METASTASIS OF UNKNOWN ORIGIN

PREPARED BY: DR.KAVITHA P PALLED, SECONDARY DNB RESIDENT, DEPARTMENT OF ENT, NARAYANA HRUDAYALAYA.

INTRODUCTION

The definition of an unknown or occult primary carcinoma is 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.

Metastasis most commonly occurs to nodal levels II and III

with less frequent involvement of levels I,

IV, Vand VI.

Squamous carcinoma is the most common histological tumour

type.

Isolated supraclavicular nodal involvement is almost

invariably related to malignant disease arising below the

clavicles, with the most likely origin of squamous carcinoma being from lung and oesophagus and adenocarcinoma from thyroid,

breast, gastrointestinal and gynaecological tracts

One of the most important prognostic factors in head and neck cancer is the

presence or absence, level and size of metastatic

neck disease.

Many tumours of head and neck will

metastasize to lymph nodes and a number of factors control the natural history and spread of disease.

• Rof Several controversies about

the management

Varying practices,choices,modalities of

management.

Paucity of high level of evidence of many treatment

paradigms

Trend may be reversing with randomized control

trails and systemic reviews

Identifies the evidence based and discusses

the principles of management of head and neck HNSCC at initial presentation,

residual and recurrent disease

TUMOUR BIOLOGY AS RELATED TO METASTASIS

Tumours do not have primary lymphatics and cancer cells werethought to gain access to the lymphatic system through preexisting lymphatic vessels near the tumour.

Recent studies onanimal models have

shown that solid tumours can induce

Lymphangiogenesis.

Vascular endothelial growth factor(VEGF)-C and VEGF-D, secreted by the tumour,

Lymphangiogenesis

Binding to VEGF receptor-3, a tyrosine kinase receptor,

Expressed on lymphatic endothelial cells

This pathway is also the focus for research into ANTILYMPHANGIOGENETIC THERAPEUTICS.

Metastatic potential of primary tumours varies considerably,even among tumours of the same site and extent.

One factor that affects the metastatic potential is the GENETIC MAKE UP of the tumour.

• This metastatic profile includes genes related to -extracellular matrix,

-adhesion, -motility and -protease inhibition. • The products of thesegenes help local invasion and spread into the intra- andperitumoral lymphatics,

METASTATIC CASCADE.

METASTATIC CASCADE

CAM: E cadherin, -tissue architecture and differentiation, downregulated. -making the cancer cells free to migrate.

Active migration of cancer cells into lymphatics

is driven by the production of autocrine and paracrinecytokines, mediated by integrin receptors. Tumour cellhoming to lymph nodes is probably mediated by L-selectin, amigratory cell-cell interaction molecule.

INTEGRINS adhesion receptors, linkage cell cytoskeleton and the extracellular matrix.-Overexpressionincreased cellular motility and matrix metalloproteinases (MMP 1, 2, 3, 9 and 14) enhance migration. MMPs are produced by tumour and stromal cells, 'soil' plays in the metastatic cascade. A meta-analysis pooling data from 710 patients indicated that MMPs significant role in metastatic behaviour.CATHEPSINS are lysosomal endopeptidases promoting metastases.

• SUMMARY

Genotypic (e.g.. p53 and MET oncogene mutation),

Phenotypic (e.g. E cadherin downregulation) and

Microenvironmental(e.g. expression of VEGF-C) processes conspireto facilitate what is probably an inefficient process.

Role of the regional lymph node system in the spread of HNSCC has yet to be fully defined, not simple mechanical barriers, anti-tumour immunity, cytotoxic T lymphocytes. Defects in the antigen-

presenting machinery of the cancer cells and reduced expression of HLA class I antigens are the mechanisms

Evolved to avoid detection by immune effector cells

BEHAVIOUR OF DISEASE WITHIN THE CERVICAL LYMPHNODES

Multiple afferent lymph vessels bring lymph into the lymph node,branching extensively in the capsule of the node.

Several variations exist in the way afferent vessels interface with the node.

This is important in understanding patterns of lymph nodal infiltration and why extracapsular spread (ECS) can occur earlier

While the afferent channels may penetrate the capsule and discharge the lymph into the subcapsular sinus,many run obliquely into the capsule, while others travel along the capsule for considerable distances before penetrating it.

Valves are often found in these afferent channels that run on the capsule, forming a network of capsular lymphatics.

Toker9 described four distinct growth patterns of squamouscell carcinoma (SCC) within cervical lymph nodes:

1. Following initial cancerous deposits in the subcapsular sinus, growth within

the affected node takes place, replacing the architecture of the node before ECS occurs. Ultimately, ECS occurs by thedirect penetration and destruction of the capsule, orby the

arrest of further underlying capsular or juxtacapsular lymphatics.

