13.

Which of the following chromosomal and/or genetic abnormalities

is/are associated with the development of breast cancer?

a. Mutations in the p53 tumor suppressor gene

b. A mutation in the short arm of chromosome 2
c. The presence of a BRCA 1 gene on chromosome 17
d. The presence of the BRCA 2 gene on chromosome 13
Answer: a, b, c, d

There are four inherited syndromes associated with the development of

breast cancer. The Li-Fraumeni syndrome has an autosomal dominant
mode of inheritance. The syndrome is attributed to mutations in the p53
tumor suppressor gene, a gene that codes for a protein that serves as a
G1-S checkpoint regulator of the cell cycle. More recently, a mutation has
been characterized on the short arm of chromosome 2 in a gene
associated with DNA repair. Predisposition to a wide range of
malignancies, including breast and colon cancer is associated with
abnormalities at this locus. The most exciting development in inherited
susceptibility to breast cancer relate to the identification and cloning of
the BRCA 1 gene, which was initially localized on the long arm of
chromosome 17 by linkage analysis. Germline abnormalities in BRCA a
may be responsible for as many as 5% of all breast cancers in the United
States. The gene is characterized by autosomal dominant inheritance with
a high degree of penetrance. Almost 60% of women inheriting the gene
will develop breast cancer by age 50, and a lifelong risk approaches 85%.
Another breast cancer susceptibility gene, dubbed BRCA 2, has been
localized by linkage analysis to a small region of chromosome 13q12-13.
BRCA 2 apparently confers the high-risk of early onset female breast
cancer. Similar to BRCA 1, the lifetime breast cancer risk approaches
90% in carriers of this gene.

14. A 45-year-old woman presents with a weeping eczematoid lesion of

her nipple. Which of the following statement(s) is/are true concerning her
diagnosis and management?

a. Treatment is with warm compresses and oral antibiotics

b. Biopsy of the nipple revealing malignant cells within the milk
ducts is invariably associated with an underlying invasive carcinoma
c. The appropriate treatment is mastectomy
d. The lesion always represents a high-risk disease with a significant
risk of subsequent metastatic disease
Answer: c
Pagets disease is characterized by weeping, eczematoid lesion of the
nipple. There is often accompanying edema and inflammation. Biopsy of
the nipple reveals malignant cells within the milk ducts. The lesion is
invariably associated with an underlying invasive or in situ ductal
carcinoma. The prognosis of Pagets disease is that of the underlying
cancer. Standard treatment is mastectomy with axillary lymph node
dissection only if invasive cancer is present.

15. Which of the following treatment(s) is/are of proven benefit in the

treatment of mastodynia associated with fibrocystic breast disease?

a. Avoidance of methylxanthine compounds, particularly caffeine

b. Cessation of smoking
c. Vitamin E
d. Danazol
Answer: a, b, d

The relationship of methylxanthines, particularly caffeine, to mastodynia

and breast nodularity remains controversial. Most women do, however,
experience diminution of their symptoms and are subject to improvement
in breast nodularity by limiting or eliminating caffeine intake.
Mastodynia patients should be advised to eliminate caffeine beverages for
a period of 2 to 3 months to determine if there has been improvement in
their symptoms. In addition to caffeine abstention, patients should be
urged to stop smoking because nicotine is purported to worsen
mastodynia. A number of medications have been advocated for the
treatment of mastodynia. Unfortunately, because of the subjective nature
of the disease and its propensity to be better tolerated by patients with
reassurance, the exact method of most of these interventions is unclear.
Vitamin E has been touted as beneficial, however, clinical data do not
support the use of this or other vitamins for this condition. The use of
hormonal agents to treat mastodynia has been more extensively treated.
Danazol, a weak antigen, is the most effective drug available for
treatment of mastodynia related to fibrocystic disease. Unfortunately,
Danazols androgenic side effects are troublesome enough to restrict its
use to the most problematic cases of mastodynia. Other hormonal agents
have been investigated for the management of mastodynia. In young
women, oral contraceptives have a variable effect on mastodynia. A trial
and error search for optimal preparations may be necessary as the effect
of oral contraceptives is dependent on the formulation of the pill.
16. Which of the following statement(s) is/are true concerning breast
reconstruction?

