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 Table of Contents  
Year : 2017  |  Volume : 29  |  Issue : 2  |  Page : 111-114

Micrometastasis: Neglected enough!

Department of Oral Medicine Diagnosis and Radiology, Krishnadevaraya College of Dental Sciences and Hospital, Bengaluru, Karnataka, India

Date of Submission11-May-2016
Date of Acceptance22-Oct-2017
Date of Web Publication9-Nov-2017

Correspondence Address:
Prathyusha Chavva
Department of Oral Medicine Diagnosis and Radiology, Krishnadevaraya College of Dental Sciences and Hospital, Bengaluru - 562 157, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiaomr.JIAOMR_53_16

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Oral cancer, being the sixth most common cancer in the world, accounts for approximately 13% of deaths worldwide. Metastasis to the lymph nodes is one of the major prognostic factor for oral cancer. Micrometastasis are microscopic deposits of malignant cells lodged in lymph nodes. Tumor recurrence usually reflects the presence of such deposits which cannot be detected initially by conventional methods. Early screening of such cells using immunological and molecular markers would help in better staging of the primary tumor followed by prompt treatment, thus reducing tumor relapse. Therefore, the concept of micrometastasis has resulted in a paradigm shift in the staging of epithelial tumors and the overall understanding of the malignant process.

Keywords: Molecular detection, oral field cancerization, sentinel lymph node, tumor staging

How to cite this article:
Chavva P, Devaiah D, Vasudevan V, Venkatappa M. Micrometastasis: Neglected enough!. J Indian Acad Oral Med Radiol 2017;29:111-4

How to cite this URL:
Chavva P, Devaiah D, Vasudevan V, Venkatappa M. Micrometastasis: Neglected enough!. J Indian Acad Oral Med Radiol [serial online] 2017 [cited 2021 Dec 3];29:111-4. Available from: https://www.jiaomr.in/text.asp?2017/29/2/111/217918

   Introduction Top

Oral cancer is a serious public health problem accounting for over 7.6 million deaths annually across the globe. In India, the incidence of oral cancer is 73.6 per 100,000 population. The overall mortality rate for intraoral cancer remains high at approximately 50%, even with modern medical services available.[1] Five-year survival rates of oral cancer are not improving despite the progression of multidisciplinary treatment because distant metastasis is the major cause of death in individuals suffering from cancer. Metastasis, the spread of tumors, is one of the important characteristics of malignancy, which has a definite bearing on prognosis.[2] Micrometastasis is a microscopic deposit of malignant cells distinct from the primary lesions.[3],[4] Lymph node metastasis decreases survival by 50%, and spread beyond the lymph node capsule further decreases survival.[5] Tumor recurrence and failure of treatment usually reflects the presence of occult malignant cells, which are not detected by diagnostic procedures.[6] At present, there are various ways of identification of micrometastasis, i.e. histopathological serial sectioning, molecular methods of detection by the use of polymerase chain reaction (PCR) assays,[7] detection of molecular markers of specific mutations,[8],[9] keratin mRNA (mRNA) detection,[10] etc. The present review discusses the pathology of micrometastasis, methods of detection of lymph node micrometastasis, and the significance of detecting circulating tumor cells and bone marrow deposits in head and neck cancer.

   Micrometastasis Top

De Masceral et al. defined micrometastasis as metastatic deposits which measured less than 0.5 mm in diameter.[11] Tumor deposits within the lymph nodes were classified and staged according to the revised guidelines which were set by the UICC (International Union Against Cancer): metastasis ≥2 mm, micrometastasis >0.2 and <2 mm, and isolated tumor cells ≤0.2 mm.[12] The detection of micrometastasis has resulted in an “upstaging of tumors” and the incorporation of micrometastatic disease into the TNM staging system.[13] The UICC/TNM protocols have been established for head and neck sentinel nodes.[12]

Generic TNM coding for sentinel nodes:

  • pNX (sn) Sentinel lymph node could not be assessed
  • pN0 (sn) No sentinel node metastasis
  • pN1(sn) Sentinel node metastasis.