2. Metastatic deposits extensively infiltrate the lymphatic sinuses, leaving

the germinal centres and trabeculae intact. ECS occurs by the direct

penetration and destruction of the capsule, or by the arrest of tumour emboli in underlying capsular or

juxtacapsular lymphatics.

3. A less common pattern involves the deposition of a malignant embolus

within the subcapsular sinus ' 'together with the simultaneous arrest of tumour

within capsular or juxtacapsular lymphatics. This results in the

coincident and equivalent proliferation of cancer both within and outside the

node.

4. Another uncommon metastatic pattern is where capsular or

juxtacapsular emboli grow wida no intranodal cancer. In these instances,

ECS can occur much earlier in the natural history of the disease

process.

Metastatic involvement of various lymph node regions

Usually progresses

from superior to inferior in an orderly fashion,

But it has been

shown that in

some situations

lymph node groups can

be bypassed, leading to '

SKIP METASTASES'.

Once tumour cells arrive at

a draining lymph node,

They can proliferate, die, remain dormant

or enter the circulation

HAEMATOGENOUS SPREAD From the node, efferent channelsleave the hilum to join the terminal collecting trunks (the right and left lymphatic ducts) and drainage is into the venous system.

There are other routes whereby cancer cells can access the bloodstream and these include entering directly from a node.

Vascularization of tumours usually occurs when growths are greater than 0.1-1 mm in size and following this, rapid rates of neoplastic growth and increased rates of vessel invasion can occur.

These may be released as single cells, cell clumps or a thrombus fragment containing tumour cells.

Very small numbers of cells in the circulation, low levels of tumour-specific markers and heterogeneity of marker gene expression transcripts, work in this field has been hampered.

However, using highly sensitive and specific techniques and a panel of tumour markers, circulating tumour cells have been demonstrated in the setting of HNSCC andshown to predict disease-free survival

CLINICAL IMPLICATIONS OF METASTASES

•

The presence of regional lymph node metastases acts as anindicator of the ability o f the primary tumour to metastasizelocally and to distant sites, rather than acting as an instigatorof distant metastases on their own

. Therefore, elective removal of regional lymph nodes serves as a biopsystaging procedure to ascertain whether or not metastaticdisease is present and to identify high risk patients who mightbenefit from systemic adjuvant therapy, but is not expected'todiminish the metastatic potentialThis is because lymph

node involvement indicates a host response which is permissivefor the development of metastases, not only i n theregional lymph nodes, but also to distant sites. Therefore, thedegree o f lymph node involvement should be regarded as anindirect index of the systemic tumour burden

This means that, like breastcancer, tumour-free survival depends more on the biology ofthe tumour present at the operation rather that the extent ofsurgery. This explains why patients with metastatic lymphnodes in HNSCC have a significantly reduced chance ofsurvival when compared with those who are disease free.

It has long been recognized that systemic spread can occurearly in man)' solid tumours and this includes HNSCC. Thequestion that one must ask is, ' I f cancer is a systemic disease,how can cure ever be effected?' Traditional teaching has been tooffer wide margin radical surgery to the neck, with the premisethat patients who have a large number of occult positive nodesfare better since these nodes are discovered earlier. This philo1sophy is now being questioned with regard to locoregionaldisease being cured with locoregional treatments, since recentadvances mean patients are now living longer only to die morefrequently of second primaries or distant metastases. Overallsurvival has not changed significantly.

It becomes clear from the above discussion that the spread ofHNSCC to the regional lymph nodes indicates an aggressivetumour where the tumour-host balance has swung in favour ofthe tumour. While there are structural and immunobiologica!mechanisms drat may affect tumour lysis within the lymph nodeitself, in a certain proportion of cases, systemic spread occursearly on. This can take place by lymphaticovenous or haematologicalroutes. These processes of spread and tumour arrest can beaffected by pre\ious treatment. As the systemic immunosuppressiveeffects of multimodaliry head and neck cancer therapyare taken into consideration, both the number and the complexityof modalities that are used become ever more important.

NECK LEVELS

1981,.the Memorial Sloan-Kettering Hospital published a number oflevels or regions within the neck which contain groups of lymphnodes representing the first echelon sites for metastases fromhead and neck primary sites

American Academy of Otolaryngology andHead and Neck Surgery i n 1991 has been updated by the

Committee for Neck Dissection Classification of the AmericanHead and Neck Society i n 2002 and is widely used:

Classification

Radical neck dissection Removal of levels l-V, accessory nerve, internal jugular vein and sternomastoid muscle

Modified radical neck dissection Removal of levels l-V dissected; preservation of one or more of the accessory nerve,Internal jugular vein orsternomastoid muscle (types1, II and III, respectively)

Selective neck dissection Preservation of one or morelevels of lymph nodes

Extended radical neck dissection Removal of one or more additional lymphatic and/or non-tymphatic structures(s) relative to a radical neck dissection, e.g. level VII,retropharyngeal lymph nodes, hypoglossal nerve

NECK DISSECTION TERMINOLOGY

The term'elective neck dissection (END) is used to describe any typeof neck dissection that is performed on the neck that isclinically and radiologically free of disease.

