EScoP, Craiova, 2012

The lobar nature of breast carcinoma

and its consequences

Tibor Tot M.D., Ph.D.

Central Hospital Falun, Sweden
 Breast cancer risk factors
• Female gender
• Family history
• Living in a high incidence country
• BRCA1, BRCA2

characteristics of the entire organism and influence the

genetic construction, as well as the milieu,
of all the cells in the body
Image courtesy of Dr James Going
Image courtesy of Dr James Going
 The lobe
• All of the ducts and terminal units
belonging to a single lactiferous duct,
together with the surrounding stromal
elements, comprise a breast lobe, a
pyramid-like structure with its tip in the
nipple and base towards the pectoralis
muscle.
 Breast carcinoma is a lobar disease in the
meaning that the simultaneously or
asynchronously appearing, often multiple,
in situ and/or invasive tumor foci originate
in a single lobe of one breast.
(The theory of the sick lobe)

Tot T: Correlating the ground truth of mammographic histology with the success or
failure of imaging. Technology In Cancer Research and Treatment, 4(1):23-8; 2005
Tot T: DCIS, cytokeratins and the theory of the sick lobe. Virchows Arch 2005; 447:1-8
Tot T: The theory of the sick lobe and the possible consequences,
Int J Surg Pathol 15(4:) 369-75, 2007
0 50 80 300y
1. Breast cancer is a lobar disease, originating
most often in a single sick lobe.

2. The sick lobe is mal-constructed during its

embryonic development.

3. Breast cancer is a life-long disease, which

can only be interrupted by elimination or
destruction of the entire sick lobe.
The Sick Lobe

EVIDENCE
Morphological evidence
 Amy D. Lobar Ultrasound of the breast.
In Tot T. Breast Cancer – a Lobar Disease, Springer 2011, pp 19-37
Going JJ. Lobar anatomy of human breast and its importance for breast cancer.
In Tot T. Breast Cancer – a Lobar Disease, Springer 2011, pp 19-37
Courtesy of Dr James Going
Brachtel et al. Occult nipple involvement in breast cancer: Clinicopathologic
findings in 316 consecutive mastectomy specimens. JCO 27:4948-54. 2009
Twelves D. Nerurkar A, Osin P, Ward A, Isacke CM, Gui GPH. The anatomy
of fluid-yielding ducts in breast cancer. Breast Cancer Res Treat 2011
Twelves D. Nerurkar A, Osin P, Ward A, Isacke CM, Gui GPH. The anatomy
of fluid-yielding ducts in breast cancer. Breast Cancer Res Treat 2011
 • 83% (29/35) tracing of the cancer-affected
duct system
• 6/35 duct system uneffected by cancer
• 12/35 perfusion extravaseted

Twelves D. Nerurkar A, Osin P, Ward A, Isacke CM, Gui GPH. The anatomy
of fluid-yielding ducts in breast cancer. Breast Cancer Res Treat 2011
”So far I have never found more than one
ductal system involved in spite of multiple
lesions scattered by mammography. They
always seems to connect to a single ductal
tree”.

Professor William C Dooley,

University of Oklahoma, USA
(personal communication)
 ”The pattern of spread of intraductal carcinoma
has a pyramid-like shape with a summit toward
and occasionally extending up to the nipple.”

”In 27/30 mastectomy

specimens contained
DCIS, invasive ca,
ADH, severe DH were
confined to the area of
a single lactiferous duct”

Mai et al. Pattern of distribution of intraductal and infiltrating ductal carcinoma:

Three-dimensional study using serial coronal giant sections of the breast.
Hum Pathol 2000, 31:464-74.
32 patients, nearly identical morphology and IH in MMC

Early - stage synchronous tumors are a

clonal proliferation of a single
mammary carcinoma

Middleton et al. Multicenric Mammary Carcinoma, Evidence

of Monoclonal Proliferation. Cancer 2002:94:1910-6.
Middleton et al. Multicenric Mammary Carcinoma, Evidence
of Monoclonal Proliferation. Cancer 2002:94:1910-6.
• “The 'sick lobe' hypothesis asks questions
about the development of breast cancer in time
and space, and observes that concentrating on
events in a few cubic millimetres of tissue is not
enough.”

(James Going, 2011).