Sentinel nodes with micrometastasis only are identified by (mi):

  • pN1 (sn) (mi) Single ipsilateral node with micrometastasis
  • pN2 (sn) (mi) Multiple ipsilateral nodes with micrometastasis.

Sentinel nodes with isolated tumor cells are coded separately for morphological and nonmorphological techniques such as PCR or flow cytometry:

  • pN0 (i-)(sn) No sentinel lymph node metastasis histologically, negative morphological findings for isolated tumor cells (ITC)
  • pN0 (i+)(sn) No sentinel lymph node metastasis histologically, positive morphological findings for isolated tumor cells (ITC)
  • pN0 (mol-)(sn) No sentinel lymph node metastasis histologically, negative nonmorphological findings for isolated tumor cells (ITC)
  • pN0 (mol+)(sn) No sentinel lymph node metastasis histologically, positive nonmorphological findings for isolated tumor cells (ITC).

This has been evaluated in the study conducted by Atula et al. to study the micrometastasis in sentinel lymph nodes in oral and oropharyngeal squamous cell carcinoma.[14] Regional metastasis to the lymph nodes had a definite bearing on prognosis. Any proposal to treat micrometastasis must first clarify which detection methods should be used to identify these malignant cells.

   Detection of Lymph Node Micrometastasis Top

Oro and oropharyngeal cancers spread through lymphatic pathways to the cervical lymph nodes. Thus, nodal status determines prognosis in epithelial malignancies and governs the indications for adjuvant therapy.[15] Early detection of micrometastatic disease could identify the patients who are most likely to benefit from adjuvant therapy.[16] The various methods of detection have been described below.

Sentinel lymph node biopsy

Lymphatic afferents from a primary tumor drain into a single focus, termed sentinel node, before drainage into regional lymphatic basin.[17] It localizes the first draining node of a tumor site for more accurate histological staging.[18],[19] The procedure consists of injecting a radiolabelled colloid around the primary tumor that drains into the first echelon lymph nodes, which can be detected by the use of gamma probes.

Advantages of sentinel node biopsy

  1. Detailed pathological examination for micrometastatic deposits are possible because of small tissue volume
  2. Reduces the morbidity of nodal acquisition and may obviate formal lymph node dissection in patients with negative sentinel nodes
  3. Accurate identification of metastatic cells are possible because of rigorous examinations of multiple sections through the nodes.

The Sentinel Node European Trail (SENT) pathology protocol [12] has advised evaluation of the sentinel lymph node biopsy that has the ability to detect all micrometastatic deposits with certainty. It was used in oral cancer by Blide et al.[20] who demonstrated upstaging from 4 to 22% using the SENT protocol.


Epithelial cells in the lymph nodes may be detected by the use of specific anti-cytokeratin (CK) antibodies against cytokeratin proteins, which form an essential constituent of the cytoskeleton of the epithelium, serving as reliable markers for identifying micrometastasis.[21] This technique has been shown to be far superior to hematoxylin and eosin (H and E) staining alone.[22] Because CKs are highly expressed in epithelial tumors, CK19 and CK20 have been evaluated frequently. Germani et al. conducted a study to identify Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) by immunohistochemical analysis in oral SCC and concluded that MT1-MMP positivity is suggestive of aggressive tumor types, evidenced by the presence of micrometastasis.[23]

Molecular detection

Molecular assays are 500 times more sensitive than standard histopathological techniques. Initially, PCR-based assays using p53 gene for detection of micrometastasis in head and neck cancer was carried out by Brenan et al.[8] They found that only 5 of 33 nodes examined by light microscopy had evidence of metastasis, whereas it increased to 11 of 33 nodes by the use of molecular studies.

