MUO, CUP, Unknown primary

1. CARCINOMA OF UNKNOWN
PRIMARY
Dr Bharti Devnani

2. WHAT IS CUPS
 Histologically confirmed metastatic tumor whose primary site can not
be identified during std pre-treatment evaluation
 Poor prognosis
 Aggressive, early dissemination,
 Median survival-8-12 months
 Favourable-12-36 months

4. HISTOLOGICAL TYPES IN CUP
Histological Subtype Proportion of Cases
Adenocarcinoma
(Incl G1 & 2 differentiated Ca)
45-61%
Poorly differentiated tumor
(carcinoma, lymphoma,
sarcoma, melanoma, germ
cell tumor)
24-39%
Squamous Cell Carcinoma 4-15%
Neuroendocrine carcinoma 3-4%

5. EVALUATION

6. IMMUNO-HISTOCHEMISTRY FOR DIFFERENTIAL DIAGNOSIS

8. IMMUNOHISTOCHEMISTRY
 Epithelial origin
 cytokeratins
 Melanoma
 S100
 HMB45
 Germ Cell Tumour
 AFP
 bHCG
 PLAP
 Neuroendocrine
 chromogranin
 Synaptophysin
 CD56
 Lymphoma
 CD45
 CD20
 CD10
 CD3
 Thyroid
 thyroglobulin
 TTF1
 Prostate
 PSA
 Sarcoma
 AML
 CD31
 CD34

12. FAVOURABLE SUBSETS
1. Women with isolated axillary adenopathy
2. Women with papillary serous adenocarcinoma of the
peritoneal cavity
3. Squamous cell carcinoma (SCC) involving cervical lymph
nodes
4. Isolated inguinal adenopathy from SCC
5. Men with bone metastases, elevated serum PSA, or PSA
positive on tumor staining
6. Men with poorly differentiated carcinoma of midline
distribution
7. Poorly differentiated neuroendocrine carcinoma
8. Single, small & potentially resectable metastatic site

13. UNFAVOURABLE SUB-SETS
1. Adenocarcinoma metastatic to the liver or other organs
2. Non-papillary malignant ascites (adeno)
3. Multiple cerebral metastases (adeno or squamous carcinoma)
4. Multiplelung/pleuralmetastases (adeno)
5. Multiple metastatic bone disease (adeno)

15. TREATMENT OF SPECIFIC SUBSETS OF THE PATIENT

16. WOMEN WITH ISOLATED AXILLARY
LYMPHADENOPATHY

18. WOMEN WITH ISOLATED AXILLARY
ADENOPATHY
• Breast cancer should be suspected in women who have AUP (adenocarcinoma
• Lymph nodes should be tested for ER, PR, and HER-2/neu .
• Evaluation : includes
• Physical examination of both breasts
• Mammography is indicated to search for a primary site.
• Bilateral breast MRI is indicated if mammography is negative
• Clinically occult breast cancer will be found in approximately one-third of
cases.
• Modified radical mastectomy recommended, evenwhen the results of physical
examination and mammography are normal. Treatment options for ipsilateral
breast include mastectomy or whole breast radiation therapy
• Axillary node dissection recommended.

19. Advantages of MRI
 Breast MRI is more sensitive.
 Breast MRI can detect a primary breast cancer in
approximately 75 % of women who present with ALN mets
with negative clinical exam & imaging.
 Identification of a primary breast cancer by MRI may
facilitate BCS instead of mastectomy.
 Some lesions found on MRI can be identified on
subsequent, targeted "second-look” ultrasound and may
then be biopsied under US guidance.
Disadvantages
 High false positive results. (29 %)
 All suspicious findings on MRI require pathologic
confirmation.

20. TREATMENT- OCCULT PRIMARY WITH AXILLARY
NODES
 All patients should undergo ALND
 Optimal treatment for the ipsilateral breast is controversial. Standard
approach is to perform MRM at the time of ALND.
 For women who wish to preserve their breast, WBI is an acceptable
option.
 Observation alone for the ipsilateral breast is not recommended.
 Systemic adjuvant therapy according to published guidelines for stage
II primary breast cancer is recommended.
 Women with ALN mets who have adenoca or poorly differentiated
carcinoma histology, compatible IHC staining, and no evidence of a
breast cancer primary but who have evidence of other distant
metastases should be treated according to guidelines for metastatic
breast cancer

21. OBC
ALND
alone
MRM+
ALND
ALND +
XRT

22. LRFS
RFS
BCSS

24.  Patients with OBC who present with axillary lymph node metastasis
should receive the standard treatment.
 No differences in outcomes were observed between patients who
received ALND followed by subsequent breast radiotherapy and
patients who underwent mastectomy plus ALND.

25. 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.
Treatment decisions:
• MRM + ALND  chemotherapy ± hormonal therapy/RT.
• Neoadjuvant chemotherapy for N2 disease .

27. SQUAMOUSCELL CARCINOMA INVOLVINGCERVICAL
LYMPH NODES

28. HISTOLOGICAL DIFFERENTIATION
 The majority of patients have either
squamous cell or poorly differentiated carcinoma.
Adenocarcinoma
 High chances of primary lesion below the clavicles
If nodes are located in the upper neck
 Salivary gland
 Thyroid
 Parathyroid primary tumor.