a. The timing of breast reconstruction is of no oncologic significance

b. Breast reconstruction may interfere with detection of local
recurrence of breast cancer
c. Maintenance of an effective subpectoral pocket for a breast implant
requires preservation of the pectoralis fascia
d. Because of its complexity, the TRAM flap is seldom used for
primary breast reconstruction
Answer: a, c

Breast reconstruction is suitable for any woman who has undergone

mastectomy who desires reconstruction. Breast reconstruction may be
performed at the time of mastectomy (immediate) or sometime
subsequently (delayed) Because the presence of reconstruction may
interfere with the accurate planning and administration of radiation
therapy, reconstruction is generally delayed if the use of local or regional
radiation therapy is anticipated. Otherwise, timing of breast
reconstruction is of no oncologic significance. Because most local
recurrences occur in the skins subcutaneous tissues, the presence of a
reconstruction will not interfere with detection. Similarly, a
reconstruction does not complicate the administration of chemotherapy.
Breast reconstruction techniques utilize either autogenous tissue or
synthetic prostheses to recreate a breast mound. Prosthetic reconstruction
is usually accomplished by sub-pectoral placement of a saline-or silicone
gel-filled implant. Maintenance of an effective sub-pectoral pocket for an
implant requires preservation of the pectoralis fascia and the medial
pectoral nerve during mastectomy. The transferase rectus abdominous
myocutaneous (TRAM) flap is the autogenous reconstruction of choice.
The TRAM operation is complex and time consuming. Despite the
magnitude of the procedure, it is still commonly used for immediate
reconstruction.

17. Which of the following statement(s) is/are true concerning the

histologic variants of invasive breast carcinoma?

a. The presence of an in situ component with invasive ductal

carcinoma adversely affects prognosis
b. Medullary carcinomas, although often of large size, are associated
with a better overall prognosis than common invasive ductal cancers
 c. Mucinous or colloid carcinoma is one of the more common
variants of invasive ductal cancer
d. Invasive lobular carcinoma is associated with a higher incidence of
bilateral breast cancer
Answer: b, d

Although the breast is composed of both lobular and ductal elements,

most breast cancer arises in the ductal elements. Invasive ductal
carcinoma accounts for 70% to 80% of all cases of breast cancer.
Although there is no single microscopic feature specific for infiltrating
ductal carcinoma, it can be recognized histologically as an invasive
adenocarcinoma involving ductal elements. The malignant ductal cells
are often dispersed within the fibrous stroma, leading to the appellation of
scirrhous carcinoma. A number of less common types of breast cancer
arise from the ductal epithelium and are hence classified as variants of
invasive ductal carcinoma. There are distinct histologic criteria for
classifying these lesions; these criteria must be met throughout the entire
tumor. Prognostically, histologically pure examples of these variant
tumors are associated with a better long-term survival than ordinary type
invasive ductal carcinoma. When mixed histologies are encountered, the
clinical behavior parallels that of the invasive ductal element, not the
other sub-type. Hence, these mixed tumors are considered together with
pure invasive ductal carcinoma for prognostic purposes. In many cases,
when areas of in situ ductal carcinoma are seen, the presence of an in situ
component does not adversely affect prognosis, although it jeopardizes
the attempts at breast conservation. Medullary carcinoma is one of the
more common variants, accounting for approximately 6% of all invasive
breast cancers. These tumors may grow to be a rather large size within the
breast (5 to 10 cm) and are characteristically well-circumscribed.
Mucinous carcinoma, also referred as colloid carcinoma, is encountered
in 1% to 2% of breast cancer cases. Invasive lobular carcinoma arises
from the lobular component of the breast and in most series accounts for
approximately 10% of breast cancers. Almost every series has stressed
the higher incidence of bilateral cancer in patients with invasive lobular
carcinoma. The contralateral breast is involved either synchronously (3%
of patients) or metachronously in up to 30% of patients.

