Comprehensive review of Isolated Axillary lymph nodal metastasis of unknown origin- Clinically unknown primary axilla which includes detailed approach and management of inguinal lymph nodal metastasis also

1. Clinically Unknown Primary
Isolated Axillary metastasis in female
Isolated inguinal Metastasis in male
Dr.Bhavin Vadodariya
01/12/2018

2. Introduction
• Axillary metastases with unknown breast primary account for 1% of all
breast cancers
• First described by Halstead in 1907
• Staged as T0 N1 (Stage II)
• Characteristics of T0 N1 patients similar to those with stage II disease
• A primary breast cancer in the axillary tail may be confused for an axillary
node
• Limited literature with small retrospective studies
• No randomised control trials
• Comparisons from previous studies difficult as better imaging has reduced
the number of occult breast primaries

4. Pathogenesis
 Unknown
 The spontaneous regression of the primary tumour possibly as a result of
autoimmune destruction, although the exact reason is unknown.

7. Classification of cancer including CUP:
A stepwise pathological approach
Step 1: identify
broad cancer
type
• Carcinoma
• Melanoma
• Lymphoma/
leukaemia
• Sarcoma
• (Neuro-glial
tumours)

9. Diagnostic work-up of unknown primary:
IHC and Molecular Profiling
• Identify broad cancer type
– Carcinoma
– Melanoma
– Lymphoma/leukaemia
– Sarcoma
Cytokeratins
S100
CLA, CD20, CD3 etc
Vimentin, actin, c-kit etc
• If carcinoma or related, then identify its subtype
– Adenocarcinoma
– Squamous carcinoma
– Neuroendocrine carcinoma
CK7, CK20
CK5, p63
Chromogranin, CD56, synaptomysin
• If adenocarcinoma, then predict possible primary site
– Breast
– lung
– Ovary
– Colon
ER, PgR, HER2
TTF1
CA125
CDX2
Oien KA & Dennis JL. Ann Oncol 2012; 23: 271-77

11. Classification of cancer including CUP:
A stepwise pathological approach
Step 1: identify
broad cancer
type
• Carcinoma
• Melanoma
• Lymphoma/
leukaemia
• Sarcoma
• (Neuro-glial
tumours)
Step 2: if carcinoma or
related, identify
subtype
• Adenocarcinoma
• Squamous ca.
– Transitional ca.
• Solid organ ca.
(hepatocellular, renal, thyroid,
adrenal)
• Neuroendocrine ca.
• (Germ cell tumour)
• (Mesothelioma)

12. Classification of cancer including CUP:
A stepwise pathological approach
Step 1: identify
broad cancer
type
• Carcinoma
• Melanoma
• Lymphoma/
leukaemia
• Sarcoma
• (Neuro-glial
tumours)
Step 2: if carcinoma or
related, identify
subtype
• Adenocarcinoma
• Squamous ca.
– Transitional ca.
• Solid organ ca.
(hepatocellular, renal, thyroid,
adrenal)
• Neuroendocrine ca.
• (Germ cell tumour)
• (Mesothelioma)

13. Classification of cancer including CUP:
A stepwise pathological approach
Step 1: identify
broad cancer
type
• Carcinoma
• Melanoma
• Lymphoma/
leukaemia
• Sarcoma
• (Neuro-glial
tumours)
Step 2: if carcinoma or
related, identify
subtype
• Adenocarcinoma
• Squamous ca.
– Transitional ca.
• Solid organ ca.
(hepatocellular, renal, thyroid,
adrenal)
• Neuroendocrine ca.
• (Germ cell tumour)
• (Mesothelioma)
Step 3: if adeno-
carcinoma, predict
primary site(s)
• Lung
• Pancreas
• Colon
• Stomach
• Breast
• Ovary
• Prostate, etc

