Stephanie+Li

= = =__//The Story//__= = = Meet Lucia Li. A petite woman, she stands at 5'3" and can fit into a child's size L. At first glance, she seems like any normal Asian woman, always busy tidying the house, cooking delicious-smelling Chinese food in the kitchen, and working at her day job. During the day, she works as a beauty consultant for Dior (free make-up for life!), but at night, she takes on the harder task of being a mother to a college student. Born and raised in Suzhou, China, she was the youngest of three girls. Their mother was never around, so they were raised by their grandmother, who was of old age and practically incapable of taking on 3 sprightly young women. Because of her mother not being around for most of her childhood, Lucia always told her own daughter that she promised to be with her every second of every day for as long as she lived.

But there came a day where she thought that that promise would be broken. Back in June of 2010, during her yearly mammogram, Lucia was diagnosed with 3 fibroadenomas in her right breast. Her doctor explained to her that she needn't worry because fibroadenomas are benign tumors that have a very low chance of turning into cancerous tumors. With a sigh of relief, she thanked the doctor and continued on with her day.

The August of next year, during her yearly mammogram, her doctor decided to perform a fine-needle aspiration biopsy, guided with an ultrasound to make sure that her fibroadenomas were still benign. There were only slight changes in their sizes (Table 1). She received a staple in her biggest lump so that the doctors could easily take its measurements the next time she comes around.


 * || **6/3/10 (Mammography)** -- || **8/17/13 (Biopsy)** -- || **8/15/11 (Ultrasound)** -- || **8/20/13 (Ultrasound)** -- || **5/8/14 (Ultrasound)** -- || **7/11/14 (Ultrasound)** ||
 * **10:00** || 2.9 x 2.6 x 1.3 || 3.0 x 2.6 x 1.3 || 2.8 x 2.4 x 1.2 || 2.9 x 2.7 x 1.4 || 4.5 x 4.5 x 2.7 || 6.4 x 6.8 x 4.0 ||
 * **10:00** || - || - || - || 1.4 x 1.2 x 0.8 || 2.7 x 1.4 x 3.3 || 3.1 x 1.6 x1.6 ||
 * **11:45** || 1.9 x 2.3 x 0.9 || 2.3 x 0.9 x 1.9 || 1.6 x 1.9 x 0.9 || 2.1 x 1.0 x 1.7 || 1.5 x 1.8 . 0.9 || - ||
 * **2:00** || 0.7 x 0.8 x 0.5 || - || 2.3 x 0.9 x 1.9 || 0.9 x 0.5 x 0.9 || 0.9 x 1.2 x 0.5 || - ||
 * **2:30** || - || - || - || - || 0.7 x 0.3 x 0.8 || - ||


 * **Table 1. Measurements of tumor size and positions from types of tests performed during respective dates.** All measurements are taken in centimeters. Any small discrepancies in the values of the measurements are due to different doctors measuring differently. ||

The year 2013 brought some concern to Lucia, as she picked up the phone and called the doctor. She explained that she had felt a new lump growing in her right breast. (Table 1) Her ultrasound results showed that indeed there had been a new growth. The doctor biopsied that lump as well, to ensure that it was a fibroadenoma (which it was). The growth of a new lump worried Lucia and brought two words to her mind: breast cancer. In 2008, her eldest sister was diagnosed with Stage I breast cancer, and had metastasized to her lymph nodes. Luckily, through a successful surgery removing the tumor and 3 of her lymph nodes and after many chemotherapy sessions, she had finally won her war against cancer. Lucia was frightened that it was her turn to fight, and she just wasn't ready for it. She was under a lot of stress from work and other personal issues, so she thought she was doomed to the fate that her sister had. She knew that the gene for breast cancer did not run in the family, and concluded that it had occurred in her sister because of the high-stress levels her sister was experiencing from work. Luckily for Lucia, her new lump was benign.

However, around May of 2014, she noticed that her largest lump was in fact, growing much larger (Table 1). She called up the hospital and asked for an ultrasound of her breast. Her largest lump (10:00) had grown more than six times as large since 2011, to the size of a 50mL tube, and her smaller lump (new 10:00 position) had grown 12 times as large since 2013, and was in fact growing faster than the larger lump. Expressing concern for the growth of these fibroadenomas (which is not supposed to occur), her doctor suggested for her to have them surgically removed. In the meantime, he suggested that he take another biopsy to make sure that they are still fibroadenomas. Her results came in the same as before: they were benign tumors.