18. Which of the following statement(s) is/are correct concerning

cystosarcoma phyllodes?

a. The tumor is most commonly seen in post-menopausal women

b. Total mastectomy is necessary for all patients with this diagnosis
 c. Axillary lymph node dissection is not necessary for malignant
cystosarcoma phyllodes
d. Most patients with the malignant variant of cystosarcoma
phyllodes die of metastatic disease
Answer: c

Cystosarcoma phyllodes is a tumor arising in the mesenchymal tissue of

the breast. The tumors usually present as a painless breast mass.
Phyllodes tumor is most commonly encountered in women age 3040
years of age but can occur at any age, even before puberty. The
differentiation of a benign from a malignant phyllodes tumor may be
difficult. About one-fourth of all phyllodes tumors are histologically
malignant, but only a fraction of these patients actually develop
metastatic disease. The optimum treatment for benign or malignant
phyllodes tumor is wide excision with a margin of normal breast tissue.
The margin must be histologically free of involvement because even
benign lesions can recur after incomplete excision. If this can be done
leaving an adequate cosmetic appearance, mastectomy is not necessary.
Total mastectomy is reserved for large lesions in small-breasted women
or recurrences after previous local excision that is not amenable to repeat
local excision. Axillary lymph node dissection is not performed in the
absence of biopsy-proven nodal involvement, even for malignant
phyllodes tumors, because axillary metastases are uncommon.

19. Which of the following statement(s) is/are true concerning local

recurrence of breast cancer?

a. The percentage of patients with chest wall recurrence as their

initial site of failure following mastectomy is similar for node-negative
and node-positive patients
b. Most patients with local-regional recurrence of their disease will
eventually die of metastatic disease
c. The treatment of local recurrence following mastectomy includes
local radiation therapy and systemic chemotherapy
d. In-breast recurrence following breast conserving surgery is not a
negative prognostic factor
e. Regional lymph node recurrence following axillary node dissection
is rare
Answer: a, b, c, e

Recurrence in the chest wall after mastectomy is ominous. In a large

series of patients treated with mastectomy, 6.5% of node-negative and
8.8% of node-positive women had chest wall recurrence as their initial
site of failure. By ten years after local-regional recurrence, about 60% of
initially node-negative and almost all (> 90%) of initially node-positive
patients had evidence of metastatic disease. Patients with local
recurrence, who have not had prior chest wall radiation, should receive
radiation therapy. A full course of at least 4500 to 5000 cGy should be
delivered to the entire chest wall, with consideration given to a boost dose
at any sites of gross tumor. Because post-mastectomy recurrence is often
rapidly followed by metastatic disease, it is logical to postulate a role for
adjuvant systemic therapy once local measures have achieved control of
chest wall disease.
Recent data suggests that in-breast recurrence following breast
conservation is a prognostic factor. Women who develop an in-breast
recurrence have a higher likelihood of developing systemic disease than
do women who remain disease-free in their breast. Fewer than 3% of
patients develop recurrence of disease in the axilla after axillary node
dissection.

20. Which of the following statement(s) is/are correct concerning

prognostic factors for breast carcinoma?

a. Prognosis is improved with estrogen or progesterone receptor

positivity
b. Increased thymidine labeling index, a measure of the proportion of
cells in the DNA synthetic phase (S-phase), is associated with improved
survival
c. High tumor levels of cathepsin D are associated with an improved
prognosis
d. Immunohistochemical demonstration of active angiogenesis
correlates with increased metastatic potential and poor prognosis
Answer: a, d

21. Which of the following statement(s) is/are true concerning adjuvant

systemic therapy?

