>>> CONTINUED OVERLEAF

ISSUE 3, 2017

National Cervical Screening Management GuideDr Jason Stone

INSIDE THIS ISSUE:> National Cervical Screening

Management Guide

> Merkel Cell Carcinoma: An Update

> Subclinical Hypothyroidism in Early Pregnancy: An Update

A BRIEF OVERVIEW

Cancer Council Australia has recommended significant changes to the National Cervical Screening Program. The new 2016 Guidelines will replace the 2005 NHMRC Guidelines.

From December 2017, the Pap smear process will now be known as the Cervical Screening Test. The cervical cells will be collected in the same way as previously collected for Pap smears, with the only difference being that the sample is to be placed in a ThinPrep® vial with liquid media rather than smeared onto glass slides. Testing the sample for oncogenic Human papillomavirus (HPV) will replace cytology as the primary screening process. Liquid-based cytology (LBC) will be performed on the sample

by the laboratory if the HPV test is positive (i.e. reflex cytology) or in specific clinical circumstances (i.e. HPV and cytology co-test).

The cervical screening program will be available to women between the ages of 25 and 74 years. Women over the age of 25 will be invited by the National Cancer Screening Register to participate in the new National Cervical Screening Program. The recommended interval between cervical screening tests will change from 2 to 5 years.*

Women who have had the HPV vaccination must still participate in the screening program.

A detailed explanation of the program is available from Cancer Council Australia.

From 1st December 2017 the new National Cervical Screening Guidelines will take effect.

If you would prefer to receive the newsletter electronically, please email enquiries@tmlpath.com.au

FEATURE ARTICLE

HPV TESTING

Human papillomavirus is a common virus. Most infections are harmless and resolve spontaneously in about a year. In some patients, persistent infection with one of the oncogenic genotypes of HPV can lead to cervical pre-cancer or cancer. Types 16 and 18 are more virulent than other HPV types, consistently causing around 75% of all cervical cancers.*

Testing for oncogenic HPV types has been shown to be as sensitive as cytology in identifying women at risk of developing cervical neoplasia. However, it is the strong negative predictive value of HPV testing that has the most clinical use.*

Tasmanian Medical Laboratories will use the latest HPV testing technology for the detection of the 14 HPV genotypes known to be associated with cervical cancer. The test specifically detects HPV 16 and 18 (which cause 75% of cervical cancers) while simultaneously detecting the 12 other oncogenic genotypes. There is an internal control which minimises the risk of false negative results for each patient.

Remember, a positive HPV result does not necessarily indicate that the woman has cervical neoplasia, but does indicate an increased risk.

ROUTINE 5-YEARLY CERVICAL SCREENING

For women aged 25 to 69

Depending on the result of the HPV, and any additional reflex cytology testing, women are assigned a clinical risk category – Low Risk, Intermediate Risk or Higher Risk. Each risk category follows a different clinical pathway. (Please see flowchart of pathways below):

Cervical Screening Pathways1. Low Risk = the HPV test is negative → The woman will be invited to rescreen in five years

2. Intermediate Risk = the HPV test is positive for one of the other oncogenic HPV types (i.e. NOT 16/18) and the reflex cytology performed by the lab is either negative or only shows low grade changes.

→ The woman will be invited to have another HPV test in 12 months

→ If the repeat HPV test in 12 months is negative then the woman can return to routine 5 yearly screening

→ If the repeat HPV test in 12 months is positive (regardless of type) then referral to colposcopy is advised

3. Higher Risk:

→ If the test is positive for HPV 16/18 then referral for colposcopy is advised (regardless of the result of the reflex cytology)

→ If the test is positive for other oncogenic HPV types (i.e. NOT 16/18) and the reflex cytology performed by the lab shows possible or definite high grade changes then referral for colposcopy is advised

Low Risk

Intermediate Risk

High Risk

102

6. CerviCal SCreeNiNg gUiDeliNeS

MANAgEMENT OF ONCOgENIC hPv TEST RESuLTS

EvIDENCE-BASED RECOMMENDATION gRADE

REC6.6: Positive oncogenic HPV (not 16/18) test result at routine screeningWomen with a positive oncogenic HPv (not 16/18) test result, with a lBC report of negative or prediction of plSil/lSil, should have a repeat HPv test in 12 months.

C

PRACTICE POINT

REC6.7: Referral of women with a positive oncogenic HPV (not 16/18) test result and LBC prediction of pHSIL, HSIL or any glandular abnormality

Women with a positive oncogenic HPv (not 16/18) test result, with a lBC prediction of pHSil/HSil or any glandular abnormality, should be referred for colposcopic assessment at the earliest opportunity, ideally within 8 weeks.

