Management of ca unknown primary

Management of Carcinoma
Unknown Primary
Dr. Varshu Goel
First Year Post-Graduate Resident
Department of Radiotherapy
Maulana Azad Medical College, Delhi

Definition And Epidemiology
Mechanism
History And Clinical Presentation
Diagnostic Evaluation
Management Of Specific Clinicopathologic Subgroups
2
Cancerof Unknown PrimarySite(CUP)
The MD Anderson Manual of Medical Oncology, 3rd edition

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Cancerof Unknown PrimarySite(CUP)
Manual of Clinical Oncology, 8th edition
• CUP is a heterogeneous group of diseases consisting of biopsy-
proven metastatic solid tumors for which the site of origin is
not suggested by thorough history, physical examination,
imaging and laboratory studies, and histologic evaluation
• Primary site is found in <30% of cases, and that discovery
rarely affects the prognosis or treatment
• Two basic categories of CUP
• Treatable
• Not treatable

4
Epidemiology
• Incidence : 2-3% of all cancers
• 75% originate below the diaphragm
• Average age at onset – 60 years except for patients with
midline distribution of poorly differentiated carcinoma with a
median age of 39 years (10% of all CUP patients)
• Median survival 3-4 months with <25% patients surviving at 1
year and <10% at 5 years

6
Mechanism
• Mechanism that explain the presence of occult primary
neoplasm include the following:
1. Excision or electrocautery may have removed unrecognized
primary lesion years before the appearance of metastatic
lesions
2. The primary cancer may have shed metastases and then
undergone spontaneous regression
3. The primary tumor may be too small to be detected, even at
autopsy
4. The site of origin may be obscured by the extensiveness of
metastases or by the atypical pattern of dissemination

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PrognosticFactors
Poor Prognostic Factors Good Prognostic Factors
Male Gender
Poor Performance status
Adenocarcinoma involving
multiple organs
Malignant Ascites
Multiple Brain metastases
Adrenal Metastases
Liver metastases (non-
neuroendocrine)
Pleural or Lung metastases
Women with adenocarcinoma of peritoneal cavity
Women with adenocarcinoma in axillary lymph nodes
only
Squamous cell carcinomas involving cervical lymph
nodes only
Poorly differentiated neuroendocrine carcinomas
Men with elevated PSA levels and bone metastases
Potentially resectable tumor
Isolated inguinal adenopathy
Extragonadal germ cell syndrome
Isolated single small metastasis

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Clinical Presentation
• Multiple sites (three or more organs) are involved in more
than 50% patients with symptoms of metastasis
• General deterioration – 73%
• Pain – 60%
• Liver mass or other abdominal manifestations – 40%
• Lymphadenopathy – 20%
• Ascites – 26%
• Bone pain or pathologic fracture – 15%
• Respiratory symptoms – 15%
• CNS abnormalities – 5%
• Weight loss – 5%
• Skin nodules – 2%

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DiagnosticWork-up
NCCN version 1.2018

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Performinga Biopsy
• Patients with metastases to neck lymph nodes only
• Suspicious cervical nodes should not undergo excisional biopsy
until a complete diagnostic evaluation of the head and neck has
been performed. About 35% of these patients have potentially
curable cancers of the upper aerodigestive tract.
• However, supraclavicular lymph nodes may be directly excised for
histologic examination.
• Other patients who have suspected metastatic cancer
• Biopsy of the most accessible site should be performed before
specialized blood or radiologic studies
• Biopsy proof of metastatic cancer is necessary at only one site.
• If several areas of tumor involvement are suggested by the
findings from the screening evaluation, the preferred biopsy site
is that associated with the least morbidity (e.g., peripheral lymph
nodes when palpable, cytology of sampled effusions, or
suspected skin lesions).

