general oncology from devita presentation

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.