SOLID TUMORS WORKSHOP - AAIM

SOLID TUMORS SOLID TUMORS

WORKSHOPWORKSHOP

October 13October 13--19, 201219, 2012

Jack SwansonJack Swanson

Brad HeltemesBrad Heltemes

2006 Estimated US Cancer Cases*2006 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladderSource: American Cancer Society, 2006.

Men720,280

Women679,510

31%31% BreastBreast

12%12% Lung & bronchusLung & bronchus

11%11% Colon & rectumColon & rectum

6%6% Uterine corpus Uterine corpus

4%4% NonNon--HodgkinHodgkinlymphoma lymphoma

4%4% Melanoma of skinMelanoma of skin

3% Thyroid3% Thyroid

3%3% OvaryOvary

2%2% Urinary bladderUrinary bladder

2%2% PancreasPancreas

22%22% All Other SitesAll Other Sites

Prostate 33%

Lung & bronchus 13%

Colon & rectum 10%

Urinary bladder 6%

Melanoma of skin 5%

Non-Hodgkin 4% lymphoma

Kidney 3%

Oral cavity 3%

Leukemia 3%

Pancreas 2%

All Other Sites 18%

National Cancer Institute. SEER Cancer Statistics Review 1975-2008. Lifetime Risk (Percent) of Being Diagnosed with Cancer by Site and Race/Ethnicity: Males, 17 SEER Areas, 2006-2008 (Table 1.15) and Females, 17 SEER Areas, 2006-2008 (Table 1.16). 2011. Accessed at http://seer.cancer.gov/csr/1975_2008/results_merged/topic_lifetime_risk_diagnosis.pdf on December 8, 2011.

Lifetime Probability of Developing Cancer, by Lifetime Probability of Developing Cancer, by

Site, Men, 2006Site, Men, 2006--20082008

†† All Sites exclude basal and squamous cell skin cancers and in sAll Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladderitu cancers except urinary bladder..

Site Risk

All sites† 1 in 2

Prostate 1 in 6

Lung and bronchus 1 in 13

Colon and rectum 1 in 19

Urinary bladder † 1 in 26

Melanoma 1 in 41

Non-Hodgkin lymphoma 1 in 43

Kidney 1 in 51

Leukemia 1 in 64

Oral Cavity 1 in 69

Pancreas 1 in 69

Lifetime Probability of Developing Cancer, by Lifetime Probability of Developing Cancer, by

Site, Women, US, 2006Site, Women, US, 2006--20082008

Site Risk

All sites† 1 in 3

Breast 1 in 8

Lung & bronchus 1 in 16

Colon & rectum 1 in 20

Uterine corpus 1 in 38

Non-Hodgkin lymphoma 1 in 52

Melanoma 1 in 64

Pancreas 1 in 69

Thyroid 1 in 69

Ovary 1 in 71

Kidney 1 in 84

National Cancer Institute. SEER Cancer Statistics Review 1975-2008. Lifetime Risk (Percent) of Being Diagnosed with Cancer by Site and Race/Ethnicity: Males, 17 SEER Areas, 2006-2008 (Table 1.15) and Females, 17 SEER Areas, 2006-2008 (Table 1.16). 2011. Accessed at http://seer.cancer.gov/csr/1975_2008/results_merged/topic_lifetime_risk_diagnosis.pdf on December 8, 2011.

†† All Sites exclude basal and squamous cell skin cancers and in sAll Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladderitu cancers except urinary bladder..

Breast CancerBreast Cancer

�� Diagnosed in about 210,000 individuals/yearDiagnosed in about 210,000 individuals/year

� 1 in 8 women will be diagnosed in their lifetime. If found early, 95% will be cured.

� 1,600 men

�� Over 40,000 deaths per yearOver 40,000 deaths per year

� Second most common cause of death due to cancer in women (lung cancer is #1)

� Leading cause of death in woman aged 45-55

� 400 breast cancer deaths in men

Breast Cancer Case #1 Breast Cancer Case #1

�� 72 y/o female. 2003 72 y/o female. 2003 –– Suspicious mammogram. Suspicious mammogram. Core needle biopsy:Core needle biopsy:

� Ductal carcinoma in situ, 11 mm. Cribriform pattern, grade 1-2.

�� Lumpectomy Lumpectomy -- no residual cancer. Followed by no residual cancer. Followed by radiation. radiation.

�� Regular followRegular follow--ups, mammography normal ups, mammography normal untiluntil…………

�� 2008: Suspicious MRI, same area previous DCIS. 2008: Suspicious MRI, same area previous DCIS. Core needle biopsy, lumpectomy; 2 cm tumor:Core needle biopsy, lumpectomy; 2 cm tumor:� Grade 2-3 cribriform DCIS + areas of grade 3

comedonecrosis. No invasive cancer.

� Tumor in superior margins of resection.

Breast Cancer Case #1Breast Cancer Case #1

�� Mastectomy, early 2009. Pathology on mastectomy: Mastectomy, early 2009. Pathology on mastectomy:

� NO evidence of residual in situ or invasive breast cancer.

�� Close followClose follow--ups since, w/ left mammography. All negative. ups since, w/ left mammography. All negative.

�� Questions: Questions:

� Survival statistics - treatments for ductal CIS?

� After mastectomy, main concern?

� After 4 years, mortality risk (low, intermediate, high)?

� Can pathologists miss invasive foci in DCIS?

� Compare prognosis cribiform vs. comedonecrosis

� Is sentinel node biopsy indicated in DCIS?

� Compare MRI with mammography.

� Compare prognosis - Ductal CIS vs. Lobular CIS.

Staging Staging –– Tumor sizeTumor size

�� T1 T1 —— Tumor 2 cm or less in greatest dimensionTumor 2 cm or less in greatest dimension� T1mic — Microinvasion, 0.1 cm or less in size

� T1a — Tumor more than 0.1 but not more than 0.5 cm

� T1b — Tumor more than 0.5 cm but not more than 1 cm

� T1c — Tumor more than 1 cm but not more than 2 cm

�� T2 T2 —— Tumor more than 2 cm but not more than 5 cm in Tumor more than 2 cm but not more than 5 cm in greatest dimensiongreatest dimension

�� T3 T3 —— Tumor more than 5 cm in greatest dimensionTumor more than 5 cm in greatest dimension

�� T4 T4 —— Tumor of any size with direct extension to (a) chest Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below:wall or (b) skin, only as described below:� T4a — Extension to chest wall

� T4b — Edema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules in the same breast

� T4c — Both (T4a and T4b)

� T4d — Inflammatory carcinoma

10 and 20 year relapse10 and 20 year relapse--free survival free survival

rates (node negative)rates (node negative)

�� Although the majority of relapses occur Although the majority of relapses occur

within the first five years after treatment, within the first five years after treatment,

the risk persists up to 30 yearsthe risk persists up to 30 years

� Tumors <1.0 cm — 91 and 88 percent, respectively

� Tumors 1.1 to 2.0 cm — 77 and 72 percent




�� 59 y/o female. Hysterectomy age 35 59 y/o female. Hysterectomy age 35 -- endometriosis, 1988, endometriosis, 1988, then prescribed HRT. then prescribed HRT.

�� Mastectomy, right, age 42, May 1996, after removal of 3 Mastectomy, right, age 42, May 1996, after removal of 3 masses, largest measuring 2.3 x 1.6 x 1.6 cm.masses, largest measuring 2.3 x 1.6 x 1.6 cm.� Microscopic: “Mixed mucinous (colloid) carcinoma

predominant pattern plus infiltrating ductal carcinoma within mucoid carcinoma. Extensive lymphatic invasion, extension to margins of resection by intralymphatic carcinoma. Multicentricity due to intralymphatic spread.”Deep margin of resection free of tumor.

� Two of 16 axillary lymph nodes: metastatic ductal (not colloid) carcinoma. One + node level I, the other level III.

�� Four series of chemotx first. Estrogen receptor positive. Four series of chemotx first. Estrogen receptor positive. Next 5 yrs Tamoxifen, then 5 yrs. Femera. Dismissed Next 5 yrs Tamoxifen, then 5 yrs. Femera. Dismissed oncology care 2009. Last chemotx oncology care 2009. Last chemotx –– 2003.2003.

