Invasive cribriform carcinoma of the breast (ICCB), also termed invasive cribriform carcinoma, is a rare type of breast cancer that accounts for 0.3% to 0.6% of all carcinomas (i.e. cancers that develop from
epithelial cells) in the breast.
It originates in a
lactiferous duct as opposed to the lobules that form the
alveoli Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit.
Uses in anatomy and zoology
* Pulmonary alveolus, an air sac in the lungs
** Alveolar cell or pneumocyte
** Alveolar duct
** Alveolar macrophage
* ...
in the breasts'
mammary glands (lobules make the milk which the ducts channel to the breast's nipple). ICCB was first described by Dixon and colleagues in 1983 as a tumor that on microscopic
histopathological inspection had a cribriform pattern,
i.e. a tissue pattern consisting of numerous "Swiss cheese"-like open spaces and/or sieve-like small holes (see adjacent Figure).
The latest edition (2019) of the World Health Organization (2019) termed these lesions invasive cribriform carcinomas indicating that by definition they must have a component that invades out of their ducts of origin into adjacent tissues. ''In situ'' ductal cancers (i.e. cancers localized entirely within their tissues of origin) that have a cribriform
histopathology
Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spe ...
are regarded as belonging to the group of
ductal carcinoma in situ tumors.
Rarely, cancers with the histopathological cribriform pattern develop in other organs such as the
prostate gland (termed invasive cribriform prostate cancer or cribriform prostate cancer),
salivary gland (termed cribriform
adenocarcinoma
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
of salivary glands),
sweat gland
Sweat glands, also known as sudoriferous or sudoriparous glands, , are small tubular structures of the skin that produce sweat. Sweat glands are a type of exocrine gland, which are glands that produce and secrete substances onto an epithelial sur ...
s (termed primary cutaneous cribriform apocrine carcinoma),
thyroid gland
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobe (anatomy), lobes. The lower two thirds of the lobes are connected by a thin band of Connective tissue, tissue cal ...
(termed cribriform-morular thyroid carcinoma),
colon (termed cribriform colon cancer),
and lung (termed cribriform pattern in lung adenocarcinoma and considered to be a rare variant of
acinar adenocrcinoma of the lung).
Here, the term invasive cribriform carcinoma of the breast rather than invasive cribriform carcinoma is used in order to clearly distinguish it from these other cribriform carcinomas.
ICCB, while clearly a cancerous tumor that occurs predominantly in older females and in rare cases
males, has many favorable clinical and pathological features including a low rate of metastasizing to distant tissues and an excellent prognosis.
Earlier editions of the World Health Organization divided ICCB into two forms, the "pure" form (sometimes termed "classical"), i.e. ICCB tumors that had >90% cribriform areas, and the "mixed" form, i.e. ICCB tumors that had >50% cribriform areas with the remaining areas having a tubular histological pattern.
However, many earlier
and more recent
studies have regarded mixed ICCB as consisting of >50% cribriform areas with the remaining areas containing tubular or certain other histopathological patterns. The latter definition of mixed ICCB is used here.
Presentation
Individuals presenting with ICCB in one large study were on average 61 years/old
post-menopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
females and similarly aged males (average age 65.4
) with the males representing 1.7% of all cases.
However, individuals as young as 14
and 18
years have been diagnosed with the disease. ICCB tumors are small (i.e. 58%-75.4% less than 2-5
centimeters and 22%-38% more than 2-5
centimeters in largest diameters), asymptomatic masses first detected by
palpation or screening methods such as
mammography
Mammography (also called mastography) is the process of using low-energy X-rays (usually around 30 kVp) to examine the human breast for diagnosis and screening. The goal of mammography is the early detection of breast cancer, typically through d ...
or
medical ultrasound. Screening methods often (i.e. 32% of cases) detect areas of
microcalcification (i.e. tiny deposits of calcium) in the masses. In a relatively small percentage of cases (e.g. 15.9 to 25.5% in most studies), the workup of these individuals finds that their tumor has
metastasized (i.e. spread) to the
lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
s in the nearby
axilla (i.e. armpit).
Very rarely, individuals have presented with: an ulcerated skin lesions or
inverted nipple,
with recurrences at or near to the site were a ICCB tumor had been surgically removed,
or with metastases to distant tissues such as the
vertebral bones.
