The AJCC (www.cancerstaging.org) published the eighth edition of the AJCC / TNM cancer staging system:
Which replaced the seventh edition that had been used by clinicians, cancer registries, and researchers since 2009
On January 1st, 2018:
Tumor registries officially began using the eighth edition for tumor staging
Whereas the staging tables for medullary thyroid cancer and anaplastic thyroid cancer:
Showed only minimal changes:
The rules for the staging of well-differentiated thyroid cancer underwent substantial modifications
These included the following:
An increase of the age cutoff from 45 years to 55 years of age at diagnosis
Removal of microscopic extrathyroidal extension as a key component of the staging system
No longer mandating assignment of stage III to older patients with microscopic extrathyroidal extension or lymph node metastases
Establishment of a new T3b category for tumors of any size that demonstrate gross extrathyroidal extension involving only the surrounding strap muscles
The AJCC Differentiated Thyroid Cancer Committee carefully considered the possibility of inclusion of molecular markers (specifically, BRAFV600E and TERTpromoter mutations) in the AJCC prognostic staging definitions:
Whereas both of these mutations, particularly when present together, have been shown to be predictors of poor clinical outcomes:
They appeared to add only marginal benefit to the traditional anatomic staging factors:
Thus, molecular characterization of differentiated thyroid cancers, although providing some prognostic information, were not powerful enough factors to merit upstaging tumors to prognostic stages above those mandated by TNM risk factors
Nonetheless, similar to the approach used in the ATA risk-stratification system, molecular results can be used to refine further and individualize risk within risk categories or stages
The three critical factors that determine the prognostic stage groups of the eighth edition AJCC / TNM cancer staging system include the:
Age at diagnosis
The presence or absence of distant metastases
The presence or absence of gross extrathyroidal extension
Rather than the use of the standard TNM staging tables provided in the AJCC / TNM manual:
Tuttle el al find it easier to use the flow diagram in Figure 1 to stage patients rapidly based on the key clinical risk factors:
Age at diagnosis
Distant metastasis
Gross extrathyroidal extension
Lymph node metastases
In patients age < 55 years:
This figure rapidly classifies patients as either:
Stage I (any T, any N, M0)
Stage II (any T, any N, M1)
In patients age > 55 years:
In the older patients, additional factors, such as the presence or absence of distant metastasis, invasion of strap muscles, and extent of gross extrathyroidal extension, are also used to define the prognostic stage groups
In the eighth edition of the AJCC / TNM cancer staging system:
It was anticipated that the majority of patients would be classified as stage I or stage II:
Reflecting the excellent outcomes expected in the majority of thyroid cancer patients
A smaller number of patients, particularly the older patients with either distant metastases or gross extrathyroidal extension:
Were anticipated to do worse and are therefore classified as stage III or IV
Multiple publications have demonstrated that the eighth edition of the AJCC / TNM cancer staging system:
Moved a substantial number of patients into lower prognostic stage groups without affecting the overall survival of those lower-stage groups
The patients who remained in the higher-stage groups had poorer prognoses, as expected
This resulted in a much better separation of the four prognostic stage groups with respect to survival:
Such that 5- to 10-year disease-specific survival (DSS) was:
99% in stage I patients
88% to 97% in stage II patients
72% to 85% in stage III patients
67% to 72% in stage IV patients
Unlike previous editions of the AJCC / TNM staging system in which there was substantial overlap in survival in patients with stage I, II, and III disease:
The eighth edition provides meaningful separation among the prognostic stage groups that appear to be clinically relevant
The differences in predicted and published ∼10-year survival rates are best seen when analyzed based on age group (age <55 years vs age ≥55 years):
The predicted 10-year DSS has been validated for all age and stage groups, with only the younger (age < 55 years) stage II patients appearing to do more poorly than anticipated
The lower-than-anticipated 10-year DSS in the younger patients (age < 55 years) with stage II disease was the result of the stage migration of patients in the 45- to 55-year age group from seventh edition AJCC stage IV to eighth edition AJCC stage II
Figure 1: A simplified approach to AJCC staging in differentiated thyroid cancer, emphasizing the critical decision nodes, which include age at diagnosis, distant metastasis, and gross extrathyroidal extensions.