A second method of identification used was reverse transcriptase (RT)-PCR, in which RNA is prepared and reverse-transcribed to complementary DNA, which is amplified with primers for gene of interest. Hamakawa et al.[10] studied the expression of keratin mRNA for detecting micrometastasis in cervical lymph nodes of oral cancer. Of 166 histologically tumor free lymph nodes of oral cancer, 24 (14.4%) were found tumor positive by the detection of K13 RT-PCR. Squamous Cell Carcinoma Antigen mRNA (SCCA mRNA) has been used to detect micrometastasis in cervical lymph nodes for head and neck cancer using nested PCR. Hamakawa et al.[24] reported detection of micrometastasis in 18.7% of cases, suggesting that SCCA mRNA can be a specific marker for detection of micrometastasis.

Detection of micrometastasis in bone marrow and blood

Recurrence in oral cancer is because of the presence of tumor cells, which are disseminated and detected in the hematopoietic cell compartment. Many protocols currently employed for detection of these isolated tumor cells rely on examination of monocytes obtained from peripheral or central venous blood or bone marrow. The methods commonly used for detection are immunocytochemistry, flow cytometry, and RT-PCR.[25] It has been of poor prognostic significance in breast, lung, and colorectal cancer,[26] and little has been known about its role in head and neck cancer. Wollenberg et al. conducted a study in 108 patients with SCC of the head and neck region and identified 41 patients with bone marrow micrometastasis.[27]

Thus, if molecular or immunohistologic information is taken into account when staging is performed, a significant percentage of cases found to have micrometastasis would be upstaged; and taken together with other clinicopathological features of the tumor, this information might influence the decision regarding the need for postoperative radiotherapy, and possibly prevent treatment failure in the neck. The concept of oral field cancerization (OFC) was first described by Slaughter et al. in 1953, which highlighted that there are large areas of the head and neck that get exposed to the carcinogen making it more susceptible for development of many foci of malignant transformation.[28] van Oijen MG et al. in 2000, explained the concept of OFC on the basis of two types of migration [29] i.e.,

  1. Migration of tumor cells, example saliva, i.e., micrometastasis
  2. Intraepithelial migration of the progeny of the initially transformed cells [Figure 1].
Figure 1: Mechanisms of oral field cancerization showing (a) independent events, (b) migration of tumor cells, and (c) intraepithelial migration of progenitor cells (Jayam R. Oral field cancerizaton: A review. J Indian Aca Oral Med Radiol 2010;22:201-5)

Click here to view

As a result of proteolysis, cells from the primary tumor invade the blood vessels and migrate to a distant site where they adhere to the walls of the capillaries causing invasion of a new organ. Such cells are not detectable by conventional procedures and can survive for a longer time. The “micrometastatic concept” lays focus on the potential capacity of the tumor cells to evade immune surveillance, invade vascular channels, and develop into macroscopic disease [Figure 2].[14]
Figure 2: Metastasis of tumor cells (Pantel K, Cote RJ, Fodstad Ø. Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 1999;91:1113-24)

Click here to view

Majority of tumor cells undergo apoptosis, but a few which manage to survive become lodged in nodes depending on the local environment and host immune response. Tumor deposits ≤2 mm survive because of diffusion of nutrients from surrounding tissue, but >2 mm require neo-angiogenesis for tumor growth. If this does not occur, tumor remains dormant. A proportion of such deposits may acquire mutations overtime and ultimately proliferate to produce a new tumor focus. These provide a niche for evolution of tumor cells with a phenotype conducive to development of distant metastasis. Thus, early detection of micrometastasis has offered valuable insight into the behaviour of malignant cells, improving staging accuracy followed by prompt treatment enhancing survival of the patient.

   Conclusion Top

Although progress has been made in clinical oncology, the presence of minimal residual cancer in the form of micrometastasis has limited improvement in lethality rates. A question arises as to whether these cells are dormant representation of residual disease or do they exist in a dynamic state despite host immunity. As lymph node micrometastasis has been shown to be an important adverse prognostic factor in oral and oropharyngeal SCC, the very least that can be done is to incorporate detection of micrometastasis into future clinical trials and management strategies!