Her promise with her daughter continued to waver, especially since after her latest biopsy, her right breast took on a reddish-purple hue at the sight of the biopsy, and felt feverish to the touch. In fact, because the largest lump continued to grow, her breast protruded out sideways, making it impossible and painful to wear a bra. A call to the doctor proved to be useless; the only advice given was that the reddening and swelling was a cause of inflammation and that it would go away after a few weeks. A month passed by: the reddening went away, but the size of the tumor continued to increase, and her breast still felt like a stovetop left on for too long. She expressed her concern to her doctor, who then suggested that she go see an oncologist.

Another ultrasound showed that the largest lump had in fact grown to be the exact volume of a 150mL centrifuge tube. Her concern turned to fear when the oncologist suggested that they proceed with one of two options: either a full-on breast removal (mastectomy), or just the removal of the tumor of concern (lumpectomy). He explained that because her tumor had clean margins (it did not interfere with other breast tissues), performing a lumpectomy would be no problem. However, he illustrated that because he wasn't sure of the malignancy of the other tumors that would be left inside her breast, there was a possibility that in the future, there would be more surgeries for their removal. Along with that, he explained that since her other lumps were not small in size, that her breast would look uneven. On the other hand, a mastectomy would remove the entire breast: all of the lumps, so she would not have to worry about her other lumps growing like the one now. In addition, he said that she could always have a plastic surgeon place a breast implant in her breast to make it look more natural. Ultimately, the decision was left in her own hands.

Lucia was torn between the decision of increasing her chances of losing the promise to her daughter and losing her womanhood. Symbolically, taking away a breast is much like taking a part of womanhood from a woman. The breast is a sign of fertility, and its removal may cause negative thoughts associated with body image. One study showed that the removal of the breast is positively correlated with decreased mental health in female patients, due to anxiety and fear of how others will see her once her breast is missing. However, her love for her daughter outweighed the importance of keeping her breast and finally decided to go ahead with the mastectomy. She showed no remorse in her decision, saying that losing a breast is not making her any less of a woman, but in fact, more of a woman because she would have the scars to show a woman's strength.

Upon further analyzation after the mastectomy, researchers from Stanford concluded that her tumor had transformed from a fibroadenoma to a phyllodes tumor with a potential low-grade malignancy. A phyllodes tumor is often mistaken for a fibroadenoma when only using mammography and biopsy as tools of diagnoses. This confusion is due to the fact that one generally does not look past the surface and falls for the illusion.


 * **Timeline** ||

-Finding of new palpable mass at 10:00 (biopsied) || -New additional developing fibroadenoma at 2:30 || -US guided biopsy with staples placed on both 10:00 tumors || -Hematoma diagnosed || -Largest tumor at 10:00 position raises concern for phyllodes tumor -Discussion of mastectomy || -Identified largest lesion as phyllodes tumor -Other tumors identified as fibroadenomas ||
 * **Date** || **Event** ||
 * 6/3/10 || -Initial Mammogram ||
 * 8/17/10 || -Ultrasound (US)-guided biopsy with staples placed on 2 largest tumors (Table 1) ||
 * 8/15/11 || -US ||
 * 8/20/13 || -US
 * 5/8/14 || -Ultrasound
 * 5/9/14 || -First mention of surgical excision of largest tumor
 * 6/11/14 || -Development of swelling, bruising and feverish temperature of breast
 * 7/9/14 || -First visit with oncologist ||
 * 7/11/14 || -US
 * 7/28/14 || -Surgery performed (mastectomy) ||
 * 7/29/14 || -Tumor sample sent to Stanford for further consultation


 * **Figure 1. Timeline of Events.** Information was collected from Lucia Li's personal medical records. See Table 1 for specific measurements. ||

=//__**The Science**__//=

Looking at a fibroadenoma and a phyllodes tumor on a mammogram can be compared to looking at a low-resolution picture of two identical twins. Images provide only half of the information, but upon looking at them in real life, one may notice that perhaps the first twin has freckles, and the second twin has a small mole on their cheek. Subtle differences may be detected. That is, if we look hard enough.

The same goes for the fibroadenoma and the phyllodes tumor: both are born from the same "stromal compartment of the terminal ducto-lobular unit", (in other words: the unit that produces breast milk), but they are hard to differentiate when using mammography or an ultra-sound alone; and phyllodes tumors are often misdiagnosed as fibroadenomas. This misdiagnosis is very dangerous because phyllodes tumors, unlike their "identical twin", the fibroadenoma, can be malignant. Though these tumors share the same physical composition, their behavior inside the breast differs greatly.