a. Adjuvant tamoxifen in post-menopausal, node-positive, ER-

positive women is equivalent to cytotoxic chemotherapy
b. Tamoxifen clearly improves survival in all hormonal receptor-
positive patients
c. CMF is associated with improved overall survival in both pre-
menopausal and post-menopausal node-positive patients
 d. There is no evidence to suggest a role for chemotherapy in node-
negative patients
Answer: a

Adjuvant tamoxifen leads to a prolonged disease-free interval in post-

menopausal ER-positive women with histologically positive nodes and in
pre-menopausal and post-menopausal ER-positive women with negative
nodes. Because of similar results and, because tamoxifen is generally less
toxic than chemotherapy, this treatment is the treatment of choice for
post-menopausal, node-positive, ER-positive women. CMF
(cyclophosphamide, methotrexate, and 5-fluorouracil) is associated with
both a longer disease-free survival and overall survival time in pre-
menopausal patients with positive lymph nodes. In post-menopausal
women with positive nodes, there is an improved disease-free survival,
but there is no significant difference in overall survival. Several trials of
adjuvant chemotherapy with CMF or related regimens have been
conducted in node-negative patients. The early results of all of these trials
have been similar: disease-free survival is definitely improved with
adjuvant chemotherapy. These studies are definitely not mature enough to
draw definitive conclusions regarding overall survival. Therefore, the
National Cancer Institute has recommended the use of adjuvant
chemotherapy for all patients with tumors large enough to have hormonal
receptor levels measured.

22. Which of the following statement(s) is/are true concerning tissue

sampling techniques for breast masses?

a. The sensitivity of fine needle aspiration biopsy is such that

mastectomy can be performed in the case of malignant diagnosis
b. The accuracy of mammographic-directed fine needle aspiration
biopsy is comparable to that achieved for that of palpable lesions
c. Core-needle biopsy showing normal breast tissue is an acceptable
diagnosis
d. The technique of core-needle biopsy is not applicable to
radiographically detected lesions
Answer: b

Whatever tissue sampling method is chosen, only biopsy (examination of

cells or tissue) and not physical examination or mammography can
establish a definitive diagnosis and avoid delay in treatment. Fine needle
aspiration biopsy (FNAB) permits rapid, minimally invasive diagnosis of
many palpable and some non-palpable, radiologically detected breast
masses. The technique is both reliable and accurate. The incidence of
false-positive findings is generally less than 0.5%. FNAB is not, however,
so highly specific that definitive surgery (particularly mastectomy) should
be performed without prior intraoperative frozen-section confirmation of
the presence of cancer. Reported sensitivity of FNAB ranges from 7% to
99%; with 85% a good estimate of the true sensitivity in clinically
relevant settings. Recently, x-ray-guided FNAB has been used to offer
minimally invasive diagnosis in nonpalpable breast lesions detected
mammographically. The technique is quite effective, especially for mass
lesions. Accuracy is comparable to that achieved with FNAB of palpable
lesions. Core-needle biopsy is a helpful tissue sampling method for
palpable masses. The tissue obtained is useful for histologic analysis
although inadequate for cytosol hormone receptor determination. The
technique is also applicable by using mammographic guidance for
nonpalpable lesions.

23. A 42-year-old woman undergoes her first mammogram. Clustered

microcalcifications are seen but there is no mass palpable. Which of the
following statement(s) is/are true concerning this patients diagnosis and
management?

a. A needle localization and excision of the mass is necessary to

establish the diagnosis
b. Frozen-section examination is particularly useful in the diagnosis
of this lesion
c. Intense interlobular fibrosis and proliferation of small ductules
with loss of orientation of lobules and epithelial cells may suggest
carcinoma
d. This finding is associated with an increased risk of cancer
Answer: a, c

Sclerosing adenosis is a histologic subtype of fibrocystic change that is

not associated with an increased risk of cancer development. It is,
however, one of the benign breast processes most likely to be confused
radiologically and histologically with cancer. Most commonly, it is
detected on routine mammography as cluster microcalcifications without
an associated palpable mass. In these cases, needle localization and
excision are required to establish a diagnosis. Sclerosing adenosis
microscopically is characterized by interlobular fibrosis and proliferation
of small ductules. If the fibrous component is particularly intense, the
orientation of lobules and epithelial cells may be lost, mimicking
carcinoma. Differentiating sclerosing adenosis from cancer on frozen-
section examination can be particularly difficult and should not be
attempted.