�� Regular followRegular follow--up w/ mammography of left breast & up w/ mammography of left breast & reconstructed rt. breast. Blood chems, physicals all WNL. reconstructed rt. breast. Blood chems, physicals all WNL.

Breast Cancer Case #2 Breast Cancer Case #2 -- QuestionsQuestions

�� Cancer not staged in records. TNM Cancer not staged in records. TNM

categories & stage? categories & stage?

�� How long risk of recurrence? Does How long risk of recurrence? Does

histology influence risk? histology influence risk?

�� Do positive lymph node levels affect your Do positive lymph node levels affect your

assessment? assessment?

�� Mortality risk: low, intermediate, high? Mortality risk: low, intermediate, high?

Favorable/ unfavorable factors?Favorable/ unfavorable factors?

TNM StagingTNM Staging

�� Primary Tumor (T)Primary Tumor (T)� Tis: Carcinoma in situ

� T1mic – to 0.1cm. microinvasion (97% survival)� T1a - >0.1-0.5 cm. diam. (99% 10 yr. survival)� T1b - >0.5-1.0 cm. diam.

� T1c - >1.0-2.0 cm. diam. � T2 T = 2.1 - 5 cm

� T3: T = > 5 cm� T4: T of any size with direct extension to chest wall or

skin

�� Regional Nodes (N)Regional Nodes (N)� N0: No involved nodes; N0 (i+) - (ITC - <0.2mm)� N1mi: Micrometastases – 0.2to 2.0 mm� N1: 1-3 ipsilateral axillary nodes

� N2: 4-9 axillary nodes� N3: 10 or more nodes, or regional nodes other than

axillary

�� Distant Metastasis (M)Distant Metastasis (M)� M0: None detected� M1 Distant metastasis present (includes ipsilateral

supraclavicular nodes)

Breast Cancer TNM StagingBreast Cancer TNM Staging

�� Stage 0 Stage 0 –– TisN0M0TisN0M0�� Stage 1 Stage 1 –– T1N0M0T1N0M0�� Stage IIA Stage IIA –– T0N1M0(T0N1M0( !) (0!) (0--4%; case 1 Q4)4%; case 1 Q4)

T1N1M0T1N1M0

T2N0M0T2N0M0�� Stage IIB Stage IIB -- T2N1M0T2N1M0

T3N0M0T3N0M0�� Stage IIIA Stage IIIA –– T0T0--2,N22,N2

T3, N1T3, N1--22�� Stage IIIB Stage IIIB –– T4, N0T4, N0--22�� Stage IIIC Stage IIIC –– AnyTN3AnyTN3�� Stage IV Stage IV –– AnyT, AnyN, M1AnyT, AnyN, M1


�� 50 year old woman: mammogram BI50 year old woman: mammogram BI--RAD 4a at age 46. RAD 4a at age 46.

Core needle biopsy: Core needle biopsy: Ductal carcinoma in situ. Ductal carcinoma in situ.

�� Lumpectomy: Tumor mass 1.8x1.4x1.2 cm. Lumpectomy: Tumor mass 1.8x1.4x1.2 cm.

� Microscopic: Extensive ductal carcinoma in situ plus two foci microinvasive ductal carcinoma, each <0.1 cm. T1mic.

� Sentinel lymph node – neg. for cancer (H& E). W/ serial sections & IHC, positive for small # isolated tumor cells, no micromets. (pN0(i+) No axillary lymph node dissection. ER & PR pos., HER2 neg.

�� Tamoxifen & radiation therapy. No chemotherapy. Tamoxifen & radiation therapy. No chemotherapy.

�� Family Hx pos. for breast cancer. Mother, sister, both < 45. Family Hx pos. for breast cancer. Mother, sister, both < 45.

�� BRCA 1 & 2 testing, negative. BRCA 1 & 2 testing, negative.

Breast Cancer Case #3 Breast Cancer Case #3 -- QuestionsQuestions

�� Does extensive DCIS affect prognosis? Does extensive DCIS affect prognosis?

�� How would you consider isolated tumor How would you consider isolated tumor

cells in regional lymph nodes? cells in regional lymph nodes?

�� How would you consider How would you consider

micrometastases when evaluating?micrometastases when evaluating?

�� Should she have been treated with Should she have been treated with

chemotherapy?chemotherapy?

�� Mortality risk: Low, intermediate, high? Mortality risk: Low, intermediate, high?

Favorable/unfavorable factors.Favorable/unfavorable factors.

NOTES FOR BREAST CANCERNOTES FOR BREAST CANCER

�� IBC = Breast CancerIBC = Breast Cancer

�� DCIS = Ductal CA in situDCIS = Ductal CA in situ

�� SLNB = sentinel lymph node biopsySLNB = sentinel lymph node biopsy

�� ALND = axillary node dissectionALND = axillary node dissection

Malignant Melanoma�� 76,250 new cases of invasive melanoma anticipated in U.S. in 76,250 new cases of invasive melanoma anticipated in U.S. in

2012 (44,200 in 1999)2012 (44,200 in 1999)� Plus 54,000 cases of melanoma-in-situ� Fastest growing incidence of all cancers

�� Estimated deaths 2012: 9180 (7300 in 1999)Estimated deaths 2012: 9180 (7300 in 1999)�� Fifth most common cancer in Americans Fifth most common cancer in Americans (was sixth in 2009) (was sixth in 2009)

and the most common fatal malignancy among young adultsand the most common fatal malignancy among young adults�� Incidence of melanoma is increasingIncidence of melanoma is increasing

� 1/1500 lifetime risk in 1935� 1/250 lifetime risk in 1980� 1/50 lifetime risk in 2009 (whites)

�� Median age of onset 53Median age of onset 53�� Incidence of melanoma estimated to be 0.6, 1.6, and 2.6% at Incidence of melanoma estimated to be 0.6, 1.6, and 2.6% at

50, 70, and 80 years of age, respectively50, 70, and 80 years of age, respectively�� Rates increasing in those of European descent worldwideRates increasing in those of European descent worldwide

� Highest in Australia and New Zealand (50/100,000/yr)

� Rates have tripled in Croatia in the past 40 years

Melanoma Risk Factors

�� Hx of sun exposure, particularly blistering sunburns, Hx of sun exposure, particularly blistering sunburns, especially in childhood (est. 65% of the risk)especially in childhood (est. 65% of the risk)

�� Fair skin/freckling/tendency to sunburnFair skin/freckling/tendency to sunburn

�� Light hair/eye coloring Light hair/eye coloring –– MC1R gene in redheadsMC1R gene in redheads

�� Multiple nevi (>50Multiple nevi (>50--100 yields a RR of 5 to 17)100 yields a RR of 5 to 17)

�� Dysplastic nevi (atypical moles)Dysplastic nevi (atypical moles)� Precursor of melanoma

�� Family hx of melanoma or of atypical neviFamily hx of melanoma or of atypical nevi

�� Prior hx of melanoma Prior hx of melanoma � Risk 2-11% at 5 yrs, and twice that if also dysplastic nevi or

family history of melanoma

� With history of two melanomas, risk of a 3rd is 30% within 5 yrs

�� ParkinsonParkinson’’s, Xeroderma pigmentosum, Immunosuppressions, Xeroderma pigmentosum, Immunosuppression

Atypical (“dysplastic”) Nevi

�� Typically, people have 10Typically, people have 10--40 nevi, mostly on 40 nevi, mostly on

sunsun--exposed areasexposed areas

�� Atypical nevi however:Atypical nevi however:

� Clinically appear similar to melanoma

� A risk for developing melanoma:

�� 10% risk of transforming into melanoma 10% risk of transforming into melanoma

�� Risk increased 12 to 20Risk increased 12 to 20--fold if >10 atypical nevifold if >10 atypical nevi

�� More important if also with personal or family More important if also with personal or family

hx of melanomahx of melanoma

Melanoma and Family History

�� Approximately 10% of patients with melanoma Approximately 10% of patients with melanoma have a family history of the disease, but not all of have a family history of the disease, but not all of these individuals have hereditary melanoma these individuals have hereditary melanoma � Apparent familial inheritance pattern may be due to

clustering of sporadic cases in families with common heavy sun exposure and a susceptible skin type