Fibroadenomas are non-cancerous tumors that may be small in size and stay in its original position in the breast. However, women with these fibroadenomas may have a slightly elevated risk of developing breast cancer compared to women who do not develop them in their breast.

Phyllodes tumors, on the other hand, are much more rare, making up about "2–3% of ﬁbroepithelial neoplasms and <1% of all breast tumors". They come in three different classes: benign, borderline, and malignant. All three types of these tumors have "increased rates of copy number alteration (CNA)" in genes such as "NF1, RB1, TP53, PIK3CA, ERBB4 and EGFR, which are known cancer driver genes that have transforming ability". Increased rates of CNA means that sections of their genome have been repeated, making them high-grade tumors, or tumors with that have deviated from normal cells in their rapid growth and metastasis.

  Adding to their similar appearance, fibroadenomas and phyllodes tumors also share a common mutation, in a gene called MED12. MED12 "is associated with estrogen-related transcription and signaling". Mutations in this gene often give rise to breast neoplasms such as fibroadenomas and phyllodes tumors. This mutation just continues to add to the confusion and deception that these two tumors are essentially the same.
 * **Figure 2. Image of the Different Types of Mutations in Phyllodes Tumors and Fibroadenomas** . ||

  But not all hope has been lost: all three types of the phyllodes tumors have mutations in the FLNA, SETD2, KMT2D, BCOR and MAP3K1 genes that are not seen in fibroadenomas, helping us to finally be able to differentiate between the two. The extra mutations in these genes are speculated to be the reason behind tumorigenesis for phyllodes tumors. Most of the mutations associated with these genes are loss-of-function mutations, and that inactivation usually results in abnormal regulation of transcription.
 * **Figure 3. Images of MED12 Mutations in Both Fibroadenomas and Phyllodes Tumors** . ||

 28% of phyllodes tumors have a mutation in the FLNA2 gene. FLNA2 is an X-linked gene which codes for a protein called Filament A. This protein "...functions as a scaffolding protein involved in cell motility and invasion..." . In other words, this protein is responsible for regulating the movement of a cell around the body. When a mutation in FLNA2 leads to over-expression of Filament A in a cell's cytoplasm, the protein promotes tumor growth and invasion.

 SETD2 and KMT2D are genes that have loss-of-function mutations in 35% of phyllodes tumors. Both of these genes code for histone methyltransferases, and this mutation causes "...aberrant transcriptional regulation", or abnormal and out of control transcription of their proteins. Histone modifications usually function to help with processes such as "...transcription, replication, DNA repair, and apoptosis". When genes that code for these modifications have loss-of-function mutations, they stop regulating all of the above processes, which promotes tumor growth and proliferation.

 BCOR, in its regular, normal form, is a tumor suppressor gene, but in cancer cells, this gene goes through a loss-of-function mutation, which stops the gene from suppressing the growth of the tumor. This gene is spotted mainly in borderline and malignant phyllodes tumor cells because it promotes the proliferation and metastasis of the tumor.

 MAP3K1 is a tyrosine kinase, which is an enzyme that functions as an "on / off switch" in many types of cells. Tyrosine kinases are usually involved in a long pathway filled with phosphorylation events, much like how tipping over one domino causes all of the others to fall over as well. Usually, MAP3K1 "...functions in cell survival, apoptosis, and cell motility/migration", and when mutated, stops the regulation of these functions. In borderline and malignant phyllodes tumors, MAP3K1 is mutated such that apoptosis, cell migration, etc is no longer regulated, allowing these cells to evade cell death and can metastasize.

 Borderline and malignant phyllodes tumors show a mutation (along with CNAs) in the EGFR (epidermal growth factor receptor). The EGFR, once mutated, leads to sustained cell proliferation, which accounts for the fast-growing tumor in the borderline and malignant types. The wild-type EGFR is a tyrosine kinase, and its pathway leads to autophosphorylation and cell proliferation. The mutated version of this gene has no cap on cell proliferation, which allows the tumor to continue growing into its malignant status.

 Another difference between the two "identical" twins is that mutations in the TERT promotor are very common in phyllodes tumors (65%) but very rare in fibroadenomas (7%). This mutation activates the TERT gene, causing over-expression of telomerase, as stated later on. The TERT gene codes for a "catalytic subunit of telomerase" and is a "major determinant of telomerase activity." Telomerase is an enzyme that adds specific nucleotides to the ends of telomeres to elongate them. It is usually very heavily regulated during fetal development, and in the quiescent somatic cells (inactive cells that comprise of most of our adult body), the activity of telomerase is repressed, whereas in tumor cells, this activity is over-expressed. Therefore, a mutation in the TERT promotor is much like turning on a light switch and never turning it off again. The TERT promotor mutation causes over-expression in the TERT gene, leading to the continuous activation of telomerase. This mutation is most often associated with MED12 mutations exclusively in phyllodes tumors and rarely in fibroadenomas. Again, this shows that on the surface level, the two tumors seem to be the same. But on a molecular level, their differences are vast.