24. Which of the following conclusion(s) can be drawn from the results
of the NSABP prospective randomized trials completed in the 1970s and
1980s?

a. Delay of axillary node dissection until there is clinical evidence of

disease does not influence overall survival
b. Removal of clinically negative nodes has no therapeutic benefit
c. Breast irradiation reduces both local recurrence and overall
survival
d. Modified radical mastectomy offers no advantage of lumpectomy
with axillary node dissection
Answer: a, b, d

The scientific basis of local-regional treatment strategies for stage I and

stage II breast cancer was established by a series of studies conducted
during the 1970s and 1980s by the NSABP. In the first of these
protocols, total mastectomy with delayed node dissection only for nodes
that subsequently turned positive, total mastectomy with local-regional
radiation therapy, and radical mastectomy were clinically equivalent.
Furthermore, the finding that delay of axillary node dissection until there
is clinical evidence of disease does not influence survival emphasizes that
the role of axillary dissection in clinically node negative patients is solely
for staging. The removal of clinically negative nodes has no therapeutic
benefit if regional recurrences are detected and treated promptly. In the
second of these protocols, modified radical mastectomy, lumpectomy
with axillary node dissection, and lumpectomy, axillary node dissection,
and breast or irradiation were compared in small breast cancers. Modified
radical mastectomy offered no advantage over other treatments when
analyzed by disease-free or overall survival in either node-negative or
node-positive patients. Breast irradiation after lumpectomy reduced the
likelihood of in-breast tumor recurrence from 39% to 10% but did not
affect overall survival when compared with lumpectomy alone.

25. Which of the following statement(s) is/are true concerning non-

invasive breast carcinoma?
 a. Ductal carcinoma in situ (DCIS) is associated with a significant
risk of development of invasive ductal carcinoma in the same quadrant
of the same breast as the initial lesion
b. DCIS should not be treated with breast conservation therapy
c. Lobular carcinoma in situ (LCIS) is the most common form of non-
invasive breast cancer
d. When LCIS is found, there is an up to 50% chance of lobular
carcinoma in situ of the contralateral breast
e. About one-third of patients with biopsy-proven LCIS develop
invasive cancer, always of the same breast
Answer: a, d

Non-invasive (in situ) cancer is defined as a neoplastic entity within the

epithelium of origin and without invasion to the basement membrane.
Ductal carcinoma in situ (DCIS) arises from the ductular elements. The
age distribution of DCIS does not differ significantly from that of
invasive ductal carcinoma. Not every woman who undergoes complete
excision of a focus DCIS develops invasive ductal cancer. Various studies
suggest half or more patients develop invasive breast cancer after
excisional biopsy alone. When a subsequent invasive cancer does occur, it
is almost always of the invasive ductal type and located in the same
quadrant of the breast as the initial DCIS. The latent period before the
development of invasive cancer usually exceeds five years. Total
mastectomy is usually associated with a nearly 100% cure rate for this
condition. Although total mastectomy remains the gold-standard for
treatment of DCIS, there is increasing experience with breast-conserving
therapy. Breast conservation may be offered to DCIS patients in whom
the entire tumor can be surgically removed with negative histologic
margins and in whom the remaining breast tissue can be reliably assessed
clinically and radiographically. It would appear that the disease-free
survival following lumpectomy and radiation therapy is worse than that
achievable with simple mastectomy. Therefore, breast conservation for
DCIS commits patients to more careful long-term follow-up and will
likely subject them to additional subsequent treatment to deal with the
recurrences. Lobular carcinoma in situ (LCIS) accounts for one-third of
the non-invasive breast cancers. LCIS patients are significantly younger
than patients with invasive breast cancer. Three-fourths of affected
women are pre-menopausal. LCIS is an infrequent finding in women over
75. When the opposite breast is sampled at the time of diagnosis,
contralateral LCIS is found in 3050% of cases. The prognosis of LCIS is
solely related to the subsequent development of invasive carcinoma.
About one-third of patients with biopsy-demonstrated LCIS develop
invasive cancer; half occur in the index breast and half in the contralateral
breast. The subsequent breast cancers can be either lobular or ductal in
histology.