 The Sick Lobe

FURTHER EVIDENCE
Genetic changes similar/identical to those in invasive cancer:

DCIS: LOH (Stratton et al, 1995, Farabegoli et al, 2002)

CGH (Buerger et al, 1999)
LCIS: LOH (Lakhani et al, 1995, Vos et al, 1997)
CGH (Lu et al, 1998, Buerger et al, 2000)
ADH: LOH (Lakhani et al, 1995)
UDH: LOH (Lakhani et al, 1996)
CGH (Jones et al, 2003)
CCC: CGH (Simpson et al, 2005)
Normal: LOH close to cancer (Deng et al, 1996, Meng et al 2004)
Cloning close and distant to cancer (Lakhani et al,1999)
breast without cancer (Lakhani et al,1999)
 ”…the earliest genetic changes that fit into this multistep
model might be detected in cells that appear morphologically
normal.”

”…a field of genetic instability can exist around a tumor.”

”…such a field of genetic change can exist in morphologically

normal tissue before a tumor develops…”

”…the field is of size greater than one terminal duct-lobular

unit.”

Clarke CL at el, BJC 2006 95, 515-9

”…we have shown that genetic alterations at the single cell
level may be clustered, and extend to an area that consists
of more than one TDLU. Such clustering suggests that a
change may have occured in a precursor cell, which gave rise
to that area of the breast. This results completments the findings
of Tot (2005) who observed that multiple foci of DCIS are
sometimes found within a single lobe of the breast and suggests
that an early genetic event may give rise to a ’sick lobe’.”

Clarke CL at el, BJC 2006 95, 515-9

 By mapping geographic zones of “normal”
breast tissue adjacent to primary breast
carcinoma on DNA methylation changes, a
field of these changes extending as far as 4cm
from primary tumors was demonstrated

Yan PS, Venkataramu C, Ibrahim A, Liu JC, Shen RZ, Diaz NM,
Centeno B, Weber F, Leu YW, Shapiro CL, Eng C, Yeatman TJ, Huang
TH. Mapping geographic zones of cancer risk with epigenetic biomarkers
in normal breast tissue. Clin Cancer Res 2006 12(22):6626-6636.
Patient ML36, blood DNA Whole genome CNV
profiles of three samples
derived from the same patient
(ML36), using Illumina 1M Duo
SNP beadchip. On the Y axis,
each sample is represented by
Patient ML36, uninvolved margin of normal breast tissue two windows of data analysis;
the upper is plotting the
normalized values of total
fluorescence signal from each
of approx. 1 million probes
present on the array, which is
proportional the copy number
level of analyzed loci; the lower
Patient ML36, primary breast tumor is depicting so called “B Allele
Frequency (BAF)” values,
which display the level allelic
balance/imbalance between
three possible genotypes of
each SNP of the array. The
X-axis describes chromosome
number and position of each
probe on each chromosome.
 Trichopoulos D. Hypothesis:
does breast cancer originate in utereo
”Breast cancer may originate in utero.” ?
Lancet 335:939-40, 1990
Women with high birth weight have a 1,23 elevated risk of
getting pre-menopausal breast cancer.

”…elevated levels of growth factors that may increase the

number of susceptible stem cells in the mammary gland and
initiate tumors trough DNA mutations.”

Michels KB, Xue Fei (Harvard University).

Role of birth weight in the etiology of breast cancer.
Interntional Journal of Cancer, 119(9): 2007-25, 2006
Birth weight was found to be positively associated
with mammographic breast density, which in turn
is one of the strongest known risk factors for
breast cancer and is also hormone – related

Cerhan JR, Sellers TA, Janney CA, Pankratz VS, Brandt KR, Vachon CM.
Prenatal and parinatal correlates of adult mammographic breast density.
Cancer Epidemiol Biomarkers Prev 2005;14(6):1502-1508.
• “…the genetic mutations or epigenetic abnormalities
involved in breast cancer development are more
likely to be perpetuated by cells undergoing
continuous branching and ramification while the
lobe is being formed, rather than originating within
the terminal ductal-lobular units, the majority of
which are not developed before birth.”
Xue F and Michels KB. Harvard Medical School, Boston USA
Breast cancer may originate in utero: The importance of the
intrauterine environment for breast cancer development.
In Tot T ed, Breast cancer, a lobar disease. Springer 2011, pp 37-52.
The pool of breast stem cells may be expanded
in utero leading to increased breast stem cell
burden, which in turn may increase the
sensitivity of the breast tissue to oncogenic
mutations and epigenetic changes.
 “…experimental and epidemiological evidence
supports the concept that the in utero
environment can influence an individual’s risk of
breast cancer in adult life.”