Immediately upon identification of a suspicious thyroid nodule
In the absence of a validated peri-diagnostic risk-stratification system, I use a clinical framework that incorporates:
Tumor imaging characteristics, medical team characteristics, and patient preferences to risk stratify patients as:
Ideal
Appropriate
Inappropriate for minimalistic initial management options:
Such as active surveillance or thyroid lobectomy
This clinical framework address the key factors that differentiate actionable from non-actionable disease
Peri-diagnostic risk stratification considers medical team characteristics, imaging/clinical findings, and patient characteristics to classify patients as ideal, appropriate, or inappropriate for a minimalistic initial management approach.
The administration of neoadjuvant chemotherapy (NAC):
Offers several advantages in locally advanced breast cancer:
It allows for downstaging the disease:
Which can potentially allow for less extensive surgery in the breast and axilla
It also provides information regarding the responsiveness of the cancer to systemic therapy while the tumor remains in vivo:
Which can guide the course of therapy
Administering chemotherapy in the neoadjuvant vs. adjuvant setting:
Does not change overall survival:
As demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27 trials
The patient’s response to chemotherapy:
However, does offer prognostic information:
Particularly in patients with hormone receptor negative (HR-) disease
Patients who achieve pathologic complete response (pCR):
Which is typically defined as no residual invasive disease in the breast or axilla:
Appear to have improved event-free survival (EFS) and overall survival (OS) compared with patients with residual disease
This finding was demonstrated by a recent meta-analysis that included 36 studies including 5,768 patients with HER2 positive breast cancer:
This correlation was strongest in patients with HR- disease
Further, among patients with HER2 positive disease that do not have a pCR:
The degree of residual cancer burden appears to correlate with outcomes
Patients with HER2 positive tumors:
May complete up to 1 year of HER2-targeted therapy with trastuzamab ± pertuzamab
When planning surgery:
The pre-treatment volume does not need to be excised if the tumor has responded to chemotherapy:
However if multifocal disease is present, the satellite lesion(s) should be localized and excised with the index lesion
When considering the appropriateness for breast conservation following NAC, the distance between the lesions, location, and breast size must be considered
Placement of clips in the index lesion and any satellite lesions prior to initiation of NAC is critical for appropriate surgical planning post-NAC
References:
Rastogi P, Anderson SJ, Bear HD. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008; 10;26(5):778-785.
Broglio KR, Quintana M, Foster M, et al. Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis. JAMA Oncol. 2016;2(6):751-760.
Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.
Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg.2006;244(3):464-470.
Is a very rare special histological type of breast cancer:
Accounting for approximately 0.1% of all breast tumors
It is usually triple negative
It is much less likely to have nodal involvement
Is more common in postmenopausal women:
Most cases are in females
The median age of onset is:
Between 50 and 60 years
With a mean age of 66
The typical clinical feature is:
A single breast tumor / mass:
Multiple nodules are rare
Most ACCs are located:
Under the areola or in the upper outer quadrants
ACC of the breast has no characteristic imaging findings:
Ultrasound features are those of:
A hypoechoic solid or heterogeneous mass
On mammography:
The case may present as a lobulated mass with sharp or un sharp margins
Nevertheless, these clinical and radiographic features may be similar to any breast cancer:
Thus making their precise diagnosis difficult for radiologists
Histologically:
ACC of the breast typically consists of a dual-cell population of:
Luminal and myoepithelial-basal cells:
Which are generally negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)
In addition, some studies have also reported some HR-positive ACC cases:
The significance of a positive hormone receptor status is not known:
Compared with ACC with negative HR expression, the clinical characteristics and prognosis of this type of ACC are also unknown
Distant metastases are rare:
However, the lung is the most common site
It has a better prognosis than infiltrating ductal triple negative breast cancer:
With a 5-year overall survival rate of 88%
As prognosis is good:
Accurate preoperative diagnosis is important in the determination of suitable treatment
References
Treitl D, Radkani P, Rizer M, El Hussein S, Paramo JC, Mesko TW. Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature. Breast Cancer. 2018;25(1)28-33.
Welsh JL, Keeney MG, Hoskin TL, et al. Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast? J Surg Oncol. 2017;116(6):690-695.