Flowchart 6.1. cervical screening pathway for primary oncogenic HPv testing

LEgEND

Risk of cervical cancer precursors

Primary test

Reflex test

Test result

Recommendation

Low

Intermediate

higher

reflex lBc

HPv detected (16/18)

UnsatisfactoryHPv test

pHsil/HsilUnsatisfactory lBc

negative

repeat HPv test in 12 months

HPv detected (any

type)

HPv notdetected

reflex lBc

retest for lBc only

within 6 weeks

HPv detected (not 16/18)

HPv notdetected

plsil/lsil

Oncogenic HPV test with partial genotyping

refer for colposcopic assessment

any lBc result or unsatisfactory

reflex lBc

routine 5-yearly

screening

routine 5-yearly

screening

retest HPv within

6 weeks

refer forcolposcopicassessment

Flowchart 6.1. Cervical screening pathway for primary oncogenic HPV testing. *Source: National Cervical Screening Program: Guidelines for the management of screen-detected abnormalities, screening in specific populations and investigation of abnormal vaginal bleeding. Cancer Council Australia, Sydney (2016)

FEATURE ARTICLE

For women aged 70-74

• If the routine screening HPV test is negative, then the patient is discharged from the screening program and no further screening is required.

• Any positive oncogenic HPV result (regardless of type) should be referred for colposcopy in this age group.

• Women aged 75 years or older who have never had a cervical screening test, or not had one in previous five years may request a test and be screened.

Test of cure for women with treated high-grade intraepithelial lesion (HSIL)

• HPV testing and cytology co-testing should be performed at 12 and 24 months post treatment.

• Once a woman has tested negative by both tests on two consecutive occasions, she is regarded as passing the Test of Cure and can safely return to the normal five-yearly screening interval.

• Any positive test for HPV 16/18 or a cytology result of possible HSIL or HSIL should be referred back to colposcopy.

Follow-up of women treated for Endocervical Adenocarcinoma in-situ (AIS)

• The follow-up of women treated for AIS is annual HPV and cytology co-test indefinitely.

• Any abnormal result will require referral back to colposcopy.

• Currently, the clinical evidence does not support a Test of Cure for endocervical lesions as there is for squamous lesions.

• It is important to inform the pathology laboratory if a woman has a history of AIS so that the appropriate cytology co-test is performed and the appropriate clinical recommendation can be made.

Screening after hysterectomy

• If the hysterectomy was for benign reasons (e.g. fibroids) and there was no history of cervical abnormality, then no follow-up is required.

• If the hysterectomy was for benign reasons (e.g. fibroids) and the cervical screening history is not available, then two consecutive negative HPV tests, 12 months apart, are advised before no further testing is required.

• Any woman with a hysterectomy and a history of HSIL is advised to pass the Test of Cure (as described previously). The Test of Cure can be done either prior to or after the hysterectomy. Once the Test of Cure is passed, then no further follow-up is required.

• Any woman with a hysterectomy and a history of Endocervical AIS should have annual HPV and cytology co-testing indefinitely as described in the previous section.

• Women who have undergone a subtotal hysterectomy (the cervix is not removed) should be invited for 5-yearly HPV testing in accordance with the recommendation for the general population.

Immune-deficient women

• Women with human immunodeficiency virus (HIV) or a solid organ transplant should have 3-yearly HPV Screening tests.

• Immune-deficient women with any positive oncogenic HPV result (regardless of type) should be referred for colposcopy.

• It is important to inform the pathology laboratory if a patient is immune-deficient so that the appropriate clinical recommendation can be made.

Screening in diethystilbestrol (DES) exposed women

• Women exposed to DES in utero should be offered an annual HPV and cytology co-test indefinitely.

• Any abnormal result will require referral back to colposcopy.

• Self-collection is not recommended.

• It is important to inform the pathology laboratory if a woman has a history of DES exposure so that the appropriate cytology co-test is performed and the appropriate clinical recommendation can be made.

Investigation of abnormal vaginal bleeding

• Women with abnormal vaginal bleeding should be offered an HPV and cytology co-test.

• Regardless of the test results, referral to gynaecological assessment for investigation of the bleeding should be considered.

• It is important to inform the pathology laboratory if a woman has clinical symptoms so that the appropriate cytology co-test is performed and the appropriate clinical recommendation can be made.

For women under 25 years old

• Routine cervical screening is NOT recommended for asymptomatic women under the age of 25 years.

• For women who experience first sexual activity at a young age (<14 years) and had not received the HPV vaccine before becoming sexually active, a single HPV test between age 20 and 24 can be considered on an individual basis.

>>> CONTINUED OVERLEAF

FEATURE ARTICLE

SPECIMEN COLLECTION FOR CERVICAL SCREENING

The collection of cervical cells is completed the same way a usual Pap Smear was collected, with the only difference being that the cervical cells are now placed in a ThinPrep® vial, rather than on a slide.

1. Obtain an adequate sample from the cervix

a) Use luke warm water to lubricate and warm the speculum. A water soluble gel lubricant can be sparingly applied to the posterior blade if necessary. Do not use carbomer-based lubricants.

b) Insert the speculum.

c) Insert the central bristles of the Cervical Brush deep enough into the endocervical canal to ensure the shorter bristles contact the exocervix, then push gently and rotate the broom in a full clockwise direction 4 - 5 times.

Please note: An endocervical Brush should not be used in pregnant women.