�� Familial Atypical Multiple Mole and Melanoma Familial Atypical Multiple Mole and Melanoma (FAMMM) syndrome(FAMMM) syndrome� Clinically affected subjects have multiple (over 100)

dysplastic (atypical) nevi, and their lifetime cumulative incidence of melanoma approaches 100%

� Median age at diagnosis of 33

� Mutations in certain genes, most commonly CDKN2A and CDK4, have been identified in melanoma-prone families

Genetic Screening�� Autosomal dominantly inherited mutations in melanoma Autosomal dominantly inherited mutations in melanoma

susceptibility genes are responsible for probably less than 1 tosusceptibility genes are responsible for probably less than 1 to 2% 2% of cutaneous melanomas of cutaneous melanomas

�� Mutations in CDKN2A and CDK4 genes, have been identified in Mutations in CDKN2A and CDK4 genes, have been identified in melanomamelanoma--prone familiesprone families� The major gene resides on chromosome 9p and encodes the tumor

suppressor gene CDKN2A, also called p16INK4A or MTS1 (multiple tumor suppressor-1)

�� Approximately 20 to 40% of families with three or more affected Approximately 20 to 40% of families with three or more affected firstfirst--degree relatives have mutations in the CDKN2A gene degree relatives have mutations in the CDKN2A gene

�� Incidence of melanoma in carriers was estimated to be 14, 24, anIncidence of melanoma in carriers was estimated to be 14, 24, and d 28% at 50, 70, and 80 years of age, respectively 28% at 50, 70, and 80 years of age, respectively

�� May be increased risk of pancreatic and brain cancersMay be increased risk of pancreatic and brain cancers�� In a cohort of young patients (median age 32 years) with sporadiIn a cohort of young patients (median age 32 years) with sporadic c

melanoma, there was no increase in the prevalence of CDKN2A melanoma, there was no increase in the prevalence of CDKN2A mutations in the absence of a positive family history mutations in the absence of a positive family history

�� Low to moderately increased melanoma risk:Low to moderately increased melanoma risk:� BRCA2 (RR 2.6)� Retinoblastoma gene

� MC1R - Melanocortin-1 receptor - gene leads to red hair and failure to tan (RR 2-4)

Staging of Melanoma

�� TNM staging systemTNM staging system

� Tumor, Node, Metastasis

�� AJCC seventh edition came out in January AJCC seventh edition came out in January 20102010

� Staging system is based upon an analysis of over 38,900 patients with cutaneous melanoma from the AJCC Melanoma Staging Database

�� Staging is closely tied to prognosisStaging is closely tied to prognosis

Factors Affecting StagingFactors Affecting Staging……..

Primary Tumor (T)

�� Tumor Thickness Tumor Thickness –– Continuously increasing risk Continuously increasing risk

with increasing thicknesswith increasing thickness

� T1: < 1.0 mm

� T2: 1.01 - 2.00 mm

� T3: 2.01 - 4.00 mm

� T4: > 4.00 mm

�� Ulceration (absence of intact epithelium)Ulceration (absence of intact epithelium)

� No ulceration = “a”

� Ulceration present = “b”

�� Mitotic Rate Mitotic Rate –– Risk increases with increasing Risk increases with increasing

mitotic rate, regardless of thicknessmitotic rate, regardless of thickness

� Affects only T1 for staging though: “b” if > 1/mm2

Lymphatic Involvement (N)

�� NX: Nodes are not assessable (e.g. previously NX: Nodes are not assessable (e.g. previously resected) resected)

�� N0: No regional lymphatic metastases N0: No regional lymphatic metastases �� N1: One involved lymph nodeN1: One involved lymph node

� N1a - presence of micrometastasis (by sentinel node bx)� N1b - presence of macrometastasis (clinically detected

nodes or with extracapsular extension)

�� N2:N2:� N2a - two or three nodes with micrometastases � N2b - two or three nodes with macrometastases� N2c - without lymph node involvement but with in transit

or satellite metastasis.

�� N3: Four or more positive nodes, or matted nodes, or N3: Four or more positive nodes, or matted nodes, or in transit metastases/satellites with one or more in transit metastases/satellites with one or more positive nodes positive nodes

Distant Metastasis (M)

�� M0: No detectable evidence of distant M0: No detectable evidence of distant

metastasesmetastases

�� M1a: Metastases to skin, subcutaneous, M1a: Metastases to skin, subcutaneous,

or distant lymph node, normal serum LDHor distant lymph node, normal serum LDH

�� M1b: Lung metastases, normal LDHM1b: Lung metastases, normal LDH

�� M1c: Metastasis to other visceral sites M1c: Metastasis to other visceral sites

with a normal LDH, or any distant with a normal LDH, or any distant

metastasis with an elevated LDHmetastasis with an elevated LDH

Stage Groupings�� Stage IStage I:: T1a to T2a, N0 and M0T1a to T2a, N0 and M0

� Stage IA – T1a

� Stage IB – T1b or T2a

�� Stage IIStage II:: T2b to T4b, N0 and M0T2b to T4b, N0 and M0� Stage IIA – T2b or T3a, N0, M0

� Stage IIB – T3b or T4a, N0, M0

� Stage IIC – T4b, N0, M0

�� Stage IIIStage III:: N1N1--3, M03, M0� Stage IIIA – T1-4a, N1a or N2a

� Stage IIIB – T1-4b, N1a or N2a; or T1-4a, N1b, N2b, or N2c

� Stage IIIC – T1-4b, N1b, N2b, or N2c; or Any T, N3

�� Stage IVStage IV: M1: M1� Any T, Any N, M1a-M1c

*Isolated metastases arising in lymph nodes, skin, or subcutaneo*Isolated metastases arising in lymph nodes, skin, or subcutaneous us tissue, without an identifiable primary, are classified as stagetissue, without an identifiable primary, are classified as stage IIIIII

Melanoma Treatment

�� Surgical resection of primary tumor with adequate marginsSurgical resection of primary tumor with adequate margins

�� Sentinel node biopsy now done for lesions >1mm thicknessSentinel node biopsy now done for lesions >1mm thickness

� Not performed for early localized lesions (stage I and carcinoma in situ) unless additional high risk features present

� Generally recommended for all others

� If melanoma present, full lymph node dissection (“LND”) is done

�� LND performed if clinically evident adenopathy is presentLND performed if clinically evident adenopathy is present

�� Adjuvant interferon if node positive diseaseAdjuvant interferon if node positive disease

�� Resection of locoregional or isolated metastatic recurrenceResection of locoregional or isolated metastatic recurrence

� Rare cures obtained

�� Systemic therapy for metastatic diseaseSystemic therapy for metastatic disease

� Limited effectiveness but major advances may be on the horizon with new immunotherapies

� High dose interleukin-2, ipilimumab (a monoclonal antibody) and vemurafenib (a BRAF-inhibitor) have shown promise

Melanoma Case #1

�� 51 year51 year--old male $500,000 of Term Life, July 2011old male $500,000 of Term Life, July 2011

� 5’9” (175cm), 185 lbs (84kg), BP 128/84, Lab all normal

� Melanoma of neck 2008

� Family history of bladder cancer, no melanoma

- Stage? - Information complete?

Melanoma Case #1

�� Dermatology followDermatology follow--up every 4 monthsup every 4 months

�� Extensive solar damage, multiple basal cell Extensive solar damage, multiple basal cell

carcinomas, no additional nevi of concern notedcarcinomas, no additional nevi of concern noted

Additional Dermatology Records

- Tumor Stage?

- Favorable and unfavorable features?

- Mortality risk?

- What if this was just 4 months ago?

- What if it was 4 years later?

Melanoma Case #2

�� 47 year old female; $1,000,000 Universal 47 year old female; $1,000,000 Universal

Life InsuranceLife Insurance

� Height 65 inches (165 cm), weight 134 lbs (61 kg)

� Non-smoker, BP 118/80, insurance lab results all within normal limits

� History of skin cancer excised 2.5 years prior to application. No other health history.

Can we make an offer as is?