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Histology
1. Well or moderately differentiated adenocarcinoma (60%)
2. Poorly differentiated adenocarcinoma or undifferentiated
carcinoma (29%)
3. Squamous cell carcinoma (5%)
4. Poorly differentiated malignant neoplasm (5%)
5. Neuroendocrine tumor of unknown primary (1%)

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IHC
• Immunohistochemistry stains are peroxidase labeled
antibodies against specific tumor antigens that are used to
define tumor lineage
• It improves the chances of the diagnosis of a tissue of origin
• Stepwise approach includes :
• Markers to determine lineage, e.g., sarcoma, carcinoma,
lymphoma, melanoma
• Markers suggestive of the tissue of origin
• Tumor biomarkers that can help with treatment decisions: EGFR,
BRAF, Her2

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IHCDiagnosticAlgorithmforTumorsofUncertainOriginand/orUndifferentitated
Neoplasm
Histomorphology (spindle cell, epithelioid, small cell, pleomorphic), clinical information
(age, sex, tumor location, prior malignancy)
To determine tumor lineage with IHC : CK, CD45, S100, Vimentin
CK-
CD45+
S100-
Vimentin+
CK+
CD45-
S100-
Vimentin-
CK-
CD45-
S100+
Vimentin+
CK-
CD45-
S100-
Vimentin+
CK+
CD45-
S100-
Vimentin+
Carcinoma
Germ Cell
Tumor
NHL
Hematopoietic
Neoplasm
Melanoma
Lipogenic Tumor
Neurogenic
Tumor
Sarcoma
(various types)
Unusual Carcinoma
Hodgkin’s L.
Plasma Cell
Myeloma
Plasmablastic L.
Carcinosarcoma
Mesothelioma
Carcinoma
Sarcoma
Manual of Clinical Oncology, 8th ed.

IHCDiagnosticAlgorithmforCarcinoma/TumorofUnknownPrimary
CK7-
CD20+
CK7+
CK20-
CK7+
CK20+
CK7-
CK20-
Lung ADC
Breast Ca
Thyroid Ca
Salivary Gland
Female GYN tract
(endometrial ADC,
ovarian Ca)
Mesothelioma
Colorectal ADC
Small intestine
ADC
Merkel Cell Ca
Stomach ADC
Esophageal ADC
Pancreatobiliary
ADC
Urothelial Ca
Mucinous
ovarian Ca
Hepatocellular Ca
Renal Cell Ca
Prostate ADC
Squamous cell Ca
Granulosa cell
and germ cell
tumors
Adrenocortical
tumors

CK7+
CK20-
Lung ADC
(TTF1+,Napsin A+)
Breast Ca
(GATA3+)
Thyroid Ca
(TTF1+,
thyroglobulin+)
Salivary Gland
Female GYN tract
(endometrial ADC,
ovarian Ca)
(PAX8+)
Mesothelioma
(Calretinin+)
CA IX = carbonic anhydrase IX;
GATA3 = GATA binding protein 3,
GCDFP-15, gross cystic disease
fluid protein-15; TTF, thyroid transcription factor
Additional Markers
GYN Serous
GYN endometrioid
Breast Carcinoma
GI, upper tract (stomach)
Lung adenocarcinoma
Mesothelioma
Thyroid, follicular/papillary
Thyroid, medullary
Renal cell (chromophobe)
PAX8+, ER+, WT1+
PAX8+, ER+, Vimentin+
GATA3+, ER+, GCDFP+/-,
mammoglobin+/-
Cadherin 17+, CDX2+/-
TTF1+, Napsin A+, GATA3-, CDX2-
Calretinin+, CK5/6+, WT1+,
mesothelin
PAX8+, TTF1+, Thyg+, Calcitonin-
TTF1+, Thyg-, Calcitonin+, NET+,
mCEA+
CD10-/+, CD117+, CAIX-, PAX2/8-

CK7-
CD20+
Colorectal ADC
(CDX2, SATB2+)
Small intestine
ADC
Merkel Cell Ca
Additional Markers
GI, lower tract (colorectal)
Merkel Cell
Cadherin 17+, CDX2+, SATB2+
NET+
(neuroendocrine tumor markers
CD56, chromogranin,
synaptophysin)
CK20 paranuclear dot +

CK7+
CK20+
Stomach ADC
Esophageal ADC
Pancreatobiliary
ADC
Urothelial Ca
(GATA3+)
Mucinous
ovarian Ca
S100P = placental S100 protein
Maspin = mammary serine protease inhibitor
IMP3 = insulin like growth factor messenger RNA bonding protein 3
mCEA = monoclonal CEA
Additional Markers
Pancreatobiliary, ductal
adenocarcinoma
Urothelial Cell
CK17+, S100P+, Maspin+, IMP3+,
CA19-9+, mCEA+
GATA3+, CK5/6+, p63+, S100P+