2. Place the Cervical Brush into the ThinPrep® vial ASAP

a) Ensure the ThinPrep® vial is within the use by date. It can be stored at room temperature.

b) Push the Cervical Brush into the bottom of the vial 10 times, ensuring to push hard enough to force the bristles apart.

c) Swirl the Cervical Brush before removing it from the vial.

d) Discard the Cervical Brush.

Please note: Do not make any glass slides.

3. Secure the cap on the vial

Tighten the cap enough that the torque line on the cap is in line with the torque line on the vial.

4. Record patient details and complete request form

a) Record patient’s full name and date of birth on the vial.

b) Complete the patient’s details on the request form providing as much information as possible.

Pertinent clinical details are essential for reliable cervical screening.

Please request Cervical Screening Test, Routine in screening cases and Cervical Co-test, Symptomatic for symptomatic cases.

Other important information should be noted on the request form under clinical notes.

Doctor please consider:

• Patients who are symptomatic (e.g. history of abnormal vaginal bleeding) require both an HPV and a concurrent liquid-based cytology (LBC).

• Patients who have previously been diagnosed with Endocervical AIS, also require a concurrent LBC annually.

• Patients who are immune deficient are advised to repeat testing in 3 years not 5 years.

5. Package the sample and request form for transport

Place both the vial and request form into a specimen bag for transport to the laboratory in the usual manner.

SELF-COLLECTION

• Self-collection with a dry flocked swab is available for patients who have never been screened (>30 years old) or are under-screened (>30 years old and >2 years overdue for cervical screening).

• The accuracy of self-collected samples is limited compared to practitioner-collected samples and therefore self-collection is not advised as an alternative for women who would otherwise participate in the screening program.

• If the HPV result is positive, the woman may be referred for colposcopy or may have to return for a second sample (this time practitioner-collected) so that a LBC sample can be taken.

• For more information on self-collection see the Self-Collect - HPV Specimen Collection for the Cervical Screening Program available at tmlpath.com.au.

TURNAROUND TIME

Results will be released to the requesting Doctor approximately 2-3 days after the sample is received by the laboratory.

COST

Cervical screening requests that follow the national prescribed clinical guidelines will be bulk billed subject to Medicare guidelines and criteria.

If Medicare guidelines and criteria are not met, an out-of-pocket fee may apply. If the patient wants additional cervical cytology smears that do not fit the MBS criteria, these tests will not be rebated by Medicare.

FURTHER INFORMATION

Dr Jason Stone MBChB FRCPath FRCPA Cytopathology Head of Department

Hobart: (03) 6108 9900 Launceston: (03) 6711 2000

TML UPDATES

What do I put on the Pathology Request Form?

To meet Medicare guidelines and criteria, it is important that you complete the pathology request form correctly. The request form also plays a vital role in ensuring the laboratory performs the correct test and offers the correct clinical recommendation. Below are guidelines for requesting depending on clinical scenario.

ASYMPTOMATIC PATIENTS

Most patients will fall in this category, and will have no significant previous history or symptoms. For these cases, please clearly request “Cervical Screening Test, Routine” on the pathology request form. The laboratory will do HPV testing and/or liquid-based cytology as appropriate.

SYMPTOMATIC PATIENTS

Patients of any age who are symptomatic (e.g. abnormal vaginal bleeding) may require cervical co-testing (i.e. HPV + Cytology) as part of their investigations. In these cases, it is important that you very clearly state “Cervical Co-Test, Symptomatic” on the pathology request form. In addition, description of the relevant symptom (e.g. post-menopausal bleeding) would be helpful.

FOLLOW UP OF PREVIOUS ABNORMAL CERVICAL SCREENING TEST RESULT

If your patient’s previous Cervical Screening Test showed a positive HPV result and follow up testing was recommended, please clearly state “Cervical Test, follow up of previous abnormal result”.

TEST OF CURE

Patients with previously treated high grade squamous intraepithelial lesion (HSIL or CIN2/3) require 2 consecutive negative HPV tests, and negative cytology tests 12 months apart, before they are considered to be cured and can go back to routine 5-yearly screening. In these cases, please state “Cervical Co-Test, Test of Cure”.

PREVIOUS ENDOCERVICAL ADENOCARCINOMA IN SITU (AIS)

Patients with previously treated AIS require annual co-testing. Please state “Cervical Co-Test, Previous AIS”.

CYTOLOGY ONLY

“Cytology Only“ should be requested when patients have had a previous positive HPV test from a self-collect sample or a previous unsatisfactory cytology result. Please state ‘Cytology Only” as patients are not eligible for a second HPV test under these circumstances.

PATIENT LAST NAME GIVEN NAMES

PATIENT ADDRESS POSTCODE

TESTS REQUESTED

PATIENT COPY

TEL (HOME & MOBILE) TEL (BUS)

DATE OF BIRTH FILE No.SEX

REQUESTING DOCTOR (PROVIDER NUMBER, SURNAME, INITIALS, ADDRESS)

REQUESTING DOCTOR (PROVIDER NUMBER, SURNAME, INITIALS, ADDRESS) COPY REPORTS TO:

HOSPITAL/WARD

Doct

Copy 1

Copy 2

Copy 3

Hosp/Ward

6927

74_A

ug17

1. a private patient in a private hospital or approved day hospital facility2. a private patient in a recognised hospital3. a public patient in a recognised hospital4. an outpatient of a recognised hospital

Was or will the patient be, at the time of the service or when the specimen is obtained: ( appropriate box)

yes no

PATIENT’S SIGNATURE AND DATEMEDICARE ASSIGNMENT (Section 20A of the Health Insurance Act 1973)I offer to assign my right to benefits to the approved pathology practitioner who will render the requested pathology service(s) and any eligible pathologist determinable service(s) established as necessary by the practitioner. In the alternate, I authorise that APP to submit my unpaid account to Medicare so that Medicare can assess my claim and issue me a cheque payable to the APP for the Medicare Benefit.

