ITC, or isolated tumor cells, refer to small clusters of cancer cells that break off from the primary tumor and circulate in the bloodstream. While only 0.05% of circulating tumor cells survive to form metastases, detection of ITC can provide prognostic information. ITC can be detected using morphological or non-morphological methods like immunohistochemistry and PCR, but non-morphological methods have a higher false positive rate. The presence of ITC may have prognostic value and inform more aggressive treatment, but the evidence for their clinical significance is equivocal for many cancer types. ITC detection is most clearly prognostic in breast cancer, while data is mixed for colorectal cancer.

1. ISOLATED TUMOR CELLS
Dr Nishith Modi

2. THANK YOU…

3. ITC
• “cancer infection”
• Described first by Christopherson
• ITC ≠ Micro metastasis
• ONLY 0.05% of circulating tumor cells survive & initiate a metastatic
focus

5. DETECTION OF ITC
ITC
MORPHOLOGIC IHC
NONMORPHOLOGIC
FLOW CYTOMETRY
PCR

6. • FALSE POSITIVE : cases in which ITC are detected but metastasis
cannot be found & never develops
• MORPHOLOGIC = DIFFICULT TO REPORT = LOW FALSE POSITIVE
• NONMORPHOLOGIC = EASY TO REPORT = HIGHER FALSE POSITIVE

7. POSSIBLE CLINICAL RELEVANCE
• May have prognostic value
• May be used as selection criteria for more aggressive treatment options
• To monitor the efficacy of adjuvant treatment
• Majority of ITC are in nonproliferating phase, may be a target for antibody
therapy
• Role yet to be proven

9. Proposed classification & coding
• lymph node metastasis is not found histologically
• morphologic examination for isolated tumor cells, the symbol “i” is used in
parentheses after pN0.
• nonmorphological examinations the symbol “mol” (for molecular) is used.
• In the case of sentinel lymph nodes, the additional symbol “(sn)” may be
used e.g., pN0(i1) (sn)

12. ITC & BREAST CANCER : YES/NO/MAY BE?
• Detailed examination of sentinel nodes by serial sectioning and
immunohistochemical staining can result in the detection of
extremely small tumors.
• AJCC :
• isolated tumor cells (ITC) = tumor cell clusters that are ≤0.2 mm
• micro metastases (MM) = >0.2 mm in diameter but ≤2 mm, denoted as
pN1mi.
• It was initially reported that the presence of ITC or MM is not an
adverse prognostic factor in breast cancer.

13. • In 2009, Hansen et al.
• 8-year overall and disease-free survival of patients with negative nodal status, ITC, or MM were not
significantly different.
• They concluded that patients with ITC or MM do not have a worse prognosis than node-negative
patients. However, they also showed that patients with ITC or MM underwent adjuvant
chemotherapy and axillary LN dissection more often than node-negative patients.

14. • Conversely, de Boer et al.
• assessed a large amount of data from the Netherlands Cancer Registry
• early-stage breast cancer patients with ITC or MM in regional LNs who had
not received adjuvant therapy had a reduced 5-year disease-free survival rate.
• They also performed a meta-analysis that showed that the presence
of metastases of ≤2 mm in regional LNs is associated with poor
survival.

15. • Andersson et al. reported that MM have a negative impact on survival
whereas ITC do not. However, they also found that patients with ITC
underwent axillary LN dissection significantly more often than those
with no detected LN deposits.
• Leidenius et al. reported that the presence of ITC is an adverse
prognostic factor in early breast cancer.
• These reports suggest that small tumor deposits have a negative
impact on survival; however, the difference in survival between ITC or
MM and node-negative cases is small and might be eliminated by
adjuvant treatment.

16. BREAST: ITC, MICROMETS & AJCC 8TH
• Isolated tumor cell clusters (ITC) are defined as small clusters o f cells not larger
than 0.2 mm, or single tumor cells, or fewer than 200 cells in a single histologic
cross-section.
• ITCs may be detected by routine histology or by IHC methods.
• Nodes containing only ITCs are excluded from the total positive node count for
purposes of N categorization but should be included in the total number of nodes
evaluated.
• the number of nodes with only ITCs should be noted in the pathology report.

17. ENDOMETRIUM & ITC

18. • significantly higher rate of deep myometrial invasion
• no significant differences between the two groups in
• tumor histology
• cervical involvement
• peritoneal cytology
• number of LNs assessed
• type of adjuvant therapy.
• ITC or MM may be a predictor of extra pelvic recurrence, especially para-
aortic node recurrence when implementation of para-aortic
lymphadenectomy is not considered.