16. STEP I
Clinical, immunohistochemistry, imaging, endoscopy studies
STEP II
i.e. Breast Cancer, Germ-cell Tumors, Lymphomas
STEP III
FAVOURABLE SUBSETS
[Similarly“Curative Intent” ]
UNFAVOURABLE SUBSETS
[ With Palliative Intent” or with specific Rx
following gene profiling]

17. Immunohistochemistry

18. Markers
 Carcinoembryonic antigen (CEA)
 Cytokeratins 7 and 20
 Estrogen receptor (ER) and progesterone receptor (PR)
 Gross cystic disease fluid protein-15 (GCDFP, identified by staining with the
monoclonal antibody BRST2)
 Mammaglobin
 Thyroid transcription factor (TTF-1)
 CA125

19. CEA
 CEA is a sensitive marker for adenocarcinomas of the breast, lung, and
gastrointestinal tract, but does not help to distinguish among these sites of
origin.

20. Cytokeratins
 A differential expression of cytokeratins (CKs) can assist in this differentiation.
 CK20 is a low molecular weight cytokeratin that is normally expressed in the
gastrointestinal epithelium, urothelium, and in Merkel cells.
 CK7 is expressed by tumors of the lung, ovary, endometrium, and breast, and
not in the lower gastrointestinal tract.
 The pattern of CK20 and CK7 may be particularly helpful in suggesting a
primary site
 The presence of CK7 and absence of CK20 favors a diagnosis of breast cancer

21. TTF1
 TTF-1 is rarely positive in breast cancers, while it is positive in 70 to 80 percent
of nonsquamous cancers arising in the lung

22. CA 125
 CA-125 is commonly positive in ovarian carcinomas, but is positive in about 10
percent of breast cancers.
 As with ER/PR, its presence in an axillary node, particularly in conjunction
with other compatible IHC findings, lends support to a diagnosis of an occult
breast primary

23. ER,PR
 Although positive staining for ER and/or PR supports a possible diagnosis of
breast cancer, these markers are nonspecific and they may also be expressed
in ovarian, uterine, lung, stomach, thyroid, and hepatobiliary cancers.
However, ER/PR staining of an axillary node is compelling evidence of a
primary breast cancer.

24. GCDFP,Mammaglobin
 BRST2 is positive in 65 to 80 percent of cases and is relatively specific for
breast cancer; rarely, it is positive in skin adnexal tumors, endometrial
cancers, and salivary gland tumors .
 While mammaglobin is more sensitive, it is less specific for breast cancer
(gynecologic, lung, urothelial, thyroid, colon and hepatobiliary tumors may
stain positive , and both stains are thus typically used together.

25. HER2
 HER2 immunostaining is not generally useful for the differential diagnosis of a
carcinoma arising in the axillary nodes as it lacks specificity.
 Furthermore, only 18 to 20 percent of breast cancers overexpress this protein.
However, assay for HER2 overexpression by IHC or fluorescent in situ
hybridization (FISH) is a routine component of the evaluation of all breast
cancers as it permits the identification of those women who are most likely to
respond to treatments targeting HER2.

26. Evaluation

27. Axillary nodes
• Benign
– Infections (viral, bacterial inc. TB), trauma, inflammation (RA, SLE)
• Malignant
– Lymphomas
– Breast
– Lung
– GI
– Pancreas
– Stomach
– Ovarian
– Thyroid
• Breast is the commonest primary for women presenting with axillary
nodes with adenocarcinoma or undifferentiated morphology

28. Investigations of patient presenting with
axillary nodes
• Confirmation of malignancy
– Axillary node biopsy or excision
• Search for Breast Primary
– Mammography
– US
– Breast MRI
• Search for primary and staging
– CT scan
– PET Scan

29. Mammogram
 A nonpalpable, clinically occult lesion is identified mammographically in 10 to 20 percent of
cases.
 Many occult nonpalpable tumors are missed because of their relatively small size (in one
series 30 percent of occult breast primaries were 5 mm or less in diameter) and because they
are obscured on the mammogram by dense fibroglandular tissue .
 Furthermore, an abnormal mammogram does not necessarily indicate breast cancer
 Suspicious findings warrant biopsy to confirm the clinical suspicion, and a negative
mammogram in the appropriate clinical setting should prompt further imaging evaluation of
the breast with ultrasound and/or breast MRI.
Ref- Mammography in women with axillary lymphadenopathy and normal breasts on physical examination: value in detecting occult breast carcinoma.AULeibman AJ, Kossoff MB Am J
Roentgenol. 1992;159(3):493.