Pathology
The microscopic
histopathology
Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία '' -logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spe ...
of ICCB tumors stained with
hematoxylin and eosin
Hematoxylin and eosin stain ( or haematoxylin and eosin stain or hematoxylin-eosin stain; often abbreviated as H&E stain or HE stain) is one of the principal tissue stains used in histology. It is the most widely used stain in medical diagnos ...
shows cribriform areas covering more than 50% of the tumor with the remaining tumor areas showing tubular and/or other histopathological patterns. The cribriform areas consist of small-sized cells with amphophilic (i.e. taking up both the hematoxylin and eosin stains) cytoplasm, indistinct cell boundaries, and small-to-medium sized
nuclei that are surrounded by a sharp
nuclear membrane and contain finely stippled
chromatin (i.e.
DNA coated with protein).
Numerous open spaces and/or sieve-like small holes lie between these cells (see above photomicrograph) to give the lesions a Swiss cheese-like appearance. The spaces and holes may contain
microcalcifications and/or
mucins (i.e. high
molecular weight, sugar-linked proteins normally produced and secreted by the
mammary gland and found in milk).
The cells around these spaces and holes sometimes have "apical snouts", i.e. small protrusions on the side of the cells that faces the spaces and holes.
Tubular areas (see adjacent photomicrograph of a tubular carcinoma) consist of well-formed
tubules lined with mostly normal appearing tubular cells.
The other histopathological patterns that may occur in these tumor types include the pattern associated with
invasive carcinoma of no special type
Invasive carcinoma of no special type (NST) also known as invasive ductal carcinoma or ductal NOS and previously known as invasive ductal carcinoma, not otherwise specified (NOS) is a group of breast cancers that do not have the "specific different ...
or in uncommon cases the pattern associated with
mucinous carcinoma of the breast.
The invasive component of these tumors almost always has the cribriform histopathology pattern.
All of the tumor cells in ICCB are typically slow-growing as evidenced by their low
mitotic index Mitotic index is defined as the ratio between the number of a population's cells undergoing mitosis to its total number of cells.
Purpose
The mitotic index is a measure of cellular proliferation.
It is defined as the percentage of cells underg ...
(i.e. the ratio of the number of
dividing cells to the total number of tumor cells) or low levels of cellular
Ki-67 protein (an index of cell proliferation).
A Seer study of 750 individuals with pure or mixed ICCB reported that: a) 92.8% consisted of tumor cells that were scored well-differentiated (i.e. grade 1) or moderately well-differentiated (grade 2) (differentiation is the degree to which tumor cells resemble the non-cancerous cells in the tissue from which they derived) while 7.2% were scored poorly-differentiated (grade 3) or undifferentiated (grade 4) tumor cells; b) 76.1, 20.0, 2.6, and 1.3% of the cases had T1, T2, T3, and T4 tumors, respectively (increasing T numbers indicate increasing tumor size and/or invasion into adjacent tissues); c) 83.2, 13,6, 2.4. and 0.8% of all cases had tumors which metastasized respectively to 0 (i.e. no metastasis), 1, 2, or 3 nearby armpit lymph nodes; and d) 1.3% of all cases had metastasizes in distant tissues (the tissue sites were not identified).
In a study of 42 individuals, 16 (38.1%) had pure and 26 (61.9%) had mixed ICCB; there were no significant differences in age of presentation, tumor size, or tumor grade between pure and mixed ICCB; pure ICCB had 5 (31.5%) and mixed ICCB had 16 (61.5%) cases that were associated with lymph node metastases; and there were no cases that had distant tissue metastases.
Immunohistochemistry
Microscopic inspection of
immunostained (i.e. a method that uses specially prepared
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
which attach to specific proteins so that they can be detected and quantified) ICCB tumor cells has shown that they express
estrogen receptors in about 95.4% of cases,
progesterone receptor
The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.
In humans, PR is encoded by a single ''PGR'' gene resid ...
s in about 89.5% of cases, and the
HER2/neu protein in about 3% of cases.
The estrogen and progesterone receptors and HER2/neu protein, when expressed by breast cancer tumor cells, are
therapeutic targets for treating various forms of breast cancer including ICCB.
ICCB tumors also typically have cells that express
cytokeratin proteins but not
myoepithelial
Myoepithelial cells (sometimes referred to as myoepithelium) are cells usually found in glandular epithelium as a thin layer above the basement membrane but generally beneath the luminal cells. These may be positive for alpha smooth muscle actin a ...
marker proteins such as
tumor protein 63,
smooth muscle actin
Smooth may refer to:
Mathematics
* Smooth function, a function that is infinitely differentiable; used in calculus and topology
* Smooth manifold, a differentiable manifold for which all the transition maps are smooth functions
* Smooth algebrai ...