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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Prakash AR, Kumar GS, Shetty P. A study on the detection of micrometastasis in the cervical lymph nodes of oral squamous cell carcinomas by serial sectioning. J Clin Diagn Res 2011;5:78-89.  Back to cited text no. 2
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Myers EN, Gastaman BR. Neck dissection: An operation in evolution: Hayes Martin lecture. Arch Otolaryngol Head Neck Surg 2003;129:14-25.  Back to cited text no. 5
Patridge M, Li S-R, Pateromichelekis S, Francis R, Philips E, Huang XH, et al. Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment. Clin Cancer Res 2000;6:2718-25.  Back to cited text no. 6
Mc Donald LA, Walker DM, Gibbins JR. Cervical lymph node involvement in head and neck cancer detectable as expression of a spliced transcript of type II keratin K5. Oral Oncol 1998;34:276-83.  Back to cited text no. 7
Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, Koch WM, et al. Molecular assessment of histopathological staging in squamous cell carcinoma of the head and neck. New Engl J Med 1995;332:429-35.  Back to cited text no. 8
Brennan JA, Siransky D. Molecular staging of head and neck squamous carcinoma. Cancer Metastasis Rev 1996;15:3-10.  Back to cited text no. 9
Hamakawa H, Fukuzumi M, Bao Y, Sumida T, Kayahara H, Onishi A, et al. Keratin mRNA for detecting micrometastasis in cervical lymph nodes of oral cancer. Cancer Letters 2000;160:115-23.  Back to cited text no. 10
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Basu D, Singh T, Singhal RN. Micrometastasis in bone marrow in breast cancer. Indian J Pathol Microbiol 1994;37:159-64.  Back to cited text no. 13
Atula T, Hunter KD, Cooper LA, Shoaib T, Ross GL, Soutar DS. Micrometastasis and isolated tumor cells in sentinel lymph nodes in oral and oropharyngeal squamous cell carcinoma. Eur J Surg Oncol 2009;35:532-8.  Back to cited text no. 14
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Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392-9.  Back to cited text no. 17
Glass LF, Messina JL, Cruse W, Wells K, Rapaport D, Miliotes G, et al. The use of intraoperative radiolymphoscintigraphy for sentinel node biopsy in patients with malignant melanoma. Dermatol Surg 1996;22:715-20.  Back to cited text no. 18
Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early stage melanoma: A multicentre trial. Ann Surg 1999;230:453-63.  Back to cited text no. 19
Blide A, Von Buchwald C, Therkildsen MH, Mortensen J, Kiakegaard J, Charabi B, et al. Need for intensive histopathologic analysis to determine lymph node metastases when using sentinel node biopsy in oral cancer. Laryngoscope 2008;118:408-14.  Back to cited text no. 20
Moel R, Franke WW, Schiller DI, Geiger B, Krepler R. The catalogue of human cytokerating: Patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31:11-24.  Back to cited text no. 21
Cutait R, Alves VA, Lopes LC, Cutait DE, Borges JL, Singer J, et al. Restaging of colorectal cancer based on the identification of lymph node micrometastasis through immunoperoxidase staining of CEA and cytokeratins. Dis Colon Rectum 1991;34:917-20.  Back to cited text no. 22
Germani RH, Civantos FJ, Elgart G, Roberts B, Franzmann EJ. Molecular markers of micrometastasis in oral cavity carcinomas. Otolaryngol Head Neck Surg 2009;141:52-8.  Back to cited text no. 23
Hamakawa H, Fukuzumi M, Bao Y, Sumida T, Onishi A, Tanioka H, et al. Genetic diagnosis of micrometastasis based on squamous cell carcinoma antigen mRNA in cervical lymph nodes of head and neck cancer. Clin Exp Metastasis 1999;17:593-9.  Back to cited text no. 24
Kell MR, Winter DC, O'Sullivan GC, Shanchan F, Redmond HP. Biological behaviour and clinical implications of micrometastases. Br J Surg 2000;87:1629-39.  Back to cited text no. 25
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Jayam R. Oral field cancerization: A review. J Indian Acad Oral Med Radiol 2010;22:201-5.  Back to cited text no. 28
  [Full text]  
van Oijen MG, Pieter JS. Oral field cancerization: Carcinogen induced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 2000;9:249-56.  Back to cited text no. 29


  [Figure 1], [Figure 2]


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