29. Radiological Studies
 Chest imaging
 CT with contrast or MRI with Gd (skull base through thoracic inlet)
 PET CT scan (If other tests do not reveal a primary)
Laboratory studies
Complete blood cell count
Blood chemistry profile
 HPV testing (Suggestive of occult primary in BOT or Tonsil, helps in
customize radiation targets)
 EBV testing

30. Category 2A

32. MEN WITH SKELETAL METASTASES OR ELEVATED
PROSTATE-SPECIFIC ANTIGEN

33.  When bone metastases are the first manifestation of metastatic
adenocarcinoma, the most common primary tumor sites are the lung,
prostate, and less often, liver, kidney, thyroid, and colon
 Metastatic prostate cancer should be suspected in men with
adenocarcinoma predominantly involving bone, particularly if the
metastases are blastic or sclerotic.
 Elevated serum levels of prostate-specific antigen (PSA) or tumor
staining with PSA provides confirmatory evidence of prostate cancer,
and such patients should be treated using guidelines for metastatic
prostate cancer.
 In most of these patients, a needle biopsy of the prostate would
confirm the primary site but may not be necessary for optimalclinical
management.

34. PATIENTS WITH A COLON CANCER PROFILE

35. “COLON CANCER PROFILE”
 Predominant metastatic sites in the liver and/or peritoneum
 Adenocarcinoma with histology typical of gastrointestinal origin
 Typical IHC staining pattern including CK20 +/CK7- or CDX-2+

37. The improved survival compared to results with empiric CUP
regimens suggests that molecular profiling identifies a
subset of patients who benefit from site-specific therapy.
A sizable minority did not fit because of atypical IHC staining results. These patients
also appear to benefit from colon cancer–specific treatment and are identified only by
molecular tumor profiling.

38. SQUAMOUS CARCINOMA INVOLVING INGUINAL
LYMPH NODES

39. Site specific
squamous cell
carcinoma

40.  Most patients with squamous carcinoma involving inguinal lymph
nodes have a detectable primary site in the genital or anorectal areas.
 For the unusual patient in whom no primary site is identified, inguinal
lymph node dissection with or without radiation therapy to the inguinal
area sometimes results in long-term survival.
 These patients should also be considered for neoadjuvant or adjuvant
chemotherapy

41. WOMEN WITH PERITONEAL CARCINOMATOSIS

42. Commonly- Ovarian Cancer
Sometimes- GIT, Lung, Breast, PPC
Histological features of elevated CA-125, papillary serous carcinoma,
Psammomma bodies-----Treat as advanced ovarian cancer---(surgical
cytoreduction followed by taxane or platinum chemotherapy)

43.  Commonly- Ovary
 Extra-ovarian tissue with similar histiogenesis- Fallopian
tube/Peritonium
 Morphological features-papillary configuration or psammoma bodies
 IHC and MCCAs for diagnosis
 Syndrome has been termed serous carcinoma of the peritoneum or
multifocal extraovarian serous carcinoma.
 Primary Peritonial CA
BRCA_1, Despite TAH+BSO
 T/t- Surgical debulking and systemic chemotherapy (Taxen/Platinum)

44. POORLYDIFFERENTIATED CARCINOMAWITH MIDLINE
DISTRIBUTION ( EXTRA-GONADAL GERM CELL SYNDROME)

46. SINGLE SITE OF NEOPLASM

47.  Patients with one site of involvement (brain, liver, adrenal,
subcutaneous tissue, bone, intestine, lymph node, skin, or other sites)
usually have metastatic carcinoma, and many other sites are present
but are not detectable.
 Before initiating local treatment, a PET scan is helpful to exclude other
unsuspected metastatic sites.
 In the absence of any other documented metastatic disease, these
patients should be treated with aggressive local therapy (i.e.,
resection, radiation therapy, or both) because a minority enjoy long-
term, disease-free survival.

49. LOW-GRADE NEUROENDOCRINE CARCINOMA

50.  These tumors usually exhibit an indolent biology, and slow progression over
years is likely.
 Management should follow guidelines established for metastatic carcinoid or
islet cell tumors from known primary sites.
 Treatment with octreotide long-acting release (LAR) results in a marked
increase in time to tumor progression and is a first-line treatment of low
toxicity.
 Depending on the clinical situation, appropriate management may also
include local therapy (resection of isolated metastasis, hepatic artery ligation
or embolization, cryotherapy, radiofrequency ablation).
 Several cytotoxic agents have some activity (streptozocin, doxorubicin, 5-fl
uorouracil, temozolomide), and preliminary results with targeted agents
(sunitinib, everolimus) are promising.
 These neoplasms are usually refractory to intensive systemic chemotherapy,
and cisplatin based chemotherapy produces low response rates

51. AGGRESSIVE NEUROENDOCRINE CARCINOMAS

52. The addition of paclitaxel to a carboplatin
and etoposide regimen increased toxicity, but did not appear
to improve efficacy

53. PATIENTS WITH AUP DO NOT FIT INTO ANY OF THE
CLINICAL SUBGROUPS
 Empiric chemotherapy may be considered
 The addition of paclitaxel to a carboplatin and etoposide regimen
increased toxicity, but did not appear to improve efficacy
• 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.

54. TREATMENT OF SPECIFIC SUBSETS OF THE PATIENT