  The relationship between a phyllodes tumor and a fibroadenoma can be summarized with "things are not always what they seem." On the surface level, the two are almost identical, like Castor and Pollux, the twins of the Gemini constellation. Just like how Pollux is immortal because he is the son of a god, Zeus and Castor is mortal because he is the son of a mortal man, Tyndareus, a phyllodes tumor has mutations that render it immortal, while a fibroadenoma is mortal.
 * **Figure 4. Images of TERT Promoter Mutations in Both Fibroadenomas and Phyllodes Tumors** . ||

=__//**The Suspicion**//__=  Identical twins are often mistaken for each other. At first glance, they may look exactly the same, but upon further inspection, we may notice that perhaps the first twin has a small mole on their neck whereas the second twin does not. Such subtle distinctions are ways we can tell them apart. That is, if we look hard enough.

 For patient Lucia Li, doctors had a hard time distinguishing between a benign phyllodes tumor and a fibroadenoma in her right breast. Phyllodes tumors are often misdiagnosed for fibroadenomas and this misdiagnosis is dangerous because malignant phyllodes tumors have the potential to invade other tissues, whereas fibroadenomas can be left alone because of their benign status.

 Both tumors show up as similar images on a mammogram. The phyllodes tumor “usually manifests as a round, oval or…fine-edged lump…fibroadenomas are an oval, or lobular shaped mass, homogeneous with clear edges…”. At first glance, without any biopsy or surgical excision following the mammogram, the two tumors are virtually identical. However, suspicion that a lump is a phyllodes tumor should arise if the net mass of a tumor “is over 6-8 cm in diameter or if (it)…shows rapid growth on serial mammogram”. Fibroadenomas do not grow in size; they stay stable. After a successive number of mammograms, if the tumor stays stable in size and area of the breast, there is a high percentage that that is a fibroadenoma. Mammograms also often show calcifications (calcium deposits that reside in the breast tissue) in fibroadenomas. This is another way of differentiating between a phyllodes tumor and a fibroadenoma, but not a very efficient method. There are some cases where calcifications can also occur in cancerous tumors, where there are “tight clusters with irregular shapes”. This poses as a problem because it is hard to tell what makes an “irregular shape,” and may result in unnecessary treatment options if diagnosed incorrectly. Researchers have concluded that a mammogram alone is fine for detection of a tumor in the breast, but it is not optimal as a tool of assessment of that tumor’s malignancy.

<span style="font-family: Arial,Helvetica,sans-serif;"> <span style="font-family: Arial,Helvetica,sans-serif;"> Core needle biopsies (CNB) are tests that are performed when a suspicious lump appears in a woman’s mammogram. They require the use of a needle to penetrate the skin of the breast to take a small sample of the tumor to determine its malignancy under the microscope. A small clip is placed to mark the place of the tumor so it would be easier to find in future mammograms. However, CNBs have a reputation as a weak technique, filled with “…histologic underestimation or false-negative results”, which means that it incorrectly diagnoses a cancerous tumor as a fibroadenoma, thus delaying potential treatment. If CNBs are not paired with an ultrasound or a breast MRI, there is a chance that the needle would miss the tumor and take a sample of normal tissue instead.
 * **Figure 5. Mammogram and Ultrasound Images of Phyllodes Tumors** . ||

<span style="font-family: Arial,Helvetica,sans-serif;"> Using an ultrasound with CNBs is more useful because that way, doctors can visualize where the tumor is and correctly sample from that tumor instead of a random tissue. Ultrasounds are able to help doctors visualize the shape of a tumor. If it is a phyllodes tumor, it may have “in addition to cystic spaces, round shape…sonographic features favoring phyllodes tumor rather than fibroadenoma”. Phyllodes tumors may be larger in size compared to fibroadenomas because of the presence of cysts within the mass. An ultrasound-guided CNB is still not effective enough in determining the difference between a fibroadenoma and a phyllodes tumor because the sizes of the two tumors could be the same (if the phyllodes tumor were benign).