Savarese TM, Low HP, Baik I, Strohsnitter WC, Hsieh CC. Normal breast stem
cells, malignant breast stem cells and the perinatal origin of breast cancer.
Stem Cell Rev 2006; 2(2):103-110.
 The Sick Lobe

”PROBLEMS”
Difficulties in percieving breast cancer
as lobar disease
 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
 Randomized trials of breast cancer screening
Trial year age range Interval (m) no Fu (y) Attendance % RR mort.
HIP 1963 40-64 12 61000 18 67 0.78
Malmö 1976 43-70 18-24 60000 16 75 0.78
Two-county 1977 40-74 24,33 133000 20+ 89 0.68
Edinburgh 1978 45-64 24 44000 13 81 0.78
Stockholm 1981 40-64 28 60000 15 61 0.90
NBSS-1 1980 40-49 12 50000 13 100 0.97
NBSS-2 1980 50-59 12 40000 13 100 1.02
Gothenburg 1982 39-59 18 51000 14 86 0.79

Smith RA et al. The randomized trials of breast cancer screening:What have we learned?
Radiol Clin North Am 42:793-806, 2004
 Carcinomas by detection mode and tumor size, Falun 1996-2003

Screening Outside Interval Follow-up Refusers Sum

screening

In situ 18% (130) 8% (52) 8% (24) 14% (6) 0% (0) 12% (212)

1 – 9 mm 26% (193) 8% (51) 14% (42) 35% (15) 14% (2) 18% (303)

10 – 14 mm 23% (167) 11% (69) 18% (52) 33% (14) 14% (2) 18% (304)

15 – 19 mm 16% (123) 17% (106) 18% (55) 2% (1) 14% (2) 17% (287)

20-29 mm 11% (81) 26% (163) 26% (73) 8% (4) 42% (6) 19% (327)
30 + mm 6% (44) 23% (140) 16% (47) 6% (3) 14% (2) 14% (236)
Sum 740 620 297 43 14 1725
(2unknown) (41unknown) (2unknown) (11unknown)

45 unknown size, 11 unknown detection mode

 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
 Approach

• Detailed and systematic radiologic –

pathologic correlation
• Routine use of large-format histologic
sections
• Studying 3D images
• Systematic work-up
 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
 Difficulties in percieving breast cancer
as lobar disease

• Early breast cancer

• Non-fragmenting methods
• The complex lobar morphology of the breast
• The sick stroma
• Biological timing of malignant transformation
The theory of biological timing.

Tot T: The theory of the sick lobe and the possible consequences.
Int J Surg Pathol 15(4:) 369-75, 2007
 Darryl Shibata Heterogeneity and tumor history.
Science 336:304-5, 2012

• ”All cells are almost perfect copies of prior

cells.”
• ”Imperfect DNA replication creates
random variation, which is the substrate
for evolution.”
 Darryl Shibata Heterogeneity and tumor
history. Science 336:304-5, 2012
• Normally: 1 new mutation per human cell
division
• ”Accumulation of mutations over time can
eventually transform a single cell.”
 Darryl Shibata Heterogeneity and tumor
history. Science 336:304-5, 2012
• Public mutations are present in all cells of the
tumor and appear during the period from the
zygote to the first transformed cell.
• Semiprivate mutations are present in a
detectable fraction of the cancer cells (suclone)
• Private mutations are present in a single or few
cancer cells.
 Darryl Shibata Heterogeneity and tumor
history. Science 336:304-5, 2012
• The more advanced the tumor, the more
numerous different mutations are present.
• ”Tumorogenesis can be represented by an
ancestral tree that starts from the zygote
and ends with present-day cancer cells.”
 Darryl Shibata Heterogeneity and tumor
history. Science 336:304-5, 2012
• Molecular clock hypothesis
• Increasing heterogeneity
• Intratumoral heterogeneity is present
whereever one looks.
• Our hypothesis, the theory of biological
timing suggests that the time of malignant
transformation of the stem/progenitor cells
within the sick lobe is genetically
determined.
• This means that some stem cell become
sufficiently sensitive to oncogenic stimuli
after a certain determined, genetically
coded number of replications.
After Villadssen et al 2004
Cooper AP. On the Anatomy of the Breast. Longmans, London, 1840. Plate VI, fig.3
Cooper AP. On the Anatomy of the Breast. Longmans, London, 1840. Plate VI, fig.3
Cooper AP. On the Anatomy of the Breast. Longmans, London, 1840. Plate VI, fig.3
Patterns of distribution of CIS within the sick lobe

Peripheral Segmental Lobar

Timing pattern Disease extent Tumor burden

Peripheral

Segmental

Lobar
 Conclusion
• Breast cancer is a lobar
disease.
 The theory of the sick lobe and the theory of
biological timing are new concepts but have their
roots in previous observations and studies.
• As early as in 1855, Rudolf Virchow proposed an
embryonal rest hypothesis, stating that cancer
arises from the activation of “dominant” cells
that are reminders of embryonic tissue.
• Early morphological observations that breast
carcinoma may grow in a triangular area with its
tip in the nipple and base towards the pectoralis
muscle suggested the lobar nature of the disease
(Gibbs 1982).
• Microcalcifications detected on mammogram
may also be localised to a triangular area of
breast tissue (Lányi, 1972).
• Magnetic resonance imaging may show segmental
– lobar disease distribution in a considerable
number of cases (Barchie et al. 2011).
• The entire concept of ductal echography is based
on the hypothesis of lobar localisation of the
disease (Teboul and Halliwell 1995).
 The Sick Lobe