REGION-SPECIFIC LYMPHATIC DRAINAGE

The nasopharynx, nasal cavities and sinuses- levels II and III.

The oropharynx- levels II, III and IV.

The posterior parts of the oral cavity- level II/III.

Anterior parts of the oral cavity and tongue level Ia or levels II–IV.

The tongue especially is known to cause ‘skip metastases’ to level IV.

The supraglottis- levels III/IV.

Hypopharynx- levels III, IV, VI and VII

METASTATIC BEHAVIOUR IN THE PREVIOUSLY TREATED NECK

• Lymphatics mean that collateral channels form, and the ability to do this relates to the nature of connective tissue through which the lymphatics must grow.

• Mechanical effects can alter patterns of lymphatic metastatic spread and divert lymph flow to the contralateral neck and sometimes even cause retrograde spread.

Surgery can undoubtedly mechanically alter the

locoregional tumour

environment

Systemic cellular immune response is significantly compromised following

locoregional radiation therapy (RT) in head and neck cancer patients.

Radiation is associated with changes in the regional

lymph nodes and lymphatics in general. Thus, within a few days of starting RT, there is a decrease in

the numbers of lymphocytes within lymph nodes and thickening of the walls of both lymph nodes and

blood vessels can be noted.

Some of these changes explain why previous RT can cause lymphatic obstruction and

shunting of lymph both into the subdermal vessels and also to

the contralateral neck.

Micrometastases are deposits of cancer cells between 0.2 and 2mm in size. Presence of micrometastases upstages

the neck status (pN1mi)

Isolated tumour cells (ITC) are defined as malignant deposits within lymph nodes that measure r0.2mm in

greatest extent or appear as single cells or small clusters of 200 cells, detectable on standard processing or immunohistochemistry, that show no evidence of

metastatic activity.

Unlike micrometastases, the presence of ITCs does not upstage the pathological stage, with their presence being

denoted as pN0

PROGNOSTIC NODAL FEATURES

Site, size and number

Low neck nodes

Extracapsular spreadMorphology

Bilateral and contralateral

spread

• Tumour site• Tumour size• Tumour thickness• Previous treatment• Tumour recurrence

Factors implicate

d in pattern of metastatic nodal disease

ASSESSMENT OF CERVICALLYMPHADENOPATHY

Clinical examination.

Fine needle aspiration cytology.

Ultrasound scan.

Computed tomography.

Magnetic resonance imaging

Computed tomography–positron emission tomography fusion

imaging

Open biopsy

INDICATIONS FOR ANATOMICAL NECK IMAGING

Primary Tumour Assessment

Careful Monitoring Of N0

Necks (Ultrasonography

guided More Likely)

Assess Treatment Response

Assess The Difficult Neck

Restaging Recurrent Tumour

• Short axis diameter larger than 1 cm,

• Cluster of three or more borderline enlarged nodes larger than 0.8 cm, and

• Nodal necrosis or patchy enhancement within the nodes

The criteria used for

categorizing

metastatic deposits include lymph

nodes with

COMPUTED TOMOGRAPHY–POSITRON EMISSION TOMOGRAPHY FUSION IMAGING

Positron emission tomography (PET) using 18f-2-fluoro-2- deoxy-d-glucose (18FDG) as a radioactive tracer has proven efficacy in the functional imaging

of solid tumours.

The widespread role of ct-pet is confined to detecting the occult primary and for assessment of

residual and recurrent disease following surgery and irradiation.

Clinical examination and using conventional radiology and combined with panendoscopy and biopsy, a primary will be identified in about 50 per

cent of patients.

CT-PET scans are best done prior to the panendoscopy to reduce false positive rates.

DIAGNOSIS• When a patient presents with an isolated neck mass, a

thorough clinical history with emphasis on smoking and

drinking habits and clinical examination are essential,

including a full ear, nose and throat (ENT) assessment

with nasendoscopic examination of the upper

aerodigestive tract.

• Metastatic nodal disease –

– Level I- primary tumour of the lip, anterior tongue, anterior floor of

mouth and buccal mucosa.

– Level II/III mass will have a primary tumour of the tonsil or tongue base

and so particular attention must be paid to the examination of these areas.