30. Breast MRI
 Contrast enhanced MRI should be considered in
 Women with dense breast tissue and/or positive axillary node
 MRI Sensitivity- 90 per ent
 Accuracy-70%

31. Breast MRI
 Breast magnetic resonance imaging (MRI) is more sensitive than either
mammography or breast ultrasound for detection of invasive breast cancers.
 Data from several small series suggest that breast MRI can detect a primary breast
cancer in approximately 75 percent of women who present with
axillary adenocarcinoma/poorly differentiated carcinoma and a negative clinical
examination and mammogram
 Furthermore, the identification of a primary breast cancer by MRI may facilitate
breast-conserving surgery instead of mastectomy.

32. MRI

33. MRI
 A systematic literature review on the clinical utility of breast MRI in occult breast cancer
included eight retrospective studies, totaling 250 patients .
 A lesion suspect for primary breast cancer was located by MRI in 72 percent of cases
(pooled mean), which in 85 to 100 percent of cases represented a malignant breast
tumor.
 The pooled sensitivity and specificity of MRI for breast cancer detection in the only two
studies that reported histopathologic confirmation was 90 and 31 percent, respectively.
 Breast MRI revealed a lesion that was amenable to lumpectomy in about one-third of
cases, although some of the patients who were eligible for lumpectomy elected to
undergo mastectomy instead.

34. MRI - Problem
 High false-positive rates (up to 29 percent of all MRI scans and difficulty in
localizing small contrast-enhancing foci.
 All suspicious findings on MRI require pathologic confirmation.
 Some lesions found on MRI can be identified on subsequent, targeted
"second-look" ultrasound (US) and may then be biopsied under US guidance.
 US correlate findings have a high likelihood of malignancy.
 For the remaining lesions, targeting requires MRI guidance.

35. MRI
 Bilateral breast MRI is now considered a standard approach to evaluation of
the breasts in such patients
 Breast MRI should be performed with a dedicated breast coil by expert breast
imaging radiologists at institutions that have the capability to perform MRI
guided needle biopsy and/or wire localization of the findings

36. NICE Clinical Guidance (CG104)
Metastatic malignant disease of unknown primary origin in adults:diagnosis and
management
• Breast MRI
– Refer patients with adenocarcinoma involving the axillary nodes to a breast
cancer MDT for evaluation and treatment. If nobreast primary tumour is
identified after standard breast investigations, consider MRI to identify lesions
suitable for targetted biopsy
• MRI can detect primary breast cancer disease site in up to 70%
• MRI has high sensitivity but low specificity
• MRI biopsy can confirm primary site of disease
• This can guide appropriate surgical management

37. Role of PET
PET has low sensitivity but high specificity
May be used to monitor response to treatment

38. PET CT Scan
 Sensitivity- 84%
 Specificity- 84%
 Improve staging accuracy by detecting more metastasis than MRI or CT(20 %
More)
 Less accurate and poor anatomical configuration than MRI
 NCCN doesn’t recommend PET CT scan for routine screening for CUP
 NCCN recommends PET CT when considering local or regional therapy with
curative intent,

39. PET MRI Fusion
 Hybrid imaging
 Low ionizing
Radiation.
 Less
misclassification
of FDG uptake
than CT
PET CT(%) PET MRI(%)
TUMOUR DETECTION
Sensitivity 85 97
Specificity 69 73
LYMPH NODE METASTASIS
Sensitivity 93 100
Specificity 93 93
DISTANT METASTASIS
Sensitivity 97 100
Specificity 82 100