Melanoma Case Study

�� 47 year old female. History of skin cancer 47 year old female. History of skin cancer excised 2.5 years prior to application. No excised 2.5 years prior to application. No other health history.other health history.

�� Attending physician report:Attending physician report:� Abnormal mole noted on right upper thigh,

biopsied.

� Exam otherwise normal, no palpable axillary lymph nodes

� Treated with wide-excision, no residual melanoma

� Lab and chest X-ray normal

Now are you happy?

Case #2PathReport

- Melanoma stage?

- Favorable and unfavorable prognostic features present?

- What else would be useful information?

Melanoma Case #2

�� Sentinel Lymph node biopsy negativeSentinel Lymph node biopsy negative

�� Follows up with dermatologist after 6 Follows up with dermatologist after 6

months and then every year months and then every year –– no no

recurrence, no other suspicious skin recurrence, no other suspicious skin

lesions notedlesions noted

�� No known family history of melanomaNo known family history of melanoma

Was the evaluation and follow-up adequate?

Prognosis?

Melanoma Case #2 – What if…

What if she was subsequently found to have two atypical nevi excised?

And/or if she also had a family history of melanoma in her mother?

Melanoma Case #2 -- What if…

�� What if a sentinel node biopsy was What if a sentinel node biopsy was

positive for metastatic melanoma:positive for metastatic melanoma:

Stage then?

� How about if axillary node dissection was carried out and two nodes were positive: :

Stage then?

Prognosis?

And what if we were now 10 years out since the diagnosis?

Melanoma Case #2 – Alternative history

What if, after a year, melanoma recurred at the margins of the wide excision, and was then re-excised – does this change the prognosis?

Bibliography - Melanoma1. http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-

skin-cancer-key-statistics2. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial

disparities on premature cancer deaths. Siegel R, Ward E, Brawley O, Jemal A. CA Cancer J Clin. 2011;61(4):212.

3. Geller AC, Miller DR, Annas GD, et al. Melanoma incidence and mortality among US whites, 1969-1999. JAMA 2002; 288:1719.

4. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009; 27:3.5. 87.Goggins WB, Tsao H. A population-based analysis of risk factors for a second

primary cutaneous melanoma among melanoma survivors. Cancer 2003; 97:639.6. Prognostic significance of mitotic rate in localized primary cutaneous melanoma:

an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. Thompson JF, et al. J Clin Oncol. 2011;29(16):2199.

7. Caini S, Gandini S, Sera F, et al. Meta-analysis of risk factors for cutaneous melanoma according to anatomical site and clinico-pathological variant. Eur J Cancer 2009; 45:3054.

8. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the Surveillance, Epidemiology, and End Results (SEER) program. Lachiewicz AM, et al. Arch Dermatol. 2008 Apr;144(4):515-21.

9. The prognostic impact of the anatomical sites in the 'head and neck melanoma': scalp versus face and neck. de Giorgi V, et al. Melanoma Res. 2012 Aug 23.

10. Population-based 20-year survival among people diagnosed with thin melanomas in Queensland, Australia. Green AC, et al. J Clin Oncol. 2012 May 1;30(13):1462-7.

11. Olsen CM, Carroll HJ, Whiteman DC. Estimating the attributable fraction for cancer: A meta-analysis of nevi and melanoma. Cancer Prev Res (Phila) 2010; 3:233.

12. http://www.melanomaprognosis.org/Default.aspx

Prostate CancerProstate Cancer

Second most common cancer in men worldwide, Second most common cancer in men worldwide, with an estimated 900,000 cases and 258,000 deaths with an estimated 900,000 cases and 258,000 deaths in 2008in 2008

In the U.S. 2012 estimate In the U.S. 2012 estimate ---- 242,000 new cases and 242,000 new cases and 28,000 deaths 28,000 deaths � Most common cancer in men� Most commonly diagnosed human cancer, excluding skin

cancers� 2nd leading cause of death from cancer in men

About 1 in 6 men will be diagnosed with prostate About 1 in 6 men will be diagnosed with prostate cancer during their lifetime (yet at least 1/2 of men cancer during their lifetime (yet at least 1/2 of men over age 40 will over age 40 will developdevelop prostate cancer)prostate cancer)� Rates are 10-50 times higher than those reported in many

Asian countries (due in part to screening practices)� Many men with occult disease die of other diseases

Simplified Simplified

Schematic of Schematic of

GleasonGleason’’s s

Grading SystemGrading System

NOTES ON PROSTATE CANCER NOTES ON PROSTATE CANCER

Clinical (c) & Path (p) stagingClinical (c) & Path (p) staging::

�cT1c – Unapparent, biopsy diagnosis only

�c or p T2a – ½ of one lobe

�c or p T2b – up to one lobe

�c or p T2c – bilateral

�c or p T3a – extends through capsule

�c or p T3b – seminal vesicle invasion

Prostate Cancer Prostate Cancer –– Case #1Case #1

74 yr old man. PSAs 4.574 yr old man. PSAs 4.5--5.0, 20095.0, 2009--20102010

March 2011, PSA 7.4. March 2011, PSA 7.4. � Bx: One focus Gleason 3+4 = 7 Prostate Ca. Only

5% in 1 of 6 cores.

Active surveillance. Active surveillance.

November 2011: PSA up to 10.1. November 2011: PSA up to 10.1. � Twelve core biopsy – all benign.

Continue active surveillance. Continue active surveillance. � May 2012: PSA 9.1 - clinical lab.

� June 2012: PSA 6.4 at insurance lab.

Case #1 Case #1 –– QuestionsQuestions

Is this treatment appropriate?Is this treatment appropriate?

Mortality risk: low, intermediate, high?Mortality risk: low, intermediate, high?

Explain PSA variation, MayExplain PSA variation, May--June, 2012 June, 2012

�May 2012: PSA 9.1

�June 2012: PSA 6.4

Prostate Cancer Prostate Cancer –– Case #2Case #260 year60 year--old man, applied August 2012 old man, applied August 2012

Sept. 2006, age 54, PSA 3.2 (2.0 in 2005) Sept. 2006, age 54, PSA 3.2 (2.0 in 2005)

Sextant prostate bx. Sextant prostate bx. � Focus of atypical cells, w/ absent basal cells, right. � HGPIN on left.

Dec. 2006. Slides referred to Dr. Epstein, Johns Dec. 2006. Slides referred to Dr. Epstein, Johns Hopkins. His Diagnosis:Hopkins. His Diagnosis:� One tiny focus prostate cancer, Gleason 3+3, with absent

basal cells, right side. � HGPIN on left.

Feb. 2007. Repeat sextant bx. Dr. EpsteinFeb. 2007. Repeat sextant bx. Dr. Epstein’’s s diagnosis:diagnosis:� Small atypical focus, right, not diagnostic of cancer.

FU: All PSAFU: All PSA’’s in 2.0s in 2.0--3.0 range, most around 2.5.3.0 range, most around 2.5.

Latest PSA, April 2012: 2.5. No bx since 2007. Latest PSA, April 2012: 2.5. No bx since 2007.


Is this Is this ““active surveillanceactive surveillance”” (A.S.) ?(A.S.) ?

Is active surveillance or watchful Is active surveillance or watchful waiting usually appropriate < age 65?waiting usually appropriate < age 65?

Compare case 2 with case 1Compare case 2 with case 1

Mortality risk: low, intermediate, high?Mortality risk: low, intermediate, high?

Do you think he will soon develop Do you think he will soon develop clinical prostate cancer?clinical prostate cancer?


66 yr old. 1998, age 52, PSA 2.6. 66 yr old. 1998, age 52, PSA 2.6.

�Bx, Gleason 3+3, 3 of 12 cores

Radical prostatectomy Radical prostatectomy

�Gleason 3+3, Stage pT3a

FollowFollow--up PSAs all <0.1 for 8 years up PSAs all <0.1 for 8 years

March 2007. PSA suddenly 3.6. March 2007. PSA suddenly 3.6.

�Salvage radiation therapy

PSAs since, all <0.2, until May 2012, PSAs since, all <0.2, until May 2012, then 0.3 then 0.3


Does grade or stage explain Does grade or stage explain recurrence?recurrence?