Kulkarni N, Pezzi CM, Greif JM, et al. Rare breast cancer: 933 adenoid cystic carcinomas from the National Cancer Data Base. Ann Surg Oncol. 2013;20(7):2236-2241.
Kshirsagar AY, Wader JV, Langade YB, Jadhav KP, Zaware SU, Shekhar N. Adenoid cystic carcinoma of the male breast. Int Surg (2006) 91(4):234–6.
Pang W, Wang Z, Jin X, Zhang Q. Adenoid cystic carcinoma of the breast in a male: A case report. Med (Baltimore) (2019) 98(32):e16760. doi: 10.1097/MD.0000000000016760
Tang W, Peng WJ, Gu YJ, Zhu H, Jiang TT, Li C. Imaging Manifestation of Adenoid Cystic Carcinoma of the Breast. J Comput Assist Tomogr (2015) 39(4):523–30. doi: 10.1097/RCT.
Torrao MM, da Costa JM, Ferreira E, da Silva MV, Paiva I, Lopes C. Adenoid cystic carcinoma of the breast. Breast J (2007) 13(2):206.
Marchio C, Weigelt B, Reis-Filho JS. Adenoid cystic carcinomas of the breast and salivary glands (or ‘The strange case of Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas). J Clin Pathol (2010) 63(3):220–8. doi: 10.1136/jcp.2009.073908
National Comprehensive Cancer Network (NCCN) guidelines:
Recommend surgical management:
For local control for women with early stage invasive breast cancer
Several studies have shown an equivalence in overall and / or breast cancer-specific survival rates:
For breast conservation with radiation compared to mastectomy among early stage breast cancer patients
For patients with ER positive disease:
Endocrine therapy with tamoxifen or aromatase inhibitors is prescribed after surgery:
A systematic review evaluated the efficacy of primary endocrine therapy alone versus surgery in women over 70 years old with operable tumors:
The review reported similar survival between the two groups, but women treated with surgery had lower rates of local failure when compared to endocrine therapy alone
The authors concluded that primary endocrine therapy should be reserved for women who are unfit for surgery or decline surgery
Sentinel node biopsy:
Has become the standard method for staging the axilla in women with early stage breast cancer:
Who are clinically node negative
Axillary dissection is only performed in women with:
Fisher B, Anderson S, Bryant J, et al. Twenty-year followup of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med. 2002;347(16):1233-1241.
Litiere S, Werutsky G, Fentiman IS, et al. Breast-conserving therapy versus mastectomy for stage I-II breast cancer: 20 year followup of the EORTC 10801 phase 3 randomized trial. Lancet Oncol. 2012;13(4):412-419.
Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med. 2002;347(16):1227-1232.
Is characteristically spontaneous, unilateral, or bloody
Physiologic discharge:
Is non-spontaneous, bilateral, and milk
The most common causes for pathologic nipple discharge:
Are benign:
Intraductal papillomas
Duct ectasia
The presence of abnormal clinical findings on imaging or physical exam:
Is associated with increased risk of malignancy:
38% vs. 2%
Contemporary workup for nipple discharge includes:
Mammography
Evaluation of the retroareolar region with ultrasound
Patients with normal findings on mammography, ultrasound, and physical exam:
Can be further evaluated with breast MRI:
As it is highly sensitive and specific for cancer
Surgical management of nipple discharge includes:
Excision of a single duct or central duct apparatus:
Depending on the number of ducts involved
References:
Li GZ, Wong SM, Lester S, Nakhlis F. Evaluating the risk of underlying malignancy in patients with pathologic nipple discharge. Breast J. 2018;24(4):624-627.
de Paula IB, Campos AM. Breast imaging in patients with nipple discharge. Radiol. Bras. 2017;50(6):383-388.
Yilmaz R, Bender O, Celik Yabul F, Dursun M, Tunaci M, Acunas G. Diagnosis of nipple discharge: value of magnetic resonance imaging and ultrasonography in comparison with ductoscopy. Balkan Med J. 2017;34(2):119-126.