40. MANAGEMENT OF PATIENTS WITH
NORMAL IMAGING WORKUP

41.  In the absence of a palpable breast mass and normal imaging workup of both
breasts, the mammary origin of a
metastatic adenocarcinoma/poorly differentiated carcinoma to the axillary
lymph nodes cannot be established with certainty.
 However, if the histologic and IHC analysis is compatible, these patients are
treated according to established guidelines for anatomic stage II breast cancer

42. Completion of the staging workup
 Recommendations from the NCCN for workup of patients with isolated
axillary metastases from adenocarcinoma or a poorly differentiated carcinoma
suggest only a chest and abdominal CT scan .
 As with patients who have an identified breast primary and axillary nodal
metastases, radionuclide bone scan is reserved for symptomatic women or
those with an elevated serum alkaline phosphatase.
 The utility of PET scanning is controversial.

43. Locoregional treatment
 All patients should undergo axillary lymph node dissection (ALND).
 Besides providing prognostic information that will guide further treatment,
dissection aids local control.
 About one-half of patients with occult breast primaries will be found to have
four or more positive lymph nodes, an indication for postmastectomy chest
wall irradiation

44. The optimal treatment of the ipsilateral breast
 It is controversial.
 For women who do not have a discrete lesion identified by breast imaging,
the options are
 Modified Radical Mastectomy,
 Breast-conserving treatment using whole breast radiation therapy (RT),
 Observation alone.

45.  Patients who undergo mastectomy with ALND may have a more favorable
outcome compared with patients undergoing ALND.
 However, the same study showed that mastectomy and ALND had similar
outcomes with whole breast RT and ALND

46. Mastectomy
 A standard approach is to perform a modified radical mastectomy (MRM) at the time of
ALND.
 A breast malignancy will be found upon histologic review of the mastectomy specimen in
approximately 65 percent of patients .
 The primary tumor is usually less than 2 cm in diameter; in occasional patients, only
carcinoma in situ is identified.
 The benefits of local treatment were addressed in a retrospective analysis of 51 cases of
occult breast cancer in which women who had mastectomy had a markedly lower rate of
local recurrence compared to those who had no local therapy (77 versus 26 percent) .
Furthermore, disease-free and overall survival were also superior in the mastectomy group.

48. Radiation
 The role of whole breast RT as a breast-conserving alternative to mastectomy is
unclear.
 There are no randomized trials comparing this approach to mastectomy, and the
only available data are from small retrospective case series.
 Whole breast radiotherapy as an alternative to mastectomy was first reported by
Vilcoq et al in 1982
 Subsequent studies suggested similar local control and survival to mastectomies

49. Radiation
 Doses of 40Gy 15#and 50Gy 25# can be used
 Chest wall radiotherapy after mastectomy is consistent with benefits patients
with breast primary and involved nodes
 Radiotherapy may also be needed to the upper axilla and/or SCF depending
on the extent of nodal involvement.
 If axillary dissection has not been used the whole axilla should be treated

50.  53 patients with occult breast cancer, there was a trend toward lower five-year risk of an
ipsilateral breast tumor recurrence in patients who received RT compared with those
who did not (16 versus 36 percent).
 Similarly, the five-year rate of locoregional recurrence was lower in the RT group (28
versus 54 percent) and breast cancer-specific survival was significantly higher (72 versus
58 percent, p=0.0073).

51. Observation
 In some of the more recent case series of patients with an adenocarcinoma of
unknown primary in the axillary nodes, an occult primary breast cancer has
been identified in fewer mastectomy specimens, perhaps as a result of
improvements in imaging modalities (e.g, breast MRI).
 Overall, approximately one-half of these women will develop an in-breast
local recurrence.

52. BCT/MRM- 64.9%
ALND- 58.5%
Observation – 47.8%
P=0.4

53. Thus, in view of the high percentage of patients who will develop a
clinically manifest tumor recurrence and the possible adverse effect on
survival, observation of the breast without definitive local therapy is
generally not recommended at most institutions.