26. A 33-year-old woman is referred with nipple discharge. Which of the

following statement(s) is/are true concerning her diagnosis and
management?

a. Bilateral galactorrhea is suggestive of an underlying

endocrinopathy
b. Brownish discharge is usually suggestive of old blood and is
worrisome for an underlying breast cancer
c. Expressible bloody nipple discharge should be evaluated with a
ductogram
d. Milky breast discharge would not be expected one year after
discontinuation of breast feeding
Answer: a, c

At one time or another, many women notice a nipple discharge. The most
common physiologic basis for nipple discharge is lactation. Milk may
continue to be secreted intermittently for as long as two years after breast
feeding has stopped, particularly with breast stimulation. A milky whitish
discharge, usually bilateral, that is not related to lactation or breast
stimulation is termed galactorrhea. The presence of bilateral
galactorrhea should prompt an evaluation for underlying endocrinopathy
causing increased prolactin secretion by the pituitary. Classically, this is
associated with amenorrhea, but galactorrhea may be the only sign of
hypoprolactinemia. Nipple discharges associated with fibrocystic disease
are generally, green, yellow, or brown, Intraductal papillomas and cancer
lead to a bloody or blood-tinged serous discharge. The brownish
discharge of fibrocystic disease can easily be confused with old blood. A
guaiac test or simply dabbing the discharge with a gauze pad and
examining the stain can usually differentiate the two. A bloody or blood-
tinged discharge must be promptly evaluated to exclude carcinoma. If the
discharge is expressible at the time the patient is seen, a contrast
ductogram may be obtained.

27. Clinical features of breast cancer which are associated with a

particularly poor prognosis include:

a. Edema of the skin of the breast

b. Skin ulceration
 c. Lateral arm edema
d. Dermal lymphatic invasion
Answer: a, b, c, d

The histologic hallmark of inflammatory breast cancer is dermal

lymphatic invasion demonstrable on skin biopsy. The stigmata of this
clinical syndrome include breast warmth, tenderness, erythema, and
edema.

28. Which of the following statement(s) is/are associated with

gynecomastia?

a. If the disease is unilateral, it is unlikely drug-related

b. The standard surgical treatment is subcutaneous mastectomy
c. The presence of gynecomastia is often associated with the
subsequent development of breast cancer
d. A formal endocrine evaluation is indicated in most patients with
gynecomastia
Answer: b

Gynecomastia is defined as palpable enlargement of the male breast.

Pathologic causes of estrogen excess or testosterone deficiency are
associated with gynecomastia. In many cases, no cause is found.
Clinically significant gynecomastia has been associated with the use of a
number or drugs including cimetidine, digoxin, spironolactone and
tricyclic antidepressants. The use of marijuana has also been associated
with gynecomastia. Drug-related gynecomastia is often unilateral or
unequal between the two breasts, and discontinuation of the offending
drug does not always lead to resolution of the condition. A formal
endocrine evaluation is not indicated for gynecomastia unless some other
sign of hormonal imbalance is found on routine evaluation. The standard
surgical treatment of gynecomastia consists of subcutaneous mastectomy
performed under local anesthesia. The presence of gynecomastia is not
associated with the subsequent development of cancer, yet protracted
hyperestrogenemic states, which are associated with gynecomastia are
linked to breast cancer development.