CK7-
CK20-
Hepatocellular Ca
(HepPar-1)
Renal Cell Ca
Prostate ADC
(PSA+)
Squamous cell Ca
(p40+)
Granulosa cell
and germ cell
tumors
Adrenocortical
tumors
Additional Markers
Hepatocellular
Prostate
Small cell
Squamous cell
Renal cell (clear cell)
Adrenocrotical carcinoma
Granulosa cell and germ cell
tumors
HepPar1+, glypican3+,
arginase1+, AFP+/-
PSA+, PSAP+
NET+, pankeratin (punctate)+
CK5/6+, p63+, p40+, SOX2+,
desmocollin3+
pVHL+, CAIX+, CD10+, RCC+,
PAX2/8+
Mart1+, Calretinin+, InhA+
PLAP, OCT4, CD117, hCG and AFP

• Routine use not recommended
• Good candidates for PET/CT
• CUP Patients with cervical adenopathy/squamous cell neck LAD
• Patients with single metastatic focus – prior to definitive
locoregional therapy
• In patients with disseminated disease, some evidence exists
that PET/CT may be helpful in detection of primary in 20%
cases.
• These studies were small and retrospective
• Cost effectiveness not clear
• Additional sites of metastases may be detected more often than
the primary
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Roleof PET-CT

• Routine evaluation of current commonly used markers have
not been proven of any prognostic or diagnostic assistance
• A non-specific multiple overexpression of adenocarcinoma
markers (CEA, CA-125, CA19-9, CA-15-3) has been observed in
majority of CUP patients
• We may request :
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Roleof TumorMarkers

Management of Carcinoma
Unknown Primary Presenting as
Metastatic Cervical Adenopathy

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Management
• Combined-modality therapy (surgery and radiation therapy) is
better than either modality alone
• Neck dissection is indicated if:
• Goss disease is left behind after excisional biopsy
• Single LN> 6 cm
• ECE+
• In squamous cell carcinoma, unilateral tonsillectomy ipsilateral
to the presenting neck mass is indicated
• In unresectable squamous cell head and neck cancers
chemotherapy with cisplatin/5- fluorouracil–based and
cetuximab-based regimens has been given
• Identification of the primary site help reduce morbidity by
limiting the field of radiation and would improve surveillance.

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• Patients present with high to mid cervical or supraclavicular
adenopathy
• On histopathology, these tumors are squamous cell or PDCs
• For squamous cell carcinoma, the primary site is eventually
identified during follow-up in approximately 20% of patients,
with the tonsil being the most common site, followed by the
pyriform sinus and base of the tongue
• The prognosis is significantly worse in the presence of any of
the following:
• Adenocarcinoma
• Level III/IV lymphadenopathy
• Multiple lymph nodes
• Bulky disease
• Supraclavicular Nodes
• Right - most commonly arises from occult primary tumors of the
lungs and breast
• Left side - due to spread from intra-abdominal malignancies by
way of the thoracic duct (Virchow node) The MD Anderson Manual of Medical Oncology, 3rd edition

30
Müller von der Grün et al. Radiation Oncology (2017)

RegionalLymphNodes
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AJCC Cancer Staging Manual, 8th ed.
N
category
Clinical N criteria (cN) Pathological N criteria (pN)
Nx Regional lymph nodes cannot be
assessed
Regional lymph nodes cannot be
assessed
N0 No regional lymph node
metastasis
No regional lymph node metastasis
N1 Metastasis in a single ipsilateral
lymph node, 3 cm or smaller in
greatest dimension and ENE (-)
Metastasis in a single ipsilateral
lymph node, 3 cm or smaller in
N2a Metastasis in a single ipsilateral
lymph node, larger than 3 cm but
not larger than 6 cm in greatest
dimension and ENE (-)
Metastasis in a single ipsilateral
lymph node, larger than 3 cm but not
larger than 6 cm in greatest
OR
Metastasis in a single ipsilateral or
contralateral node, 3 cm or smaller in
greatest dimension and ENE (+)