54. Adjuvant systemic therapy
 The benefit of adjuvant systemic therapy has not been systematically studied
among women presenting with axillary metastases and an occult primary
breast cancer.
 It seems reasonable to extrapolate from modern treatment principles for
clinically apparent breast cancer, which includes adjuvant systemic therapy for
patients with node-positive disease.
 Guidelines from the NCCN, recommend chemotherapy for all women with
node-positive breast cancer, regardless of hormone receptor status

55. Adjuvant systemic therapy
 The addition of trastuzumab to adjuvant chemotherapy improves outcomes in
patients with HER2-overexpressing tumors.
 Adjuvant hormone therapy is recommended after the completion of
chemotherapy for women with hormone-responsive tumors.

56. Adjuvant systemic therapy
 The addition of pertuzumab to trastuzumab and multiagent chemotherapy in
the neoadjuvant setting has been shown to improve pathologic complete
response in patients with axillary node-positive breast cancer and can also be
used in occult breast cancer.

57. Treatment of malignant Fixed axillary
nodes (presumed breast primary)
• Patients can present with operable nodes or fixed inoperable nodes
• Operable nodes can be treated with initial surgery of axillary node dissection or
neoadjuvant therapy followed by axillary surgery.
• Neoadjuvant therapy can be chemotherapy +/- anti-HER2 treatment or endocrine
therapy (in older patients with ER+ disease)
• Inoperable nodes are treated with primary chemotherapy +/- anti-HER2 treatment and
surgery if sufficiently downstaged

59. A systematic review
• Based on 26 retrospective studies, published between 1975 and
2006, with total of 689 patients
– Incidence of 0.12-0.67%
– Mean age 52.4yrs (66% postmenopausal)
– After AND, 48% N1 and 52% N2/3
– Among 446 patients who had mastectomy, an occult breast primary was identified histologically in
321 (72%)
– MRI revealed primary in 96/162 patients (59%)
Pentheroudakis G et a. Breast cancer Res Treat 2010; 119:1-11

60. Outcome
– 5-year survival ranged from 59-88% (median follow-up of 62
months)
– Some studies compared survival with stage-matched patients
with node-positive resected breast cancer and outcome reported
as similar
Pentheroudakis G et a. Breast cancer Res Treat 2010; 119:1-11

61. Systemic treatment
In the systematic review by Pentheroudakis
– Chemotherapy used in only 40% of women
– Only 5 women (1%) received an anthracycline-taxane
combination
– No information on use of neoadjuvant chemotherapy from
individual studies
– As studies were small the impact on outcomes could not be
determined
– Preceded the introduction of trastuzumab
Pentheroudakis G et a. Breast Cancer Res Treat 2010; 119:1-11

62. Management of the axilla
• Axillary dissection provides prognostic information and local control
• Level I and II axillary node dissection has been used in the majority
of published studies
• Axillary excisional biopsy and subsequent radiotherapy is an
alternative
• Axillary relapse rates were higher when axillary dissection was not
used and excision +/- radiotherapy used, but this is from an era
when systemic treatment was less effective than what is currently
used
Pentheroudakis G et a. Breast cancer Res Treat 2010; 119:1-11

63. Conclusion
• Axillary metastases with unknown breast primary is an uncommon
presentation of breast cancer
• Characteristics of T0 N1 patients similar to those with stage II disease
• Breast MRI will identify many of the breast primaries that were not
detected by mammography or US
• Axillary dissection provides prognostic information and local control
• Chemotherapy may be used before or after surgery

64. • Ductal adenocarcinoma (40% positive ER/PR)
• Mean age 52 years
• Should be managed as stage II breast cancers
 axillary dissection with ipsilateral breast radiotherapy or MRM
 adjuvant chemo/hormone therapy
• 5- year survival : 72%
Women with adenocarcinoma involving axillary nodes