”Modified” versions of the theory

Smart CE, Simpson PT, Vargas AC, Lakhani SR. Brisbane, Australia
Genetic alterations in normal and malignant breast tissue.
In Tot T ed. Breast Cancer, a Lobar Disease. Springer, 2011
• ”Finally as in the classic Tibor Tot description,
the entire lobe is occasionally involved
because the initiation events occurred in
some of the first stem cells of the lobe early in
its development. Here either complete lobe
excision or whole breast treatment may be
required.”

William C Dooley, University of Oklahoma, OK, USA

• ”We view that breast cancer is a lobar
disease isolated to the section of the lobe
where the initiation events occurred and all
subsequent outgrowth from those stem cells.
With this change, breast cancer may be
isolated to a distal branch of the ducto-lobular
tree when initiation events occurred late in
lobar growth.”
William C Dooley, University of Oklahoma, OK, USA
• ”Some tumors develop from earlier initiation
events but still isolated to larger segmental
regions within the ducto-lobular tree. Here
excisions would need to either be wider or
have associated radiation to eliminate the
potential progression of genetically altered
proliferative cells.”

William C Dooley, University of Oklahoma, OK, USA

Redefining Lumpectomy Using a Modification of
the “Sick Lobe” Hypothesis and Ductal Anatomy

Dooley W, Bong J, Parker J.

Department of Surgery, The University of Oklahoma Breast Institute and
Division of Surgical Oncology, The University of Oklahoma Health
Sciences Center, Oklahoma, OK 73104, USA
International Journal of Breast Cancer 2011
Subgross Morphology, the Sick Lobe Hypothesis,
and the Success of Breast Conservation

Tibor Tot
International Journal of Breast Cancer
Volume 2011
• ”Three patterns of cancer development seem to
be the most typical at the early stage: the
peripheral pattern (involving the TDLUs), the
segmental pattern (involving a segmental duct
together with its branches and terminal units),
and the lobar pattern (involving the entire sick
lobe or large parts of it).”
The Sick Lobe

Practical consequences
William C Dooley, University of Oklahoma, OK, USA
 “Progenitor cell theory at the cellular level and
sick lobe theory at architectural level may help
provide a better understanding of ductal
carcinoma in situ from different perspective and
facilitate the development of individualized
therapy.”

Tang P, Hajdu SI, Lyman GH: Ductal carcinoma in situ: a review of

recent advances. Current Opinion in Obstetrics and Gynecology
2007, 19:63-67.
 Lobar DCIS with multiple invasive foci

• 39 - year - old women

• Felt a thickening in her left breast

From the Department of Pathology and Clinical Cytology

and Department of Mammography
Central Hospital Falun, Sweden Case 80
 A large breast lobe filled with
casting type microcalcifications
MRI: lobar enhancement
Reconstructed from 5 large sections
 ER PR

Ki67 HER2
 Lobar DCIS with multiple invasive foci

• Infiltrating ductal cancer of the breast with

extensive in situ component
• Multifocal (7 foci, 10x5, 9x8, 9x7, 6x6, 6x6,
6x5, 5x4 mm)
• Size 10 mm
• Extent 95 x 70 mm
• Grade 2
• ER+, PR+, Her2: 3+ ampl, Ki67: 15%, CK56-
• pN: 1mi/2
 Thinking in a lobe
• 62 - year - old
• Operated on with sectorresection
• for DCIS grade 2
• 6 years ago

Department of Pathology and

Clinical Cytology and Department of Mammography
Central Hospital Falun, Sweden Case 12
A very tiny group of microcalcifications deteced on mammography screening
Think in sick lobe
Yearly follow-up, 2011 microcalcifications were detected behind the nipple
Pounch biopsy of the nipple
• “The theory of the sick lobe and the theory of biological
timing connect the process of carcinogenesis to an
existing and well defined anatomic structure, a breast
lobe, and provide a possible explanation for the
progressive character and morphological heterogeneity
of breast carcinoma. These theories are more than a
description of morphological patterns. They put these
patterns into a unifying concept with genetic,
developmental, and morphological perspectives of
understanding breast carcinoma as a process that
develops over time under endogenous and exogenous
influences, not like a photo, but like a life-long movie.”