SIGNATURE X ................................................................ X DATE / /

Practitioner’s Use Only ...................................................................................... (Reason patient cannot sign)

Collect Date Coll. Time Test Codes Branch Ref. No. Lab. No.

Received Date Rec. Time B/C Clinic

L UA SB E

Attachments: Yes / No (please circle)If yes, no. of pages:

Description & Collector Containers

MEDICARE CARD NUMBER

PRIVACY NOTE:The information provided will be used to assess any Medicare benefit payable for the services rendered and to facilitate the proper administration of government health programs, and may be used to update enrolment records. Its collection is authorised by provisions of the Health Insurance Act 1973. The information may be disclosed to the Department of Health and Ageing or to a person in the medical practice associated with this claim, or as authorised/required by law.

Your treating practitioner has recommended that you use TML. You are free to choose your own pathology provider. However, if your treating practitioner has specified a particular pathologist on clinical grounds, a Medicare rebate will only be payable if that pathologist performs the service. You should discuss this with your treating practitioner.

PATHOLOGYREQUEST

MEDICARE CARD NUMBER

PATIENT LAST NAME GIVEN NAMES

PATIENT ADDRESS POSTCODE

TEL (HOME & MOBILE) TEL (BUS)

DATE OF BIRTH FILE No.SEX

TESTS REQUESTED

LABORATORY COPY CLINICAL NOTES

STANDARD PRECAUTIONS PRIVATE & CONFIDENTIAL CUMULATIVE REPORT

URGENT ■ PHONE ■ FAX ■ BY TIME:

PHONE/FAX No:

TML Fee ■ S.F. ■ B.B. or D.B. ■ VET AFFAIRS No:

……………………………………………………………………/………/………

DOCTOR’S SIGNATURE AND REQUEST DATE

SELF DETERMINE

Fasting ■Non Fasting ■Pregnant ■Horm Therapy ■LNMP ■EDC ■Cervical Cytology - Site

Cervix ■ Vaginal Vault ■

Endometrium ■

Other ■Post Natal ■Post Menopausal ■Radio Therapy ■IUCD ■Abnormal Bleeding ■Appearance of Cervix

Benign ■

Suspicious ■

Specialist Diagnostic Services Pty Ltd (ABN 84 007 190 043) t/a Tasmanian Medical Laboratories APA No. 000042

PERSON DRAWING BLOODI certify that the blood specimen(s) accompanying this request was drawn from the patient named above. I established the identify of this patient by direct inquiry and/or inspection of wrist band and immediately upon the blood being drawn I labelled the specimen(s).

Signature

..........................................................................................

Specialist Diagnostic Services Pty Ltd (ABN 84 007 190 043) t/a Tasmanian Medical Laboratories APA No. 000042

Launceston P: (03) 6711 2000 247 Wellington Street, Launceston TAS 7250

Hobart P: (03) 6108 9900 Level 1, 34 Argyle Street, Hobart TAS 7000

Launceston P: (03) 6711 2000 247 Wellington Street, Launceston TAS 7250

Hobart P: (03) 6108 9900 Level 1, 34 Argyle Street, Hobart TAS 7000

Cervical Screening Test, Routine

Immunodeficient

WHAT TEST IS REQUIRED? In “Tests Requested” area, enter one of the following:

Cervical Screening Test, Routine ORCervical Co-test, Symptomatic ORCervical Test, follow up of previous abnormal result ORCervical Co-test, Test of Cure ORCervical Co-test, Previous AIS ORCytology Only

ANY OTHER INFORMATION REQUIRED?Other useful clinical information includes:• Immunodeficient• Previous hysterectomy• Self-collected sample• Abnormal uterine bleeding• DES exposure

WHAT ABOUT THE TICKBOXES ON THE REQUEST FORMS?The tickboxes on pathology request forms provide additional useful information for the laboratory. The format of the tickboxes on Pathology request forms can vary, depending on pathology provider, version of form or independent GP practice management software. Please continue to complete all relevant tickboxes.

If you use independent software to electronically complete request forms, you may also wish to set up this software to include terminology as described above.

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine carcinoma that is relatively rare, but potentially aggressive. It is mainly seen in older people, but also occurs in younger individuals who are immunosuppressed. As for other tumours that are related to UV exposure, the highest incidence rates of MCC are found in Australia and New Zealand.

MERKEL CELL POLYOMAVIRUS

Up to 80% of cases of MCC in Northern America/Europe are associated with Merkel cell polyomavirus. In Australia, this association is only about 24%.