Three important areas form the foundation for the evolving use of altered fractionation:
Tissue response
Duration of treatment
Fraction size and number
Acutely responding tissues:
Are rather active in ongoing cellular proliferation
Most tumors (except perhaps prostate cancer, breast cancers, and melanoma) and some normal tissues such as skin, mucous membranes, and gastrointestinal epithelium:
Share this characteristic:
These tissues are most affected by the overall treatment duration rather than by the size or number of fractions used
Late-responding tissues:
Have a low proliferative rate and include the spinal cord, brain, bone, and cartilage
These tissues are most affected by the:
Size and number of fractions rather than by treatment duration:
Therefore are spared by decreasing the dose per fraction of radiation delivered
Because most tumors consist of rapidly dividing cells:
Local tumor control is strongly dependent on the overall treatment duration rather than on the size or number of fractions
When squamous cell carcinoma of the head and neck is exposed to radiation:
The less radiosensitive cells within the lesion:
Can undergo rapid proliferation:
Approximately 3 to 5 weeks after treatment commences
This accelerated repopulation can overwhelm the ongoing treatment effects of radiation:
Which ultimately can lead to local failure
The clinical significance of this phenomenon is that even with significant regression of the primary tumor mass:
Local failure still ultimately could result from proliferation of these resistant clones
Therefore it is essential to complete treatment in as short a time as possible so that accelerated repopulation is minimized:
Increasing the chance for local control
For this reason, split-course radiation:
Which incorporates a treatment break during the course of radiotherapy is not recommended
Based on the aforementioned principles:
The goal of altered fractionation schemes:
Is to improve the therapeutic ratio by maximizing the tumoricidal effect and minimizing acute and late toxicities while using readily available low-LET radiation
Two major categories of altered fractionation schemes exist:
Hyperfractionation
Accelerated fractionation
They share basic radiobiological principles yet have their own particular features (Table)
Accelerated fractionation:
Is the strategy of choice for rapidly proliferative tumors
Accelerated fractionation is based on the concept that the shortened overall treatment time:
Would reduce the opportunity for accelerated repopulation effectively
Hyperfractionation:
Is preferred for slowly proliferating tumors
Hyperfractionation improves the therapeutic ratio primarily through:
Redistribution of tumor cells into more radiosensitive phases as a result of multiple fractions
Differential sparing of late-responding normal tissues because of a decrease in the size of the dose per fraction
Current consensus guidelines from the American Society of Breast Surgeons:
Do not recommend CPM for women with sporadic breast cancers
A Cochrane review of 8 studies evaluating patients who underwent CPM:
Concluded that while CPM reduces risk of contralateral breast cancer:
It is not associated with improved survival
Reasons for not recommending CPM include:
A low estimated risk of cancer in the contralateral breast (2% to 6% over 10 years)
Increased complication rates
Studies showing that CPM does not improve survival or recurrence from the index cancer
References:
Lostumbo L, Carbine N, Wallace J, Ko H. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2004(4):CD002748.
Boughey JC, Attai DJ, Chen SL, et al. Contralateral prophylactic mastectomy consensus statement from the american society of breast surgeons: additional considerations and a framework for shared decision making. Ann Surg Oncol. 2016;23(10):3106-3111
This nerve is a cutaneous branch of the intercostal nerves:
Most commonly the second intercostal nerve:
Which gives off a lateral cutaneous nerve:
Which continues as the intercostobrachial nerve
The intercostal nerves arise from:
The anterior rami of the thoracic spinal nerves
The intercostobrachial nerve pierces the serratus anterior:
Crosses the axilla to the medial side of the upper arm
The intercostobrachial nerve is commonly in the surgical field during axillary lymph node dissections and may be severed during surgery, or subject to traction or postsurgical inflammation:
Thus leading to intercostobrachial neuralgia
The larger intercostal nerves:
Can be preserved with meticulous dissection
Neuropathic symptoms:
May be limited to numbness or tingling:
But may also include a burning sensation
Techniques such as a regional nerve block:
Have been described to alleviate symptoms in severe cases
In a study of 200 patients who underwent axillary dissection:
76% had symptoms of intercostobrachial neuralgia postoperatively