How effective is salvage radiation after How effective is salvage radiation after RRP?RRP?

Concern about latest PSA?Concern about latest PSA?

Favorable/unfavorable factors?Favorable/unfavorable factors?

Mortality risk: low, intermediate, high? Mortality risk: low, intermediate, high?

What if he chose active surveillance?What if he chose active surveillance?


53 y/o. Elevated PSA since 2006. (PSA in 2000: 2.7) 53 y/o. Elevated PSA since 2006. (PSA in 2000: 2.7) � Father/brother with PC before age 65

2006 until Feb 2011: PSA from 6.4 (8% free), 7.0 (6% 2006 until Feb 2011: PSA from 6.4 (8% free), 7.0 (6% F), to 15.0, 16.3, 17.4, (then 9.3 & 12.6 after F), to 15.0, 16.3, 17.4, (then 9.3 & 12.6 after dutasteride), to 23.2, to 28.7 in 2012. % free not done dutasteride), to 23.2, to 28.7 in 2012. % free not done if PSA >10.if PSA >10.

Multiple biopsies from Feb. 2006. Multiple biopsies from Feb. 2006. � First 12 core biopsy: benign w/ small focus HGPIN. � Subsequent 10 to 12 core biopsies: BPH, occasional dense

chronic or focally acute inflammation w/ comment about atrophy.

Rare mention of HGPIN, focal. Rare mention of HGPIN, focal.

In 2008, whole body scan for mets. Also 2 pelvic In 2008, whole body scan for mets. Also 2 pelvic MRIMRI’’s, 1 w/ endorectal coil. All s, 1 w/ endorectal coil. All –– no evidence of no evidence of cancer. cancer.

Prostate Cancer Prostate Cancer –– Case #4 (continued)Case #4 (continued)

Nov. 2011Nov. 2011--Feb. 2012: intense evaluation. After Feb. 2012: intense evaluation. After seven rounds of 10seven rounds of 10--12 core biopsies over the years, 12 core biopsies over the years, had saturation biopsy of 36 cores! had saturation biopsy of 36 cores! � Four of 36 cores showed HGPIN. Has never had evidence of

cancer.

2012 studies 2012 studies -- normal pelvic CT & normal bone scan, normal pelvic CT & normal bone scan,

TRUS: hyperechoic nodule, right base, o/w normal.TRUS: hyperechoic nodule, right base, o/w normal.

UA: 0UA: 0--3 WBCs/hpf & urine culture w/ 100,000 3 WBCs/hpf & urine culture w/ 100,000 Streptococci Viridans. Streptococci Viridans.

Unable to obtain recent PCA3 results. Unable to obtain recent PCA3 results.

DREs: small, firm prostate, no nodules DREs: small, firm prostate, no nodules


Possible cause of PSA elevation?Possible cause of PSA elevation?

Other helpful tests, besides PCA3?Other helpful tests, besides PCA3?

Is there hidden prostate cancer?Is there hidden prostate cancer?

Favorable/ unfavorable factors?Favorable/ unfavorable factors?

Significant mortality risk?Significant mortality risk?

Survival by Age Survival by Age

and Gleasonand Gleason’’s s

ScoreScore

Colorectal Cancer (CRC)Colorectal Cancer (CRC)

�� Approximately 143,000 new cases of CRC Approximately 143,000 new cases of CRC diagnosed each year in U.S. diagnosed each year in U.S. (1)(1)

� 4th most common cancer diagnosed (prostate, breast, lung)

�� Over 50,000 deaths each year from CRCOver 50,000 deaths each year from CRC

� 2nd most common cause of death due to cancer

�� Globally it is the 3Globally it is the 3rdrd most commonly most commonly diagnosed cancer in male and the 2diagnosed cancer in male and the 2ndnd in in femalesfemales

Trends in incidence of colorectal cancerTrends in incidence of colorectal cancer

AgeAge--standardized rate per 100,000, menstandardized rate per 100,000, men

NORDCAN (www.ancr.nu)

France: INVSIreland: www.ncri.ie

The Netherlands: www.ikcnet.nl

UK: www.cancerresearchuk.org

Australia: www.aihw.gov.au

Canada: www.statcan.gc.caIndia: Chennai cancer registryJapan: Miyagi, Osaka and Yamagata cancer registries

Republic of Korea: www.ncc.re.krUSA: SEER program: seer.cancer.gov

GLOBOCAN 2008 (IARC) , Section of Cancer Information (4/9/2012)

Trends in mortality from colorectal cancerTrends in mortality from colorectal cancer

AgeAge--standardized rate per 100,000, menstandardized rate per 100,000, men

WHO (www.who.int/gho) WHO (www.who.int/gho) WHO (www.who.int/gho)

Colorectal Cancer Case #1Colorectal Cancer Case #1

64 year old female; for $750,000 Term Life Insurance64 year old female; for $750,000 Term Life Insurance� Height 63 inches (160 cm), weight 174 lbs (79 kg)� Non-smoker, BP 136/80, insurance lab blood and urine

tests all within normal limits� No important medical problems; family history of colon

cancer in her father at age 55

• What would be the recommended colon cancer screening for her?

• How about if a brother also had colon cancer, and at age 45?

• And a paternal aunt had endometrial cancer at age 50?

�� Developed rectal bleeding 2.5 years prior to Developed rectal bleeding 2.5 years prior to application, colonoscopy revealed large mass at 10application, colonoscopy revealed large mass at 10--15 cm from the anal verge15 cm from the anal verge

Partial colectomy Partial colectomy –– pathology as follows:pathology as follows:

Colorectal Cancer Case #1 Questions:Colorectal Cancer Case #1 Questions:

� Pathologic stage?� Favorable and unfavorable prognostic features

present?� What additional prognostic information would you

like to see?� What is the expected clinical follow-up in this

situation?� Assuming she has had good follow-up and no

clinical evidence of disease, what is her likelihood of recurrence at this point?� And her mortality risk?

� What is her likelihood of developing a second colorectal cancer?� What if she had the family history of colorectal

cancer last noted (brother and aunt)?

Colorectal Cancer Case #1 Colorectal Cancer Case #1 –– What ifWhat if……

�� What if she were found to have 2 of What if she were found to have 2 of the 9 nodes positive for malignancy:the 9 nodes positive for malignancy:

� TNM stage?

� Any additional prognostic factors or treatment then?

� Prognosis?

� Prognosis if she were now 8 years out since surgery?

Anatomy of the Colon Anatomy of the Colon –– CRC LocationCRC Location

Right-sided40%

Left-sided32%

Rectal28%

Risk Factors for Colorectal CancerRisk Factors for Colorectal Cancer

�� FAP (familial adenomatous polyposis)FAP (familial adenomatous polyposis)

�� MAP (MUTYHMAP (MUTYH--associated polyposis) associated polyposis)

�� HNPCC (hereditary nonHNPCC (hereditary non--polyposis colon cancer)polyposis colon cancer)

�� Advanced age Advanced age � 2x risk with each decade after 40� 90% occur after age 50 (but this may be decreasing)

�� Inflammatory bowel disease Inflammatory bowel disease � 5-15x risk if pancolitis� 3x risk if left-sided only

�� Abdominal radiation Abdominal radiation

�� Country of birth (10x higher in N. America than Africa) Country of birth (10x higher in N. America than Africa)

�� History of CRC (1.5 to 3% new cancers within 5 years)History of CRC (1.5 to 3% new cancers within 5 years)

�� Family history of CRC (2x risk if first degree relative)Family history of CRC (2x risk if first degree relative)

�� History of colon polypsHistory of colon polyps

�� Obesity (1.5x risk compared to BMI 18Obesity (1.5x risk compared to BMI 18--25)25)

�� Alcohol (1.4x risk if Alcohol (1.4x risk if >> 3 drinks/day)3 drinks/day)

�� AcromegalyAcromegaly

�� Diet high in red meat, low in fruits/vegetables/calcium/fiberDiet high in red meat, low in fruits/vegetables/calcium/fiber

�� Smoking (1.2x risk)Smoking (1.2x risk)