CLINICAL

MCC usually presents as a painless, rapidly growing red to violaceous nodule in sun-exposed sites. Other sites can be affected in the immunosuppressed. Whilst most patients present with localised disease, 35% present with nodal disease and up to 14% with distant metastasis. Metastasis to regional and distant sites can be rapid and the overall mortality rate is twice that of cutaneous melanoma (33% vs 15%). Even the smallest primary tumour is associated with a 10-20% risk of occult nodal metastasis at the time of diagnosis.

8-12% of cases presents as a nodal metastasis without a known or detectable primary cutaneous tumour. These cases have a better prognosis, likely reflecting the success of the host immune response in destroying the primary tumour. Tumour regression, either spontaneously or following cessation of immunosuppression, is thought to be related to host immune response activation.

As for other neuroendocrine carcinomas, paraneoplastic syndromes such as cerebellar degeneration, Lambert-Eaton myasthenic syndrome and hyponatraemia can also occur in patients with MCC and, in some cases, these may be the presenting symptoms.

DIAGNOSIS AND PATHOLOGY

The diagnosis is made by biopsy. Immunohistochemistry is required for diagnosis and the main differential diagnosis based on morphology includes metastatic small cell carcinoma and lymphoma. Misdiagnosis as basal cell carcinoma is well documented and some tumours can show squamous differentiation as well as features that are suggestive of melanocytic differentiation. Terminal deoxynucleotidyl transferase (TdT) is expressed in a significant number of MCC, which can potentially lead to misdiagnosis as lymphoblastic lymphoma.

Currently, there is no recommended histological grading system and histological subtyping is not reproducible or of prognostic significance.

The growth pattern (circumscribed/nodular or infiltrative) and presence of lymphovascular invasion should be recorded. Breslow thickness and tumour – infiltrating lymphocytes should be reported as for melanoma (a brisk response is associated with a better prognosis). Although p63 expression is associated with a more aggressive course and is an important predictor of shorter survival in cases from Europe/North America, this association has not been found in Australian cases. For nodes, information on the size of largest nodal metastasis, extranodal extension and presence of isolated tumour cells are required.

TML UPDATES

Merkel Cell Carcinoma: An UpdateDr Patricia Renaut

H & E

CK20

Synaptophysin

TML UPDATES

MANAGEMENT

Following diagnosis, the patient should undergo full clinical examination of skin and regional lymph nodes. Baseline blood tests (full blood count, biochemistry and coagulation) and staging scans should be performed. Although there is increasing evidence that PET-CT offers increased sensitivity over conventional CT and MRI, the use of this for Merkel cell carcinoma does not currently attract Medicare funding. MRI is more sensitive than CT for detecting brain metastases. As false positive radiology results may occur, tissue biopsy confirmation of metastasis is recommended.

SENTINEL LYMPH NODE BIOPSY (SLNB)

For patients with disease that is localised to the skin and without clinical/radiological evidence of metastasis, SLNB is important to complete the staging process. SLNB should also be considered in patients who have clinically palpable, but radiologically negative lymph nodes. It is usually performed at the time of definitive wide local excision. The success rate of identifying the draining sentinel lymph node may be impaired if the patient has already had a wide excision or flap repair as this may disrupt the lymphatic drainage. There are also site-related difficulties in the detection of sentinel lymph nodes in the head and neck. In this location, the draining nodes are often close to the primary tumour and may be obscured by the injected tracer. The risk of surgical complications is also higher due to the proximity of nerves and blood vessels.

When it is not appropriate to perform SLNB due to high surgical risk, ultrasound evaluation with fine needle aspiration biopsy may be a suitable alternative. In patients who are not surgical candidates, SLNB is usually not performed and the nodal basin should be irradiated.

EXCISION AND MARGIN CLEARANCE

The primary tumour should be excised; however, there is no evidence-based consensus recommendation for either surgical or histological margins. Although older studies recommend wide surgical margins of 2-3cm, the current trend is for a narrower surgical margin of 1-2cm regardless of tumour size, followed by adjuvant irradiation of the tumour bed. There is no minimum recommended histological clearance, but positive histological margins should be re-excised. If Mohs surgery is used, the central portion of the tumour should be sent for permanent section analysis.

RADIATION THERAPY (RT)

Most trials have shown that adjuvant RT reduces the risk of recurrence compared to surgery alone, but there is a lack of consensus regarding its use. Whilst some experts do not consider RT to be necessary in stage 1 tumours with histological clear margins, the National Comprehensive

Cancer Network recommends post-operative RT regardless of stage. RT alone of the primary tumour and/or regional nodal basin can be used as the definitive treatment for patients who are unable to tolerate surgery or as palliation in inoperable cases.

LYMPHADENECTOMY

Patients with clinical nodal disease should undergo completion lymphadenectomy (CL). Adjuvant RT of the nodal basin is also recommended if there is extensive disease with extranodal spread. Whilst the current recommendation for positive SLNB is CL and/or RT, it is unclear whether CL provides additional benefit compared to RT alone.