65. Management of the breast
– Mastectomy -59%
– Whole breast radiotherapy- 26%
– Observation-15%
• When mastectomy was used breast malignancy was found in 72%
of cases (with an additional 6% having DCIS)
• When the breast was not treated, a primary subsequently developed
in the untreated breast in 42% of cases (46/110)
• Breast cancers developed in the untreated breast 4-64 months from diagnosis

66. Conclusion
 Chemotherapy before surgery is the treatment of choice in patients with large
volume axillary disease
 For HER2 positive disease anti-HER2 therapy with trastuzumab and
 pertuzumab is used
• Treatment of the breast with mastectomy or radiotherapy is required
to avoid a high risk of local relapse

69. Introduction
 The inguinal area is a relatively uncommon metastatic site of CUPS
 There has been a wide variety of primary sites from where inguinal nodal
metastasis has been reported.
 In one of the largest series, involving more than 2,000 patients with inguinal
nodal metastasis, the primary site could not be identified in 22 (1%), even
after a significant period of follow-up.
.
 .

70. Introduction
 The vast majority of patients with SCC involving inguinal lymph nodes have a
detectable primary site in the genital or anorectal area (including the surrounding
skin).
 ●In women, careful examination of the vulva, vagina, and cervix is important, with
biopsy of any suspicious areas.
 ●Men should undergo a careful inspection of the penis.
 ●In both sexes, digital rectal examination and anoscopy should be performed to
exclude anorectal lesions.

72. Introduction
 The clinical investigative approach toward CUPS patients is mainly directed
according to the histopathology, and every attempt should be made to obtain
a good tissue sample for detailed IHC analysis.
 Investigations should involve a multi-modality approach.
 The role of PET scan is yet to be established but has the potential to modify
the treatment in some patients whose tumor was localized with CT.

73.  Identification of a primary site in these patients is important since therapy is
potentially curative for patients with carcinomas arising in the anogenital
region, even after spread to regional lymph nodes.

74. IMAGING
 Modern imaging modalities such as CT, PET, or CT/PET scanning have gained
widespread acceptance as routine and useful staging methods for
confirmation of CUP.
 In evaluation of metastatic spread to locoregional lymph nodes, CT/PET
is significantly more accurate than CT.

75.  Since CUPS in the inguinal region is rare, there is a paucity of literature on the
management of such patients, and no clear guidelines are described.

77. Treatment- Surgery
 The mainstay of treatment is surgery, with complete surgical excision through
systematic lymph nodal dissection being mandatory.
 Aggressive surgical treatment including vascular resection and reconstruction with
grafting may be required to achieve tumor-free margins .(Anecdotal reports)

78. Treatment- RT
 Although role of postoperative radiotherapy is not clearly defined.
 It is thought that, in the presence of extensive nodal involvement and/or
extranodal spread of tumor, postoperative radiotherapy should be used as it
would be with any known primary site with squamous cell carcinoma.
 55 Gy in 40 #
 Fields?

79. Treatment- NACT
 Bulky nodes

80. Conclusion
 Carcinoma of unknown primary with inguinal metastasis is a rare entity.
 Investigations should be directed to identify the primary site according to
histopathology.
 Although there are no clear guidelines for the management of such patients,
treatment should be multimodal, including aggressive surgical resection, and
postoperative radiotherapy.
 The possible role of chemotherapy is unknown.
 A diligent follow-up is a must.
 In the future, molecular studies may increase our ability to distinguish
subtypes of CUSP and treat them differentially.

83. Definition
 The presentation of metastatic neck lymphadenopathy without the development of a
primary lesion within a subsequent five-year period.
 The term ‘carcinoma of unknown primary origin’ (UPC or CUP) should be used if no
evidence of primary tumour is found after adequate clinical examination, fibreoptic
endoscopy, imaging investigations which include fluorine 18-labelled deoxyglucose
positron emission tomography (FDG-PET) ideally with CT fusion imaging (FDG) PET-CT
and biopsy of putative mucosal sites.
 Ref- Stell and maran’S Textbook of Head & Neck Surgery 5th edition