Of these patients, 82% reported improvement or resolution of these symptoms within 1 year:
Reflecting the richness of the sensory nerve supply to the axilla and upper arm
The thoracodorsal nerve:
Is a branch of the posterior cord of the brachial plexus:
It supplies motor function to the latissimus dorsi
If injured, patients experience weakness with arm abduction, lateral flexion, and difficulty with activities such as climbing, swimming, and using the arms to pull the body up
The medial cord of the brachial plexus:
Gives rise to the medial pectoral nerve:
Which innervates both the pectoralis minor muscle and the pectoralis major muscle
The medial pectoral nerve typically pierces the pectoralis minor muscle:
But may wrap around the lateral aspect of the pectoralis minor before traveling on to innervate the distal pectoralis major muscle
The lateral cord of the brachial plexus:
Gives rise to the lateral pectoral nerve:
Which innervates the pectoralis major muscle
This nerve travels along the medial border of the pectoralis minor muscle:
Then along the undersurface of the pectoralis major muscle along with the pectoral branch of the thoracoacromial artery to supply the proximal pectoralis major muscle
The medial pectoral nerve bundle:
Is often encountered during axillary dissection as it is located lateral to the lateral pectoral nerve
If either of these nerves is injured:
Pectoralis muscle atrophy can occur:
Which can present as a late complication of surgery, with weakness of shoulder adduction, interior rotation, and flexion
The long thoracic nerve:
Typically arises from anterior rami of the cervical spinal nerve roots C5 to C7
It courses along the chest wall and supplies the serratus anterior muscle
Injury to this nerve causes a winged scapula
References:
Sclafani LM, Baron RH. Sentinel lymph node biopsy and axillary dissection: added morbidity of the arm, shoulder and chest wall after mastectomy and reconstruction. Cancer J. 2008;14(4):216-222.
Wisotzky EM, Saini V, Kao C. Ultrasound-guided intercostobrachial nerve block for intercostobrachial neuralgia in breast cancer patients: a case series. Prev Med Rep, 2016;8(3):273-277.
Roses DF, Brooks AD, Harris MN, Shapiro RL, Mitnick J. Complications of level I and II axillary dissection in the treatment of carcinoma of the breast. Ann Sur. 1999;230(2):194-201.
Porzionato A, Macchi V, Stecco C, Loukas M, Tubbs RS, De Caro R. Surgical anatomy of the pectoral nerves and the pectoral musculature. Clin Anat. 2012;25(5):559-575.
Is a clinical syndrome in women with invasive breast cancer that is characterized by:
Erythema and edema (peau d’orange) of a third or more of the skin of the breast
The differential diagnosis includes:
Cellulitis of the breast or mastitis
Because most IBC cases are first seen by healthcare providers not necessarily familiar with IBC:
The absence of complete response to a trial of antibiotic therapy should heighten suspicion of IBC and prompt further investigation:
Further trial of antibiotics is not warranted in the absence of clinical signs of infection and previous adequate antibiotic therapy
Workup includes physical exam and imaging:
Imaging may not reveal a mass:
But thickening of the skin is frequently seen
The most common signs of IBC on mammography include:
Thickening of the skin (84%)
Trabecular thickening (81%)
Asymmetric focal density (61%)
Microcalcifications (56%)
Mammography is the least sensitive diagnostic tool available for IBC:
Whereas ultrasound and MRI are more sensitive:
In a series published by Yang, et al., sonography demonstrated a mass or architectural distortion in 95% of patients with associated global skin and subcutaneous thickening and dilated lymphatics
MRI can also show skin thickening and is more sensitive than mammography in detecting an underlying mass:
The same series by Yang and colleagues found that a primary breast lesion was present in every MRI obtained in patients with IBC as either nonmass or mass-like enhancement
IBC is a clinical diagnosis:
Dermal biopsy confirmation is not mandatory:
Dermal lymphatic invasion is seen only in approximately 60% of IBC cases:
It is neither required, nor sufficient by itself for a diagnosis of inflammatory breast cancer
Treatment is multidisciplinary trimodality therapy consisting of neoadjuvant chemotherapy, modified radical mastectomy, and local regional radiation:
Yet, the median survival at 5 years for patients presenting with primary IBC is still only approximately 55%
References
Yang WT, Le-Petross HT, Macapinlac H, et al: Inflammatory breast cancer: PET/CT, MRI, mammography, and sonography findings. Breast Cancer Res Treat. 2008;109(3):417-426.
Somio G, Jones V. Inflammatory breast cancer. In: Klimberg S, Bland K, eds. The Breast: Comprehensive Management of Benign and Malignant Disease. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011:832-838.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 