<span style="font-family: Arial,Helvetica,sans-serif;"> MRI, or magnetic resonance imaging, uses “a magnetic field, radio frequency pulses and a computer to produce detailed pictures of organs, soft tissues, bone and virtually all other internal body structures”. The MRI findings are similar to the ultrasound findings. MRI is another imaging technique that is prone to the subjective interpretation of its results, much like the ultrasound. Again, just taking an MRI is not optimal for an accurate diagnosis of the tumor type, because imaging alone is not adequate for differentiating a phyllodes tumor from a fibroadenoma.

<span style="font-family: Arial,Helvetica,sans-serif;"> A more effective method that involves ultrasound is something called ultrasound elastography (EUS). This “method (is used) to assess the mechanical properties of tissue, by applying stress and detecting tissue displacement using ultrasound”. This method would be more effective in differentiating between a phyllodes tumor and a fibroadenoma, mainly because this tests for the stiffness of a fibroepithelial (or any) lesion. A phyllodes tumor is generally stiffer and firmer compared to a fibroadenoma. EUS is a fairly recent development, and most often used with musculoskeletal tissue properties to determine the correct treatment plan and therapy for injured muscles or tissues. The downsides to EUS is that because it is fairly new, quantitative measurements, such as grading the elasticity of the tissue or tumor, are products of each doctor’s own subjective point of view, and therefore problems such as “a lack of reproducibility and difficulty in comparing the results from different studies, even if the same technique” start to rise. Another issue is the amount of pressure placed on the tumor or tissue has to be well-controlled, because some tumors have a lot of fluid inside that may rupture. EUS has been reported to be even more sensitive than MRIs, but because of the limited amount of information and data collected by EUS tests, scientists are having issues with determining whether or not it can produce results that are clinically significant.

<span style="font-family: Arial,Helvetica,sans-serif;"> Researchers have concluded that imaging alone (such as MRI, ultrasound and mammograms) is not adequate for the detection of the distinction between a fibroadenoma and a phyllodes tumor. They have to be paired up with CNB, or in more severe cases, excisional biopsy. Excisional biopsy, or more commonly known as a lumpectomy, removes the whole tumor and the affected tissues around it. In some cases, if the tumor were benign or had not yet metastasized, surgery would be the end of the treatment. In other more severe cases, lymph nodes would also have to be removed and some patients may require radiation therapy as a follow-up. The cases of phyllodes tumors are very rare, comprising of only 0.5% of malignant breast tumors. Because of this, research for a therapy directed at “killing” these tumors is very limited. Scientists have found that mutations associated with malignant phyllodes tumors often result in increased cell proliferation and survival, rendering the tumors as immortal.

<span style="font-family: Arial,Helvetica,sans-serif;"> Lucia Li’s phyllodes tumor was not diagnosed as malignant, and also had not metastasized. This means that she needed no additional therapy (chemotherapies, radiation therapies, etc) besides the mastectomy, or removal of the whole breast. She fortunately received the surgery before her tumor had a chance to metastasize to the nearby lymph nodes, and therefore served as a great example for a victim of the false-negative curse that the ultrasound-guided biopsy is guilty of. Had the doctors used a method that would have diagnosed her tumor as a phyllodes tumor earlier on, she may not have needed a full mastectomy, and perhaps would have been find with just a lumpectomy. The most important and unfortunate fact was that her tumor was concluded to be a phyllodes tumor only after it was removed and sent to the Stanford and UCSF labs for further research. In the future, if ultrasound elastography could be used in a clinical setting and expand beyond the musculoskeletal regions, then perhaps phyllodes tumors and fibroadenomas would not be mistaken as one for the other so easily.

=__//**<span style="font-family: Arial,Helvetica,sans-serif;">Aperçu **//__= <span style="font-family: Arial,Helvetica,sans-serif;"> The decision for Lucia to lose a whole breast was not an easy one to make, but the complications of a lumpectomy (uneven breasts, chances of a recurrence, etc) outweighed the harsh reality that she would lose her entire breast. She had a family to care for and her whole life ahead of her. She’d rather live longer and spend more time with her daughter, living with just one breast instead of increasing her chances of getting another phyllodes tumor and losing that precious time. Lucia’s story of resilience and willingness to sacrifice a part of her womanhood for the sake of being able to spend more time with her family really exemplifies the saying “婦女能頂半邊天”, or “Women can lift half of the sky.” The second lesson to Lucia’s story is the well-known saying: “things are not always what they seem.” This is best demonstrated though the misdiagnosis between the phyllodes tumor and fibroadenomas on mammograms and ultrasounds, how they look the same on the surface, but are so different underneath. <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> - <span style="color: #ffffff; font-family: Arial,Helvetica,sans-serif;"> -