy
• also associated with other cancers not related to HPV infection including
sarcomas such as malignant peripheral nerve sheath tumors or
dedifferentiated liposarcoma
40

41. COLORECTAL CANCER PROFILE
• Recently been defined
• Includes
• typical clinical features (liver, peritoneal metastases),
• histology compatible with lower gastrointestinal tract adenocarcinoma,
• typical IHC staining (CK20+/CK7- or CDX2+)
• Colonoscopy
• Treatment according to standard guidelines for metastatic colorectal cancer
produced a median survival of 28 months
• Chemotherapy and targeted agents (bevacizumab, cetuximab)
41

42. LOW-GRADE NEUROENDOCRINE
• Typically arise from the pancreas or GI tract
• New imaging modalities such as 68Ga-DOTATATE PET/CT - sensitivity of
95%
• Treatment with octreotide long-acting release (LAR) lengthens the time to
tumor progression with low toxicity
• Depending on the clinical situation, appropriate management may also
include local therapy (resection of isolated metastasis, radiofrequency
ablation, cryotherapy, or hepatic artery chemoembolization)
• Several cytotoxic agents have some activity (5-FU, streptozocin,
capecitabine, temozolomide), and results with targeted agents (sunitinib,
everolimus) are promising
42

43. HIGH-GRADE NEUROENDOCRINE
• Includes:
• small-cell and large-cell neuroendocrine carcinomas (histologic
diagnoses)
• patients with poorly differentiated carcinoma recognized to have
neuroendocrine carcinoma by IHC staining
• Treatment with combination chemotherapy used for small-cell lung cancer
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51. EMPIRICAL CHEMOTHERAPY
• 80% of patients with CUP do not fit into any of the favorable subgroups
• Combinations containing a platinum agent and a taxane have been most
widely studied and are commonly used
• Several other combinations (i.e., gemcitabine/platinum,
gemcitabine/taxane) have similar activity
• Median survivals within a narrow range of 8–11 months
• Empiric second-line therapy has been evaluated in a few phase II trials
53

52. EMPIRICAL CHEMOTHERAPY
• Single-agent gemcitabine and the combinations of gemcitabine/irinotecan,
capecitabine/oxaliplatin, and bevacizumab/erlotinib have had modest
activity
• No definitive studies have compared survival with empiric chemotherapy
versus best supportive care alone
• The era of empiric chemotherapy for CUP is coming to an end
• Accurate identification of the tissue of origin is possible and provides more
rational framework for decisions regarding therapy
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54. RADIOTHERAPY IN
CUP

55. ROLE OF RADIATION
Curative Treatment Concepts
• Axillary CUP with adjuvant breast irradiation with or without inclusion of the supraclavicular
fossa can be adequately treated with 3D conformal radiotherapy
• In cervical CUP, radiotherapy targets not only the areas of nodal involvement but also
potential sites of occult mucosal disease
Palliative Treatment Concepts
• Patients with limited brain metastases - stereotactic radiosurgery (SRS)
• high radiation doses are applied in 1–5 fractions using a designated radiosurgery machine
like the Gamma Knife or the Cyberknife or a modified linear accelerator
• WBRT remains the treatment standard for patients with multiple intracerebral metastases
• Patients with painful bone metastases - single fraction with 8 Gy or a 1-week course of 5 ×
4 Gy
• Stereotactic body radiotherapy (SBRT) - high dose of irradiation in one or few fractions to an
extracranial target
• oligometastatic setting of lung, liver or adrenal gland metastases
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EVOLVING TREATMENT
OPTIONS

58. PROGNOSIS
POOR
• Male gender
• Poor performance status
• Adenocarcinoma
involving multiple organs
• Malignant ascites
• Brain metastases
GOOD
• Women with
adenocarcinoma of the
peritoneal cavity
• Women with
adenocarcinoma in axillary
lymph nodes only
• Squamous cell carcinomas
(SCC) involving cervical
lymph nodes only
• Poorly differentiated
neuroendocrine carcinomas
• Men with elevated PSA and
bone metastases
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63. FUTURE
PROSPECTS

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218 patients of
CUP

70. ONGOING CLINICAL TRIAL
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Actual Study Start Date : July 10, 2018
Estimated Primary Completion Date : February 28,
2023
Estimated Study Completion Date : May 31, 2024

74. TAKE HOME MESSAGE
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75. REFERENCES
1. DeVita, Hellman, and Rosenberg’s , Cancer, Principles & Practice
of Oncology, 11th edition , Cancer of Unknown Primary, (108)
3263-3272.
2. Holland-Frei Cancer Medicine, Ninth Edition, Neoplasm of
Unknown Primary site, (123), 1673-1681.
3. Abeloff’s Clinical Oncology, 6th edition, Carcinoma of Unknown
Primary, J(93), 1695-1701.
4. N. Seshadri, C. Eswar (eds.), PET/CT in Cancer of Unknown
Primary, © Springer International Publishing AG 2017, ISSN 2367-
2439.
5. A. Krämer, H. Löffler (eds.), Cancer of Unknown Primary,
© Springer International Publishing Switzerland 2016, ISBN 978-3-
319-22580-7
6. https://cup-syndrome.com/en/home.html
7. Cancers of unknown primary site: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up† Fizazi, K. et al.
Annals of Oncology, Volume 26, v133 -v138
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76. THANK YOU