– Level IV is most commonly associated with tumours of the hypopharynx

and larynx.

– Level v nodal metastasis is a typical feature of nasopharyngeal

carcinoma.

– Level VI disease is unusual, most will be carcinoma of thyroid origin,

although subglottic squamous carcinoma may occasionally present with

metastasis to this nodal level

Invasive procedures• Fine needle aspirate cytology (FNAC)- ideally using ultrasound

guidance, from the abnormal neck node should then be performed and

will often afford a clear indication of the pathological nature of the

lesion.

• In cases of uncertainty, ultrasound-guided core biopsy or open biopsy

will be necessary.

• Excision biopsy is no longer considered to compromise outcome in

metastatic squamous carcinoma provided definitive treatment, such as

neck dissection and/or radiotherapy is undertaken soon afterwards.

Imaging • Computed tomography (CT) and magnetic resonance imaging

(MRI) of the head and neck, was the next diagnostic stage of the

process and while they remain important techniques for the

staging of established disease.

• This must be undertaken before examination under general

anaesthesia and biopsy of putative mucosal sites, because if

scanning is performed after biopsy, subsequent swelling and

inflammation may result in FDG uptake and confound

interpretation

Examination under general anaesthesia

Pharyngolaryngo-oesophagoscopy and careful palpation of the tongue base. PET-CT may assist in targeting a specific structure for biopsy.

However if pet-ct is negative and there is no obvious primary on endoscopy, tonsillectomy, tongue base biopsy and biopsies of the postnasal space and

pyriform fossa should be performed.

The nasopharynx is of particular importance in patients whose nodal metastasis lies in level v and in those with an undifferentiated histology.

Tonsillectomy is recommended because up to 25 per cent of tumours are found at this site

Tongue base biopsy will subsequently reveal an additional 10–15 per cent of occult primaries. Biopsy of the tongue base can be difficult and many occult carcinomas are submucosal. Consideration should be given to performing a wedge biopsy, cutting deeply into the tongue base rather than just using cupped forceps.

Conventional processes of clinical examination, panendoscopy, CT and/or MRI followed by panendoscopy with biopsy have been shown to reveal the primary site in over 40 per cent of patients initially diagnosed with neck node metastatic squamous carcinoma of unknown primary origin.

Diagnostic accuracy may also be enhanced using laser-induced fluorescence endoscopy in parallel with conventional panendoscopy and biopsy

GENETICS AND MOLECULAR ANALYSIS

Undifferentiated carcinoma is a special example in which the diagnosis of nasopharyngeal carcinoma can be strengthened by the detection of

Epstein–Barr virus in the lymph node metastasis either by polymerase chain reaction (PCR) or insitu hybridization,

techniques which have sufficient sensitivity to detect the virus in FNAC

or in core biopsy.

Serology combining IgA with early antigen serology will also provide a

high degree of sensitivity and specificity when type III

nasopharyngeal carcinoma is suspected.

Genetic alterations in apparently normal tissue from putative primary

sites should be identical to those from a metastatic lymph node and can be defined by microsatellite

identification.

Cytomorphological characteristics, such as monolayered papillary

fronds with intranuclear cytoplasmic inclusions in thyroid papillary carcinoma; large, polygonal, keratinized cells with a low

nuclear/cytoplasmic ratio in perioral cancers; and numerous naked nuclei with marked lymphocytic

infiltrates in nasopharyngeal cancer could possibly be utilized for

presumption of primary site in cases of UPC

CLINICAL MANAGEMENT

Surgical management of the neck

Modified radical neck dissection is the most commonly used technique for management of nodal metastatic

disease.

N1 neck disease with no extracapsular extension can be managed by surgery

alone.

postoperative radiotherapy for patients with a pathologic stage N2 or higher or

with evidence of extracapsular extension.

For N2 and N3 disease, the consensus at the present time is for dual modality therapy, involving both neck dissection

and radiotherapy.

MANAGEMENT OF THE PUTATIVE PRIMARY SITE

Irradiation of lateral neck structures will largely preclude irradiation of

subsequently occurring primary sites, particularly

those which lie in the midline because there will be

considerable overlap with radiation fields required to

treat a primary site.

Treat putative mucosal sites by panmucosal

irradiation, or alternatively by selective mucosal

irradiation, using techniques which will also include the involved neck, or alternatively to irradiate the involved neck alone.

Panmucosal irradiation requires doses of 50–60Gy over 5–6 weeks

encompassing nasopharynx,

oropharyx, hypopharynx and

larynx,

Chemoradiotherapy

Concurrent chemoradiotherapy is

now a standard nonsurgical

management option for patients with locally advanced head and

neck cancers.

N2C and N3