,
calponin, or
CD10
Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...
.
Diagnosis
The diagnosis of ICCB tumors is based on the histopathology and immunohistochemistry of their hematoxylin and eosin-stained tissues,
particularly on identifying their predominantly cribriform structure and invasion into adjacent tissues.
Immunostaining to define the expression pattern of the elements outlined in the above Immunohistochemistry section have also been used to support the diagnoses in less clear cases.
Adenoid cystic carcinoma and certain
neuroendocrine tumors have been mistaken for ICCB tumors. Adenoid cystic carcinomas are distinguished form ICCB by having open spaces that are
PAS diastase stain
Periodic acid–Schiff–diastase (PAS-D, PAS diastase) stain is a periodic acid–Schiff (PAS) stain used in combination with diastase, an enzyme that breaks down glycogen. PAS-D is a stain often used by pathologists as an ancillary study in ma ...
-positive and by the presence of tumor cells which express cKit but not estrogen and progesterone receptors; ICCB tumor open spaces are PAS diastase stain-negative and their tumor cells do not express cKit but do express estrogen and progesterone receptors.
Neuroendocrine tumors with an invasive component (many of these tumors are non-invasive) are differentiated from ICCB tumors by their content of spindle-shaped cells, cells that resemble
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s, and large clear cells; these type of cells are typically not found in ICCB tumors.
Treatment
Due to their relative rarity, standard treatment guidelines have not been formally identified or defined for ICCB tumors. Consequently, current treatments for these tumors are based on protocols used to treat invasive carcinoma of no special type.
(These treatments have not been strictly examined individually or compared between each other for their effectiveness in treating ICCB.
IBBC tumors do have the potential to metastasize to distant tissues if left untreated for a very long time period.
) Virtually all patients (97.2% of the 760 cases) in the SEER review study were treated by surgical removal of their tumors.
This surgery has typically been either
breast-conserving surgery or
modified radical mastectomies.
Patients with ICCB may also receive
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesic ...
radiotherapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
and/or
chemotherapy.
In the Seer study, 52.2% were treated with radiotherapy and 22.1% with chemotherapy.
The chemotherapy regimens used to treat ICCB have included triple therapy with
cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
,
epirubicin and
fluorouracil, double therapy with
docetaxel and
epirubicin,
and triple therapy with cyclophosphamide,
doxorubicin and fluorouracil.
In more recent studies, virtually all individuals have been treated with adjuvant
hormonal therapy drugs,
such as
letrozole or
anastrozole (which block the metabolism of
androgen to estrogens by the
aromatase enzyme in non-
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...
tissues and thereby reduce estrogen levels) or with
tamoxifen (which acts indirectly to inhibit the estrogen receptor).
Individuals with mixed ICCB have been treated with the more aggressive of these protocols than individuals with pure ICCB in some
but not all
studies. It has been suggested that pure ICCB tumors might be better treated with the more conservative strategies listed here.
Prognosis
In the Seer study of 750 individuals with ICCB (pure and mixed types not distinguished), the
overall survival rates (i.e. includes deaths due to ICCB and any other cause) at 3 and 5 years after initial treatment were 94.4% and 90.3%, respectively. Larger tumor size, presence of distant tissue metastases, higher tumor stages, older age (>67 years old), single or divorced marital status, and lack of progesterone receptors in tumor cells were associated with poorer prognoses while the presence of lymph node metastases did not significantly alter prognosis.
A more recent study of 42 patients with ICCB followed for an average of 88 months (range 15–106 months) reported that the median overall survival 5 years after treatment was 100% for both pure and mixed ICCB and the projected 10 year overall survival rate was 100% for pure and 90% for mixed ICCB.
Several other studies on small numbers of patients reported that pure and mixed ICCB individuals have 10 year overall survival rates of over 90%.
Recurrent ICCB has been successfully treated with surgical removal of the tumor plus chemotherapy
and ICCB with metastases to distant tissues has been successfully treated with surgical removal of the breast tumor, chemotherapy, radiotherapy, and long-term treatment with tamoxifen followed by letrozole.
References
{{Reflist
Breast cancer
Carcinoma
Rare cancers