CHEMOTHERAPY (CT)

CT is reserved for metastatic disease. Although MCC is chemosensitive, CT only provides short term benefit and most cases recur within 4 to 15 months. Adjuvant CT is not recommended as it does not provide a clear benefit.

IMMUNOTHERAPY

In March 2017, the drug Avelumab, a programmed death ligand-1 (PD-L1) inhibitor, received FDA approval in the USA for the treatment of metastatic MCC. It activates the immune response by inhibiting PD-L1, high levels of which are found in virus-negative MCC. Clinical trials of other immune modulators are ongoing.

FOLLOW UP

As most recurrences present within 3 years of diagnosis of the primary cutaneous tumour, the suggested follow up interval is every 3-6 months for the first 2 years, reducing to every 6-12 months.

Key points

• MCC is a relatively rare but potentially aggressive tumour

• Overall mortality is twice that for melanoma

• Progression can be rapid and urgent referral is essential

• Sentinel node biopsy may be required for staging

• Radiation therapy is an integral part of the treatment

• Large excisions or flap repair may alter the tumour bed and compromise sentinel node biopsy or radiation therapy

• Avelumab is a PD-L1 inhibitor that has received FDA approval for metastatic MCC

FURTHER INFORMATION

This article has been shortened for the newsletter. A more detailed version of the article is available on the Tasmanian Medical Laboratories website.

TML UPDATES

The 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual was published at the end of 2016, with the aim of implementation in 2017. However, in conjunction with other organisations in the cancer care community, the decision was made to delay implementation until 1 January 2018 to allow the necessary infrastructure to be put in place for its use.

In the 8th edition, there are significant changes that affect the staging of cutaneous squamous cell carcinoma (SCC) along with some changes to the staging of malignant melanoma. As the changes pertaining to SCC are quite significant, the parameters have already been incorporated into our day-to-day reporting at Tasmanian Medical Laboratories. We will continue to use the 7th edition until the end of 2017.

SQUAMOUS CELL CARCINOMA

In the 8th edition, staging is only required for cutaneous SCC arising in the head and neck. This includes vermillion lip, but excludes the eyelid as tumours arising in the eyelid are staged separately. The same staging system can be used for other cutaneous cancers of the head and neck, with the exception of Merkel cell carcinoma and melanoma, both of which have their own separate staging systems.

Significant changes have been made to tumour (T) staging. T1 and T2 tumours, which are considered to be low risk tumours, are now defined by tumour diameter (T1 <2cm; T2 ≥2cm but <4cm). Tumours ≥4cm or with high risk features are now placed in the T3 category, with T4 being reserved for bone invasive tumours.

The high risk features that upstage a tumour have also changed and include any of the following:

• Thickness >6mm (as measured from the granular layer of the adjacent normal epidermis to the base of the tumour)

• Invasion beyond the subcutaneous fat

• Perineural invasion (PNI)*

• Minor bone erosion

*PNI is only significant if any of the following parameters are met:

• Involvement of nerves lying deeper than in the dermis (any size)

• Involvement of dermal nerves measuring ≥0.1mm in diameter

• Clinical/radiological involvement of named nerves

Low magnification of SCC with high risk pattern of perineural invasion seen bottom left corner. Note the ‘skip’ of just over 1mm between the main tumour and the focus of perineural tumour.

High magnification of perineural invasion.

T-stage AJCC 7th edition (2010)

AJCC 8th edition (2017)

T1 <2cm, <2HRF <2cm

T2 ≥2cm or any size + ≥2HRF

≥2cm but <4cm

T3 Invasion of orbit, maxilla, mandible or temporal bones

≥4cm or any size with deep invasion or perineural invasion or minor bone erosion

T4 Invasion of skeleton (axial or appendicular) or PNI of skull base

T4a Gross cortical bone/marrow invasion T4b Skull base invasion &/or skull base foramen involvement

What’s new in Skin Cancer Staging?Dr Patricia Renaut

HRF = high risk features

TML UPDATES

Histological grade/differentiation is no longer used as a high risk feature to stage tumours, but needs to be recorded in the pathology report. Although tumour subtype is not incorporated in staging it also needs to be recorded, making particular note of sarcomatoid or desmoplastic (infiltrative) subtypes as aggressive subtypes.

There are also changes to nodal (N) staging to take into account the significant impact that extranodal extension has on survival.

What should be included in the pathology report?

• Tumour thickness, differentiation and subtype (if applicable)

• Tissue level of invasion

• PNI – including diameter and location of nerves, as well as margin clearance

• Lymphovascular invasion

• Histological margin clearance – acceptable distance is determined by tumour characteristics and the presence of high risk features

• If PNI is present, a comment should be made on whether this is present in a low or high risk pattern and whether specialist referral is recommended

What information should be provided on the request form?

• Tumour location and clinical size

• High risk features (immunosuppression, scar/burn/radiation, nerve pain etc)

MALIGNANT MELANOMA

AJCC 8th Edition

The main changes in T-staging in the 8th edition include:

• Breslow thickness (BT) measurement is now rounded up or down, to one decimal place

• Histological microstaging of T1:- A cut-off of BT 0.8mm and the presence of ulceration is used- Mitotic count is no longer used, but is still an important

parameter to record

Nodal staging has also changed, whereby non-nodal locoregional metastases** are staged according to the number of concurrent nodal deposits present.