�� DiabetesDiabetes

Colon Polyps and Cancer RiskColon Polyps and Cancer Risk

�� History of villous polyp or adenomatous polyp History of villous polyp or adenomatous polyp >1.0 cm (3.5 to 6.5x risk)>1.0 cm (3.5 to 6.5x risk)

�� Serrated adenomasSerrated adenomas

� Flatter and more difficult to visualize endoscopically

� Characteristically carry BRAF V600E mutations, microsatellite instability, and greater HNPCC concern

�� Patients with proximal hyperplastic polyps may Patients with proximal hyperplastic polyps may have a similar risk for developing adenomas have a similar risk for developing adenomas within 5 years as patients who have baseline within 5 years as patients who have baseline adenomasadenomas

� Veterans Affairs Cooperative Study 380

Familial adenomatous polyposis (FAP)Familial adenomatous polyposis (FAP)

Hereditary nonpolyposis colorectal cancer (HNPCC)Hereditary nonpolyposis colorectal cancer (HNPCC)

�� Represent very high risk for colorectal cancerRepresent very high risk for colorectal cancer�� However, less than 5% of CRC cases are due to theseHowever, less than 5% of CRC cases are due to these�� Autosomal dominant inheritanceAutosomal dominant inheritance�� FAPFAP

� Average age of symptom onset ~16 years � CRC occurs in 90% of untreated individuals by age 45 � Attenuated form has an older average age of cancer

diagnosis of 54 years �� HNPCC (Lynch Syndrome)HNPCC (Lynch Syndrome)

� Mean age at initial cancer diagnosis is ~45 years�� But few are before the age of 30, unlike FAPBut few are before the age of 30, unlike FAP

� Lifetime risk of developing CRC is approximately 60%� Approximately 10% will have synchronous cancers � Extracolonic cancers are also common, including

endometrial carcinoma in ~40% of female gene carriers

Amsterdam II criteria for HNPCCAmsterdam II criteria for HNPCC

�� There should be at least three relatives with an HNPCCThere should be at least three relatives with an HNPCC--associated cancer (colorectal cancer, cancer of the associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis)endometrium, small bowel, ureter, or renal pelvis)

�� One should be a first degree relative of the other twoOne should be a first degree relative of the other two

�� At least two successive generations should be affectedAt least two successive generations should be affected

�� At least one should be diagnosed before age 50At least one should be diagnosed before age 50

�� Familial adenomatous polyposis should be excluded in the Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if anycolorectal cancer case(s) if any

�� Tumors should be verified by pathological examinationTumors should be verified by pathological examination

�� If criteria are met, then MMR (mismatch repair) gene testing in If criteria are met, then MMR (mismatch repair) gene testing in the youngest living member of the family with colorectal the youngest living member of the family with colorectal cancer is advisedcancer is advised

Limitations to Amsterdam CriteriaLimitations to Amsterdam Criteria

�� Misses many with deleterious mutationsMisses many with deleterious mutations

� Sensitivity of only 36% in one study

� Specificity good though at 97%

�� Immunohistochemistry of tumor is betterImmunohistochemistry of tumor is better

� Sensitivity 86%

� Specificity 92%

�� Not all gene mutations are similarNot all gene mutations are similar

� Cumulative cancer risk by age 70 for the three main mutations (95% of cases)9

�� 4040--50% for MLH1 and MSH250% for MLH1 and MSH2

�� Just 12% for MSH6 Just 12% for MSH6

Bethesda Criteria for HNPCCBethesda Criteria for HNPCC

Tumors from individuals should be tested for MSI:Tumors from individuals should be tested for MSI:

�� Colorectal cancer diagnosed in a patient who is less than Colorectal cancer diagnosed in a patient who is less than 50 years of age 50 years of age

�� Presence of synchronous, metachronous colorectal, or Presence of synchronous, metachronous colorectal, or other HNPCCother HNPCC--associated tumors, regardless of age associated tumors, regardless of age

�� Colorectal cancer with the MSIColorectal cancer with the MSI--like histology diagnosed in like histology diagnosed in a patient who is less than 60 years of agea patient who is less than 60 years of age

�� Colorectal cancer diagnosed in a patient with one or more Colorectal cancer diagnosed in a patient with one or more firstfirst--degree relatives with an HNPCCdegree relatives with an HNPCC--related tumor, with related tumor, with one of the cancers being diagnosed under age 50 yearsone of the cancers being diagnosed under age 50 years

�� Colorectal cancer diagnosed in a patient with two or more Colorectal cancer diagnosed in a patient with two or more firstfirst-- or secondor second--degree relatives with HNPCCdegree relatives with HNPCC--related related tumors, regardless of age tumors, regardless of age

Clinical Manifestations of Colon CancerClinical Manifestations of Colon Cancer

�� NoneNone�� Abdominal painAbdominal pain

� Partial obstruction -- cramping, change in stool shape

� Peritonitis� Tumor dissemination

�� Change in bowel habit Change in bowel habit (esp. left(esp. left--sided tumors)sided tumors)�� Hematochezia (BRBPR) Hematochezia (BRBPR) (esp. rectal tumors)(esp. rectal tumors)�� Anemia Anemia (esp. right(esp. right--sided tumors)sided tumors)�� MelenaMelena�� Weakness, malaise, anorexia, weight lossWeakness, malaise, anorexia, weight loss�� Palpable abdominal mass, fever of unknown Palpable abdominal mass, fever of unknown

origin, stool in urine or in vaginal secretionsorigin, stool in urine or in vaginal secretions�� Unknown primary siteUnknown primary site

Screening for Colon Cancer*Screening for Colon Cancer*

�� For average risk individuals, beginning at age 50:For average risk individuals, beginning at age 50:� Fecal occult blood testing annually + flexible sigmoidoscopy

every 5 years� Colonoscopy every 10 years� Double contrast barium enema every 5 years� Virtual colonoscopy every 5 yrs

�� For those with a family history of CRC or adenoma in a first For those with a family history of CRC or adenoma in a first degree relative (FDR) or 2 or more second degree relatives: degree relative (FDR) or 2 or more second degree relatives: � Screening as above but beginning at age 40 (or 10 years before

age at diagnosis in a FDR if was before age 50)

�� For those with ulcerative colitis or CrohnFor those with ulcerative colitis or Crohn’’s disease, s disease, colonoscopy:colonoscopy:� Beginning 8-10 years after symptom onset if pancolitis� Beginning 15-20 years after symptom onset if left-sided colitis

�� Intense screening and genetic counseling advised for those Intense screening and genetic counseling advised for those with familial cancer syndromeswith familial cancer syndromes

**Joint guidelines from the American Cancer Society, the United StJoint guidelines from the American Cancer Society, the United States Multiates Multi--Society Society

Task Force on Colorectal Cancer (ACSTask Force on Colorectal Cancer (ACS--MSTF), and the American College of Radiology: MSTF), and the American College of Radiology:

Published 2008.Published 2008.

Earlier screening and/or treatment recommended for Earlier screening and/or treatment recommended for

those considered high risk:those considered high risk:

�� Familial adenomatous polyposisFamilial adenomatous polyposis

� Total colectomy generally advised

�� Hereditary nonpolyposis CRC syndromesHereditary nonpolyposis CRC syndromes

� Colonoscopy every one to two years beginning at age 20 to 25, or 10 years earlier than the youngest age of colon cancer diagnosis in the family (whichever comes first)

� Consider screening also for endometrial, ovarian, gastric cancers

Stage at DiagnosisStage at Diagnosis

�� The increase in colorectal cancer The increase in colorectal cancer

screening has been associated with an screening has been associated with an

earlier stage at which colorectal cancer is earlier stage at which colorectal cancer is

diagnosed. From the SEER database:diagnosed. From the SEER database:

� Localized - confined to the primary site and to the mucosa, submucosa, and muscle layer (TNM stage I or II ) — 40%

� Lymph node involvement (TNM stage III) — 37%

� Distant metastases (TNM stage IV) — 19%

Synchronous CRCsSynchronous CRCs

�� Two or more distinct primary tumors Two or more distinct primary tumors

separated by normal bowel and not due to separated by normal bowel and not due to

direct extension or metastasisdirect extension or metastasis

� Present in about 2.5 percent of patients with colon cancer (when patients with hereditary nonpolyposis colorectal cancer are excluded)