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AJCC Cancer Staging Manual, 8th ed.
N
category
Clinical N criteria (cN) Pathological N criteria (pN)
N2b Metastasis in multiple ipsilateral
lymph nodes, none more than 6
cm in greatest dimension and
ENE (-)
Metastasis in multiple ipsilateral
lymph nodes, none more than 6 cm in
N2c Metastasis in bilateral or
contralateral lymph nodes, none
more than 6 cm in greatest
Metastasis in bilateral or contralateral
lymph nodes, none more than 6 cm in
N3a Metastasis in a lymph node,
Metastasis in a lymph node, larger
than 6 cm in greatest dimension and
ENE (-)
N3b Metastasis in any lymph node(s)
with clinically overt ENE (+)
Metastasis in any lymph node(s) with
clinically overt ENE (+)
OR
Metastasis in single ipsilateral node,
dimension and ENE (+)
A designation of “U” or “L” may be used for any N category to indicate metastasis
above the lower border of the cricoid (U) or below the lower border of the cricoid (L)

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Management of Women with
Carcinoma Unknown Primary
Presenting And Isolated Axillary
Adenopathy
(Favourable Subset)

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• Lymph nodes should be tested for ER, PR, and HER-2/neu.
• Evaluation : includes
• Physical examination of both breasts
• Mammography to search for a primary site.
• Bilateral breast MRI indicated if mammography is negative
• Prognosis is similar to lymph node positive breast cancer
• Mobile lymph nodes (N1) - Treat as stage IIA breast cancer
• Fixed lymph nodes (N2) - Treated as stage IIIA breast cancer
• Axillary node dissection recommended.
• Treatment decisions:
• MRM + ALND f/b chemotherapy ± hormonal therapy/RT
• Neoadjuvant chemotherapy for N2 disease

Management of patients with
Presenting As isolated Inguinal
adenopathy

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• Undifferentiated (anaplastic) carcinoma is identified in at least
half of these cases.
• A detailed investigation for primary lesions in these areas is
important because curative therapy is available for carcinomas
of the anus, vulva, vagina, and cervix even with spread to
regional lymph nodes.
• In patients with carcinomas and PDCs confined to the groin
nodes, where no primary site was identified, a superficial
groin dissection should be performed with or without
radiation therapy.
• Chemotherapy, before definitive therapy, may be offered to
patients with bulky locoregional adenopathy

Presenting As isolated Brain
Metastases

41
• In up to 15% of patients presenting with brain metastases, the
primary site remains unknown
• Patients with single metastatic lesions should be considered
for surgery, and those with multiple lesions should receive
radiotherapy.

And isolated Pleural Effusion

43
• Most patients with isolated pleural effusions have
adenocarcinomas, which may sometimes be difficult to
differentiate from mesotheliomas.
• Newer IHC markers (eg, calretinin, CK 5/6, and WT1 [Wilms
Tumor-1]) that are more sensitive in differentiating epithelioid
malignant mesothelioma from pulmonary adenocarcinoma
can assist in the diagnosis
• Additional IHC markers, including TTF-1, CK 7/20, and breast
markers, should routinely be done as first- and second-tier
diagnostics
• If the effusion reaccumulates quickly, pleurodesis may be
attempted to slow the rate of fluid reaccumulation, or a
pleural catheter for daily aspirations may be placed (this can
be removed after chemotherapy response is noted and the
flow decreases
• Taxane plus carboplatin versus gemcitabine plus cisplatin are
commonly used

Presenting As Malignant Ascites

45
• Two subsets
1. Patients with mucin-producing adenocarcinoma, who may
present with ascitic fluid that contains signet-ring cells; have
multiple peritoneal implants, with the primary site most
likely being the GI tract
2. Women patients with primary serous papillary peritoneal
carcinomatosis, associated with pelvic adenopathy or
masses. These patients may have elevated CA 125 levels but
do not have detectable ovarian cancer
Disease management should be the same as for women with
Stage III ovarian carcinoma.
• More common in women with BRCA-1 mutation and may also
be seen after prophylactic oophorectomy .
A prolonged median survival of 13 months, with 25% of
patients having a progression-free survival lasting more than 2
years, is reported for paclitaxel/ carboplatin-based
chemotherapy in patients with peritoneal carcinomatosis.