**Definition of non-nodal locoregional metastases:• Microsatellite: Microscopic metastasis found adjacent/

deep to the primary melanoma• Satellite: Grossly visible cutaneous or subcutaneous

metastasis within 2cm of the primary melanoma• In-transit metastasis: Clinically evident metastasis >2cm from

the primary melanoma, in the region between the primary tumour and the first echelon of regional lymph nodes

What should be included in the pathology report?

Primary melanoma:• Subtype• Breslow thickness and Clark level• Histological Margins• Regression

For invasive melanoma, the following also need to be recorded:• Ulceration• Mitoses• Tumour infiltrating lymphocytes• Lymphovascular invasion/angiotropism• Neural invasion• Microsatellites• The presence of a desmoplastic component

Sentinel lymph nodes:• Presence of metastasis, location and size including

isolated tumour cells• Number of positive nodes• Detection technique

Who should be offered sentinel lymph node biopsy (SLNB)?

Patients with tumour Breslow thickness >1mm who have no clinical evidence of metastatic disease should be offered SLNB.

SLNB should also be considered in patients with tumour BT <0.8mm, but who have high risk features such as mitoses, ulceration or lymphovascular invasion.

SLNB should be performed at the same time as the definitive wide local excision of the primary melanoma as the success rate of identifying the sentinel node is reduced if the patient has already had a wide excision or flap repair.

FURTHER INFORMATION

Dr Patricia Renaut FRCPA; MBBS; BSc (Hons) Consultant Histopathologist & Dermatopathologist

P: (03) 6108 9900 / (03) 6711 2000 E: enquiries@tmlpath.com.au

T-stage Breslow thickness (mm)

T1 T1a T1b

≤1.0mm <0.8mm without ulceration <0.8mm with ulceration or 0.8-1.0mm +/-

ulceration

T2 T2a T2b

1.1-2.0mm without ulceration with ulceration

T3 T3a T3b

2.1-4.0mm without ulceration with ulceration

T4 T4a T4b

>4.0mm without ulceration with ulceration

TML UPDATES

BACKGROUND

Subclinical hypothyroidism refers to a situation where the serum thyroid stimulating hormone, or TSH, is mildly raised (above the relevant reference interval, but less than 10 mU/L) and the free thyroxine (Free T4, or FT4) is normal. The clinical relevance to pregnancy is that this group of women has been shown to be at increased risk of certain pregnancy complications, particularly early pregnancy loss and premature birth, and particularly if both TSH and thyroid antibodies are high. The risk has been shown to be reduced by L-thyroxine therapy.

There has been considerable controversy surrounding this topic in pregnancy, specifically in the first trimester, for a number of reasons.

The first controversy is whether to universally screen pregnant women in early pregnancy, or to identify and test only high-risk women (such as those with a personal or family history of thyroid disorders, those with a history of thyroid surgery or neck irradiation, autoimmune disorders etc.). Proponents of universal screening point to the fact that thyroid disorders are common and, particularly for the more common hypothyroidism, the availability of a safe and effective therapy (levo-thyroxine, or L-T4 therapy). The 2017 ATA guidelines make no recommendation either way.

The second controversy is what actually defines a “normal” TSH in pregnancy. Tasmanian Medical Laboratories has developed reference intervals for each of the three trimesters of pregnancy, as recommended in both the 2011 and 2017 guidelines.

Both of these guidelines also make the suggestion of a “universal” upper limit of normal for TSH to be applied where local ranges are unavailable. This appears flawed due to the ongoing differences in TSH results between different test manufacturers. The 2017 guidelines have, however, “relaxed” this suggested upper limit to 4.0 mU/L (from 2.5 in 2011), as evidence has accumulated in the interim. The latest evidence suggests that for premature birth in particular, evidence of risk is seen at TSH above 2.5 mU/L where thyroid antibodies, particularly anti-thyroid peroxidase (TPOAb), are positive and at TSH 5-10 where TPO antibodies are negative.

KEY POINTS

If performed, a TSH should be done preferably about 8-10 weeks. Note, in women with known hypothyroidism on thyroxine, TFTs should be assessed as soon as pregnancy is suspected or confirmed. Note, measurement of Free T4 attracts a Medicare rebate only under certain circumstances and, of most relevance to screening, if the TSH is raised.

Thyroid antibodies (particularly TPOAb) should be performed if TSH >= 2.5 mU/L.

Treatment decisions should be based on TFTs and thyroid antibodies. Target TSH in the lower half of the pregnancy related interval.

Abnormal results should be reviewed 4 weekly until mid-pregnancy and, in general, treatment should be discussed with or monitored by a specialist.