� Synchronous primaries have the same prognosis as solitary malignancies when the highest stage of disease is compared

Metachronous cancers Metachronous cancers

�� Nonanastomotic new tumors developing at least Nonanastomotic new tumors developing at least six months after the initial diagnosissix months after the initial diagnosis� Develop in 1.5 to 3 percent of patients in the first

five years postoperatively and roughly 9 percent after several decades in survivors of the primary cancer

� In those with HNPCC, 20-40% will develop metachronous cancer if colectomy not performed

� In one report of 6579 subjects followed for an average of 4.3 years after CRC resection, the standardized incidence ratio (SIR) for a second cancer was 1.5 overall but was significantly greater in younger patients (38.3, 7.6, 2.2, and 1.2 for patents age 30-39, 40-49, 50-59, and over 60 years old, respectively)

Prognostic Factors for CRCPrognostic Factors for CRC

�� Stage Stage –– Single most important factorSingle most important factor� Serosal involvement of T4 lesions – now subdivided into T4a (tumor perforates

the visceral peritoneum) and T4b (direct invasion or histologic adherence to other organs and/or structures)

� However, histologic determination of serosal penetration is difficult, and conservative interpretation may lead to understaging of disease. For example, cytologic examination of serosal scrapings from pT3 specimens found malignant cells in up to 26 percent (12)

�� Lymph nodesLymph nodes� Number involved w/ tumor

�� CRC mortality roughly twice as high for N2 vs N1 statusCRC mortality roughly twice as high for N2 vs N1 status

� Number in surgical specimen�� Recommended at least 13 nodes retrieved at surgeryRecommended at least 13 nodes retrieved at surgery

�� Some advocate using Some advocate using ““Lymph node ratioLymph node ratio”” –– more predictive than number of positive nodes alonemore predictive than number of positive nodes alone

�� See tableSee table

� Mesenteric tumor nodules are each considered as a positive node (N1c)

� Micrometastases/Isolated tumor cells (ITCs): single tumor cells or small clusters of tumor cells measuring <0.2mm in size

�� Appears to have worse outcome per a metaAppears to have worse outcome per a meta--analysisanalysis1414

�� However considered only as pN0(i+) if detected by standard histoHowever considered only as pN0(i+) if detected by standard histologic techniques or IHC, or pN0 logic techniques or IHC, or pN0 (mol+) if detected only by special molecular techniques such as (mol+) if detected only by special molecular techniques such as RTRT--PCRPCR

�� Rectal vs colon cancerRectal vs colon cancer

�� Residual tumorResidual tumor� Based largely on the status of the circumferential resection margin

Additional Prognostic Factors for CRCAdditional Prognostic Factors for CRC

�� Lymphovascular invasionLymphovascular invasion

�� Grade (well/moderately vs. poorly differentiated)Grade (well/moderately vs. poorly differentiated)�� Signet cell variantSignet cell variant�� Adenosquamous carcinomasAdenosquamous carcinomas�� Appendiceal cystadenomacarcinoma Appendiceal cystadenomacarcinoma

� often associated with pseudomyxoma peritonei

�� CEA >5.0CEA >5.0� Independent of tumor stage

�� Tumor regression after neoadjuvant therapyTumor regression after neoadjuvant therapy�� Microsatellite instabilityMicrosatellite instability

� Seen in HNPCC tumors and in 15-20% of sporadically occurring tumors� Despite being poorly differentiated, the prognosis is more favorable� Similarly, mismatch repair deficiency and tumor infiltrating lymphocytes

�� 18q deletions18q deletions� Loss of heterozygosity at 18q portends a worse prognosis

�� Tumor borderTumor border —— irregular, infiltrating pattern of growth is an irregular, infiltrating pattern of growth is an independent adverse prognostic independent adverse prognostic � may predict liver metastasis.

Chemotherapy OptionsChemotherapy Options

�� Survival outcomes for Stage IIIA CRC Survival outcomes for Stage IIIA CRC often better than for Stage IIoften better than for Stage II

�� Adjuvant chemo advised if node positive Adjuvant chemo advised if node positive –– roughly 30% reduction in mortalityroughly 30% reduction in mortality

� Oxaliplatin based regimen – 6 month course initiated within 6-8 weeks after CRC resection

�� FOLFOX FOLFOX -- includes Leukovorin and 5includes Leukovorin and 5--FUFU

�� Irinotecan, bevacizumab, and cetuximab Irinotecan, bevacizumab, and cetuximab usually reserved for metastatic disease usually reserved for metastatic disease

�� TASTAS--102 on the horizon?102 on the horizon?

TNM Staging System for Colorectal CancerTNM Staging System for Colorectal Cancer

�� Primary tumor (T)Primary tumor (T)� Tis (intramucosal) -- Carcinoma in situ; intraepithelial or invasion of lamina propria

� T1 -- Tumor invades submucosa

� T2 -- Tumor invades muscularis propria

� T3 -- Tumor invades through the muscularis propria into pericolorectal tissues

� T4a -- Tumor penetrates to the surface of the visceral peritoneum

� T4b -- Tumor directly invades other organs or structures

�� Regional lymph node (N)Regional lymph node (N)� NX -- Regional nodes cannot be assessed

� N0 -- No regional nodal metastases

� N1 -- Metastasis in 1 to 3 regional lymph nodes

�� N1a N1a –– Metastasis in one regional lymph nodeMetastasis in one regional lymph node

�� N1b N1b –– Metastasis in 2Metastasis in 2--3 regional lymph nodes3 regional lymph nodes

�� N1c N1c –– Tumor deposit(s) in the subserosa, mesentery, or nonperitonealiTumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolorectal tissues zed pericolorectal tissues without regional nodal metastasiswithout regional nodal metastasis

� N2 -- Metastasis in 4 or more regional lymph nodes

�� N2a N2a –– Metastasis in 4Metastasis in 4--6 regional lymph nodes6 regional lymph nodes

�� N2b N2b –– Metastasis in 7 or more regional lymph nodesMetastasis in 7 or more regional lymph nodes

�� Distant metastasis (M)Distant metastasis (M)� MX -- Distant metastasis cannot be assessed

� M0 -- No distant metastasis

� M1 -- Distant metastasis

�� M1a M1a –– Metastasis confined to one organ siteMetastasis confined to one organ site

�� M1b M1b –– Metastasis in more than one organ/site or the peritoneumMetastasis in more than one organ/site or the peritoneum

AJCC TNM Staging for Colorectal Cancer, 7AJCC TNM Staging for Colorectal Cancer, 7thth editionedition

TNMTNM AJCC StageAJCC Stage MAC*MAC* DukeDuke’’ss

TisTis N0N0 M0M0 00 --

T1T1 N0N0 M0M0 II AA AA

T2T2 N0N0 M0M0 B1B1 AA

T3T3 N0N0 M0M0 IIAIIA B2B2 BB

T4aT4a N0N0 M0M0 IIBIIB

T4bT4b N0N0 M0M0 IICIIC B3B3

T1T1--22 N1/N1cN1/N1c M0M0 IIIAIIIA C1C1

T1T1 N2aN2a M0M0

T3T3--4a4a N1/N1cN1/N1c M0M0 IIIBIIIB C2C2

T2T2--33 N2aN2a M0M0 C1/2C1/2

T1T1--22 N2bN2b M0M0 C1C1

T4aT4a N2aN2a M0M0 IIICIIIC C2C2 CC

T3T3--T4aT4a N2bN2b M0M0

T4bT4b N1N1--22 M0M0 C3C3

Any TAny T Any NAny N M1aM1a IVaIVa DD

Any TAny T Any NAny N M1bM1b IVbIVb --

Compared to Modified Astler-Coller (MAC) and Duke's Staging Systems

Recurrence RatesRecurrence Rates

�� Large database found recurrence rates as Large database found recurrence rates as

12% at one year, 14% year 112% at one year, 14% year 1--2, then 8%, 2, then 8%,

5%, and 3% over the next three years 5%, and 3% over the next three years

respectively respectively

�� Overall, 80% of recurrences occurred Overall, 80% of recurrences occurred

within the first 3 yrs. within the first 3 yrs.