19. ITC & LUNG CANCER

20. • It recently became evident that isolated tumor cells undetectable by conventional tumor staging are
frequently present in bone marrow of patients with apparently localized non-small cell lung cancer (NSCLC).
• Cytokeratin-18-positive cells in bone marrow were demonstrated in 59.7% patients at the time of primary
surgery and in 6 of 12 representative patients analysed twice 3 to 18 months after surgery.
• In patients without histopathological lymph node metastases (Pn0) the occurrence of 2 or more tumor cells
in bone marrow at primary surgery was a strong and independent predictor for overall survival (p =0.007) in
univariate analysis.
• The multivariate analysis showed a 2.8 times increased risk for shorter survival in patients with disseminated
tumor cells versus patients without such cells.
• Four of the 6 patients with a positive cytokeratin status after surgery developed a tumor recurrence 11 to 44
months after the operation, while none of the patients with a negative bone marrow at all time intervals
showed a tumor relapse.

21. • Minimal residual bone marrow involvement is an independent
prognostic factor for overall survival in patients with node-negative
NSCLC, which may help to identify patients in need of an adjuvant
systemic therapy.
• The postoperative persistence or reappearance of tumor cells in bone
marrow indicates that these are not only shedded cells but rather
represent true metastasis.

22. • At multivariate analysis, only T status resulted to be a factor significantly
influencing long-term disease-free (p = 0.0022) and disease-related survival
(p = 0.013); in particular the presence of lymph nodes micro metastatic
tumor cells (ITC or pN1mi) was confirmed not to affect long-term survival.

23. ITCs in Colorectal Ca : Devita
• Sirop et al. found only 8 papers that reported definitely poorer outcomes, whereas the remainder were
either equivocal in their conclusions or demonstrated no influence on outcome at all.
• Jeffers et al. evaluated LNs from 77 patients who were found to have negative LNs by routine examination
with immunocytochemical staining for cytokeratin AE1:AE3. Nineteen patients (25%) were found to have
immunohistochemical evidence of micrometastases; however, there was no difference in survival between
the microscopically positive and negative patients.
• Although the actual TNM staging is not altered by the presence of micrometastases, many clinicians choose
to regard the presence of such a finding as a poor prognostic variable in their consideration of adjuvant
treatment.

24. • Immunohistochemistry showed that 5% of pts had micro metastases and 26%
had isolated tumor cells. A median of 5 years of follow-up revealed local or distant
recurrence in 23% of stage I/II patients with micro metastases or isolated tumor cells,
compared with 7% without micro metastases or isolated tumor cells (P = .010).
• Five-year disease-free survival for patients with and without micro
metastases or isolated tumor cells was 75% and 93%, respectively (P = .012). When
analysed separately, patients with isolated tumor cells (excluding micro metastases) had
also lower survival than node-negative patients (P = .012).
• CONCLUSION: The presence of micro metastases and isolated tumor cells was found to
be a prognostic factor for recurrence and disease-free survival.

25. ITCs in Colorectal Ca
• Immunohistochemical staining with an ant cytokeratin antibody is
useful in identifying isolated tumor cells in lymph nodes missed in
routine haematoxylin-eosin staining, but clinically it seems to be of
little prognostic value in patients with Dukes B colorectal carcinoma.

27. • “ In CRC, In bone marrow and peritoneal cavity samples, the
detection rate increased in parallel with the tumor stage.
Interestingly, already 19% of patients with a stage I tumor had
positive cells within the peritoneal cavity. “
• After 4 years, 28% of patients with positive immunocytologic findings
in the peritoneal cavity were alive versus 60% of patients with
negative findings (p = 0.0079). No correlation was found by evaluating
the results of bone marrow samples.
• Similar impact was noticed in gastric cancer subjects.

28. • Strongly indicated that in gastrointestinal cancer, the investigation of
peritoneal cavity cells is more relevant than the bone marrow
approach.
• The cumulative survival rates significantly correlated with the
immunocytologic findings.
• Patients with small tumors (stage I or II) and positive peritoneal cavity
samples showed a worse prognosis.
• Strongly suggested that the immunocytologic staining of peritoneal
lavage samples serves as a new prognostic marker.

29. • Proven role in carcinoma breast
• Equivocal data for role in CRC
• Inconclusive evidence for role of itc in Ca endometrium, GI
Malignancy & cutaneous malignancies.
• May be viewed as a means for targeted therapy.