Subclinical Hypothyroidism in Early Pregnancy: An Update based on the 2017 American Thyroid Association (ATA) GuidelinesDr George Marshall

2017 ATA Guideline Recommendations – taking into account Tasmanian Medical Laboratories’s pregnancy reference intervals

First trimester TSH (mU/L) R.I.: 0.1-2.8 Free T4 TPOAb Recommendation (Strength of recommendation)

Normal N (if done)t Neg No treatment (Strong)

Normal* N (if done)t POS

4 weekly TSH until mid-pregnancy (Weak) *L-T4 therapy may be considered:� If TSH is high-normal (2.5-2.8)� In the context of recurrent early pregnancy loss

High, but less than 10** N NegL-T4 therapy may be considered (Weak) **Treatment should probably be considered at or above 4.0 mU/L

High, but less than 10 N POS TREAT with L-T4, 4 weekly review (Strong)

High, but less than 10 Low# AnyTREAT with L-T4, 4 weekly review (Strong) #This denotes “overt” hypothyroidism and should be treated

>=10 Any Any TREAT with L-T4, 4 weekly review (Strong)N = normal. Neg = negative. POS = positive. L-T4 = levothyroxine. TPOAb = anti-thyroid peroxidase antibody.tNo Medicare rebate applies for free T4 if the TSH is normal, unless specific indications are noted on the request form (known thyroid

disease, suspected pituitary disease, investigation of infertility, psychiatric disturbance, dementia or the patient is on drugs known to interfere with thyroid function).

The pathologists and staff at Tasmanian Medical Laboratories wish you a joyous festive season, filled with peace and good health.

Festive Season Opening HoursCollection centre opening hours over the holiday period will be updated on our online Collection Centre Search.

Locate collection centres within a desired region from suburb or postcode information.Obtain collection centre operational hours and contact information.Receive up-to-date public holiday or temporary closure times.Search for collection centres who perform specific tests.Find licence details and general centre features (e.g. on-site parking, on-site bathroom facilities, and test payment options).

To check hours please visit tmlpath.com.au/IamaPatient/PatientCollectionServices/CollectionCentres.aspx

From the Education Desk - November 2017

THE CYTOLOGY PAP SMEAR AUDIT

We say goodbye and close this Audit 1st December 2017 In line with National Cervical Screening Program’s “The Renewal”. Last uploads of points will be for the end November report 2017 which will be completed and to you in late December. I would like to thank all participants over the years and hope that the statistical findings, + HPV & STI component included over the existence of this audit has been beneficial to you.

THE SURGICAL SKIN AUDIT

This year has seen a record number of registrations from many practitioners with many Drs qualifying for their Cat 1 points so far this year. As a reminder The Surgical Skin has specialised request forms, to order, please use your stores request forms via your local laboratory or via the website,

please use these requests with the reverse of the request form completed to ensure your specimen is included in your count.

We have new literature available soon on Merkel Cell & What’s new in Skin Cancer staging as well as updated material on Basal & Squamous Cell carcinoma to view on our website.

For further information on all of our upcoming educational activities please visit our website www.tmlpath.com.au or contact your local Medical Liaison officer or education directly via email at education@tmlpath.com.au

Warm regards and hope to see you soon at our events, The Tasmanian Medical Laboratories Education team

TML UPDATES

INFECTIOUS DISEASES REPORT: SEPTEMBER 2017

Further historical clinical data can be obtained by contacting enquiries@tmlpath.com.au.

ORGANISM GROUP JULY AUGUST SEPTEMBER TOTAL

Adenovirus (not typed) 3 3

Adenovirus (typing pending) 3 3

Bordetella pertussis 1 1 2

Chlamydia trachomatis, not typed 15 14 11 40

Epstein-Barr virus (EBV) 1 3 4

Hepatitis C virus 1 1 2 4

Herpes simplex Type 1 6 7 3 16

Herpes simplex Type 2 3 3

Human Metapneumovirus 1 1 2 4

Influenza A virus 9 35 54 98

Influenza B virus 6 19 18 43

Mycoplasma pneumoniae 3 2 2 7

Neisseria gonorrhoeae 1 1

Parainfluenza virus 1 3 4

Respiratory Syncytial virus 5 4 1 10

Rhinovirus (all types) 1 1 3 5

Streptococcus Group A 1 1

Toxoplasma gondii 1 1 2 4

Treponema pallidum 4 3 7

Varicella Zoster virus 3 6 4 13

TOTAL 58 103 111 272

Changes to Medicare Eligibility for QuantiFERON® Tuberculosis Testing from 1 July 2017On July 1st Medicare released updated criteria for QuantiFERON testing. If these criteria are not met by patients an out of pocket charge of $60 will apply.

Those patients that have been referred from any Tuberculosis Clinics should be covered under section (a) of schedule 69471 under Medicare.

Quantiferon Testing: 69471 – Test of cell-mediated immune response in blood for the detection of latent tuberculosis by interferon gamma release assay (IGRA) in the following people:

(a) a person who has been exposed to a confirmed case of active tuberculosis;(b a person who is infected with human immunodeficiency virus;(c) a person who is to commence, or has commenced, tumour necrosis factor (TNF) inhibitor therapy;(d) a person who is to commence, or has commenced, renal dialysis;(e) a person with silicosis;(f ) a person who is, or is about to become, immunosuppressed because of a disease, or a medical treatment, not mentioned

in paragraphs (a) to (e)

CLINICAL DATA