� Mayo ACCENT study, J Clin Oncology 2005 Dec 1; 23(34).

FollowFollow--up After CRC Diagnosisup After CRC Diagnosis(National Comprehensive Cancer Network Guidelines)(National Comprehensive Cancer Network Guidelines)

�� History and Physical ExamHistory and Physical Exam� Every 3-6 months for the first 3 years then every 6 months years 4 and 5, then

annually

�� ColonoscopyColonoscopy� Within three months if exam was incomplete pre-operatively.

� Otherwise follow-up colonoscopy in one year and if negative for polyps repeat in three years, then every five years

� Proctosigmoidoscopy every six months for 5 years if rectal cancer

�� CEACEA� Every three to six months for the first two years, then every six

months for three additional years for T2 or higher stage disease.

�� Chest and abdomen CT scans for Stage IIChest and abdomen CT scans for Stage II--IVIV� Annually for three years usually advised if patient would be a candidate for

additional treatment� Annual pelvic CT for three years should be considered for rectal cancer

surveillance (especially if not treated with pelvic radiation)

�� Generally little else is advised for specific followGenerally little else is advised for specific follow--up for stage I up for stage I CRC since the prognosis is so favorableCRC since the prognosis is so favorable

CEACEA

�� Carcinoembryonic AntigenCarcinoembryonic Antigen

� Screening use is very limited as not too sensitive or specific

�� NonNon--cancercancer--related causes of an elevated CEA include related causes of an elevated CEA include gastritis, peptic ulcer disease, diverticulitis, liver gastritis, peptic ulcer disease, diverticulitis, liver disease, chronic obstructive pulmonary disease, disease, chronic obstructive pulmonary disease, diabetes, and any acute or chronic inflammatory state diabetes, and any acute or chronic inflammatory state

� Independent prognostic marker in those with CRC however:

�� PrePre--op levels >5 portend a worse prognosis, stage for op levels >5 portend a worse prognosis, stage for stage, than those with lower levels (HR ~1.6)stage, than those with lower levels (HR ~1.6)

�� Node negative CRC with an elevated CEA fare worse Node negative CRC with an elevated CEA fare worse than node positive disease with a normal CEAthan node positive disease with a normal CEA1515

� Also for monitoring for recurrence

�� See CRC followSee CRC follow--upup

Colorectal cancer Colorectal cancer -- BibliographyBibliography

1)1) Cancer statistics, 2008. Jemal A; Siegel R; Ward E; Hao Y; Xu J;Cancer statistics, 2008. Jemal A; Siegel R; Ward E; Hao Y; Xu J; Murray T; Thun MJ. CA Cancer J Clin. 2008 MarMurray T; Thun MJ. CA Cancer J Clin. 2008 Mar--Apr;58(2):71Apr;58(2):71--96. 96.

2)2) Surveillance, Epidemiology, and End Results (SEER) Program (httpSurveillance, Epidemiology, and End Results (SEER) Program (http://seer.cancer.gov) SEER*Stat Database: Incidence ://seer.cancer.gov) SEER*Stat Database: Incidence --SEER 17 Regs LimitedSEER 17 Regs Limited--Use, Nov 2006 Sub (1973Use, Nov 2006 Sub (1973--2004 varying), National Cancer Institute, DCCPS, Surveillance Re2004 varying), National Cancer Institute, DCCPS, Surveillance Research search Program, Cancer Statistics Branch, released April 2007.Program, Cancer Statistics Branch, released April 2007.

3)3) Colon cancer survival rates with the new American Joint CommitteColon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. O'Connell JB; e on Cancer sixth edition staging. O'Connell JB; Maggard MA; Ko CY. J Natl Cancer Inst 2004 Oct 6;96(19):1420Maggard MA; Ko CY. J Natl Cancer Inst 2004 Oct 6;96(19):1420--5.5.

4)4) Gunderson, LL, et al. Impact of Tand N stage and treatment on suGunderson, LL, et al. Impact of Tand N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled rvival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 2004; 22:1785analysis. J Clin Oncol 2004; 22:1785

5)5) LongLong--term risk of colorectal cancer after excision of rectosigmoid adterm risk of colorectal cancer after excision of rectosigmoid adenomas. Atkin WS; Morson BC; Cuzick J. N Engl J enomas. Atkin WS; Morson BC; Cuzick J. N Engl J Med 1992 Mar 5;326(10):658Med 1992 Mar 5;326(10):658--62. 62.

6)6) The National Cancer Data Base report on patterns of care for adeThe National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985nocarcinoma of the rectum, 1985--95. Jessup JM; 95. Jessup JM; Stewart AK; Menck HR. Cancer. 1998 Dec 1;83(11):2408Stewart AK; Menck HR. Cancer. 1998 Dec 1;83(11):2408--18. 18.

7)7) New tumorNew tumor--nodenode--metastasis staging strategy for nodemetastasis staging strategy for node--positive (stage III) rectal cancer: an analysis. Greene FL; Stewpositive (stage III) rectal cancer: an analysis. Greene FL; Stewart art AK; Norton HJ. J Clin Oncol 2004 May 15;22(10):1778AK; Norton HJ. J Clin Oncol 2004 May 15;22(10):1778--84. 84.

8)8) Lymph node evaluation and survival after curative resection of cLymph node evaluation and survival after curative resection of colon cancer: systematic review. Chang GJ; Rodriguezolon cancer: systematic review. Chang GJ; Rodriguez--Bigas MA; Skibber JM; Moyer VA. J Natl Cancer Inst. 2007 Mar 21;Bigas MA; Skibber JM; Moyer VA. J Natl Cancer Inst. 2007 Mar 21;99(6):43399(6):433--41. 41.

9)9) Cancer Risk Associated With Germline Mutations in MLH1, MSH2, anCancer Risk Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. Bonadona V, et d MSH6 Genes in Lynch Syndrome. Bonadona V, et al. JAMA. 2011;305:2304al. JAMA. 2011;305:2304--23102310

10)10) AJCC (American Joint Committee on Cancer) Cancer Staging Manual,AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th edition, Edge, SB, Byrd, DR, Compton, CC, et 7th edition, Edge, SB, Byrd, DR, Compton, CC, et al (Eds), Springer, New York 2010. p.143.al (Eds), Springer, New York 2010. p.143.

11)11) Synchronous colon primaries have the same prognosis as solitary Synchronous colon primaries have the same prognosis as solitary colon cancers. Passman MA, Pommier RF, Vetto JT. colon cancers. Passman MA, Pommier RF, Vetto JT. Dis Colon Rectum. 1996;39(3):329.Dis Colon Rectum. 1996;39(3):329.

12)12) Serosal cytologic study to determine free mesothelial penetratioSerosal cytologic study to determine free mesothelial penetration of intraperitoneal colon cancer. Zeng Z, et al. Cancer. n of intraperitoneal colon cancer. Zeng Z, et al. Cancer. 1992;70(4):737.1992;70(4):737.

13)13) Association between lymph node evaluation for colon cancer and nAssociation between lymph node evaluation for colon cancer and node positivity over the past 20 years. Parsons HM, et ode positivity over the past 20 years. Parsons HM, et al. JAMA. 2011;306(10):1089al. JAMA. 2011;306(10):1089

14)14) Molecular detection of tumor cells in regional lymph nodes is asMolecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in sociated with disease recurrence and poor survival in nodenode--negative colorectal cancer: a systematic review and metanegative colorectal cancer: a systematic review and meta--analysis. Rahbari NN, et al. J Clin Oncol. 2012;30(1):60.analysis. Rahbari NN, et al. J Clin Oncol. 2012;30(1):60.

15)15) CC--stage in colon cancer: implications of carcinoembryonic antigen stage in colon cancer: implications of carcinoembryonic antigen biomarker in staging, prognosis, and management. biomarker in staging, prognosis, and management. Thirunavukarasu P, et al. J Natl Cancer Inst. 2011;103(8):689Thirunavukarasu P, et al. J Natl Cancer Inst. 2011;103(8):689

16)16) https://www.adjuvantonline.com/online.jsphttps://www.adjuvantonline.com/online.jsp

Documents

SOLID TUMORS WORKSHOP - AAIM