And Isolated Bone metastases

47
• When bone metastases are detected, men should be
evaluated for prostate cancer and women for breast cancer
• Other cancer profiles include lung, cholangiocarcinoma, renal,
and rarely melanoma.
• Patients with a single bony metastasis may be candidates for
surgery or radiation and then monitored.
• Therapy with bone-seeking radioisotopes (eg, strontium 89)
may be useful in the treatment of disseminated painful bone
metastases in a few patients.
• Bisphosphonates are routinely used
• PET-CT is the imaging modality of choice to follow response to
therapy for disseminated osseous metastatic disease

Presenting As hepatic
metastases

49
• Relatively poor prognosis, with reported median OS between
49 days and 7 months
• The two most common histologies in primary CUP of the liver
are adenocarcinoma (55%) and poorly differentiated/
undifferentiated carcinoma (30%).
• Recommended initial therapy for unresectable disease is
systemic chemotherapy, and surgery may be considered an
option for those with resectable disease

And extragonadal germ cell
syndrome

51
• Patients who have undifferentiated carcinoma or PDC are
younger than 50 years and present with rapidly growing
midline tumors involving the lymph nodes, mediastinum, or
retroperitoneum; their tumors have been found to be very
responsive to chemotherapy, particularly to platinum-
containing regimens.
• These patients have poorly differentiated extragonadal germ
cell tumors.
• They have response rates to chemotherapy of 35% to 50%.

Neuroendocrine tumor of
Unknown primary site

53
1. Neuroendocrine tumors can be well differentiated or low
grade, with features that are typical of carcinoid or islet cell
tumors
• In patients with limited disease, surgical resection or
chemoembolization may be appropriate.
• Targeted therapy may be considered with anti-VEGF agents,
including sunitinib, or mammalian target of rapamycin [mTOR]
inhibitors, including everolimus.
2. High-grade neuroendocrine tumors may present as PDC by
light microscopy but have strong neuroendocrine features
revealed by IHC (ie, neuron-specific enolase, chromogranin
A, and synaptophysin positive).
• Treated like small cell lung carcinoma with etoposide plus
platinum or irinotecan plus platinum combinations

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• Choice of the regimen should be based on the histologic type
of cancer.
1. Paclitaxel and Carboplatin: Choice for first-line therapy,
based on the relatively large experience with this
combination in AUP
• Addition of a third drug (either Etoposide or Gemcitabine) to a
taxane and platinum regimen may improve efficacy
2. Second line therapy - Single agent Gemcitabine (1000
mg/m2 weekly three of four weeks) has modest activity.

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ChemotherapyRegimens
• PCE
• Paclitaxel: 200 mg/m2 IV on day 1
• Carboplatin: AUC of 6, IV on day 1
• Etoposide: 50 mg alternating with 100 mg PO on days 1–10
Repeat cycle every 21 days
• EP
• Etoposide: 100 mg/m2 IV on days 1–5
• Cisplatin: 100 mg/m2 IV on day 1
• PEB
• Cisplatin: 20 mg/m2 IV on days 1–5
• Etoposide: 100 mg/m2 IV on days 1–5
• Bleomycin: 30 units IV on days 1, 8, and 15
Physician’s Cancer Chemotherapy Drug Manual 2015

57
• GCP
• Gemcitabine: 1000 mg/m2 IV on days 1 and 8
• Carboplatin: AUC of 5, IV on day 1
Repeat cycle every 21 days for 4 cycles. This is to be followed by
paclitaxel at 70 mg/m2 IV every week for 6 weeks with a 2-week rest.
Repeat for a total of 3 cycles.
• Gemcitabine + Cisplatin + Paclitaxel
• Cisplatin: 75 mg/m2 IV on day 1

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• Gemcitabine + Irinotecan
• Irinotecan: 100 mg/m2 IV on days 1 and 8
Repeat cycle every 21 days.
• Capecitabine + Oxaliplatin
• Capecitabine: 1000 mg/m2 PO on days 1–14
• Oxaliplatin: 130 mg/m2 IV on day 1
Repeat cycle every 21 days.
• Bevacizumab + Erlotinib
• Bevacizumab: 10 mg/kg IV on day 1
• Erlotinib: 150 mg PO daily
Continue until disease progression.

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