Carcinoma In Situ diagnosis

Hi Clyde,

First, the was a typo. The basement membrane is thin, not thick.

I was the opposite. The CT scan for my bladder cancer showed an enlarged prostate. A year later my urologist
did the first TURBT, he did TURP. It was benign. Now I can go for a 2 hrs walk with my puppy without my looking for the bush to hide. My GP was prescribing Flowmax and did not think of sending me to a urologist. I did not know about bladder cancer. Neither I knew the anatomy of the bladder or its location back then. It was good that you found the tumor early.

Progression of CIS

Data show that CIS without treatment has a high probability to progress. A case in point is the study I referenced
in the previous post said about 50% of CIS cases had recurrence or progression even with intravesical chemotherapy. The report does not say how many of 50% had recurrences or progression. Also, the report does not say how many of those recurred was CIS or TaLG. But, considering the current recommended treatment of CIS with recurrence of CIS is radical cystectomy, AUA must be thinking that CIS has a tendency to progress.

Progression of CIS after BCG treatment

A large study was done by the same group in 2002 on the progression of papillary type and CUS after BCG treatment says that based on a median followup of 2.5 years and a maximum of 15 years, the percent of patients with progression was low (6.4% of 2,880 patients with papillary tumors and 13.9% of 403 patients with carcinoma in situ). It means 86% of CIS after BCG therapy did not progress.

BCG unresponsive treatment
Suppose your CIS did not respond to BCG as the other 86% of patients.
You will have a choice of bladder salvage treatment or radical cystectomy and live with a new norm.

If you choose for bladder salvage, it is important first, your hospital follows a certain protocol to
determine if your CIS is truly BCG unresponsive or not. Dr. Ashish Kamat of MD Anderson often states
that how BCG therapies are done is inconsistent among hospitals and urologists. He suggests not
consider BCG unresponsive if a recurrence happens after 6 weeks induction course, but continue at least
do one maintenance course after 3 months. In this context, Dr. Stephan Boorjian of Mayo Clinic explains that BCG-unresponsive NMIBC is defined as persistent/recurrent high-grade Ta or T1 urothelial carcinoma within 6 months of completion of an adequate quantity of BCG or persistent/recurrent carcinoma in situ (CIS) (±Ta or T1 disease) within 12 months of completing an adequate course of BCG. Adequate BCG was considered to be 5 of 6 instillations of induction BCG and 2 of 3 maintenance treatments or 2 of 6 courses of the second round of induction. The only exception was patients who presented with high-grade T1 disease at their first evaluation after induction BCG.

What if your CIS became truly BCG unresponsive and you want to choose bladder salvage treatment?

There are ample of new treatments, including immunotherapy, which you can discuss with your urologist.
Dr. Peter Black of professor of UBC/Vancouver General listed it as follows.

Comparison Across Trials: CR in BCG-Unresponsive CIS

Pembro 102 40% 30% 21% ASCO 2019
ALT-803-BCG 11 82% 64% = AUA 2019
Vicinium 66 40% 28% 17% Sesen Business Update Nov 2019
r-AfIFN2a 103 53% 41% 24% SUO 2019
CG0700 45 - 50% 28% Packiam AUA 2018

I think they are listed # of cases, the complete response at 3 months, 1 year, and 2 years.
Also, there are other treatments like Gemstabine + Docetaxel (heated or unheated) with good efficacy.
I am sure there will be more options if and when your CIC becomes BCG unresponsive though the probability seems to be very low by reading the studies.


How fast bladder cancer grow?

I do not know either. I read somewhere it takes years. But, when I attended a patients education seminar, a speaker/urologist said he was very surprised to see cancer came back just 3 months after the cystoscopy of one of his patients.

If you can take it as just an entertainment, below is my attempt to estimate how fast bladder cancer can grow.

An epithelial cell of bladder is cuboidal with 10-20 micro meter (0.010 millimeter) long. A grain of table salt can contain 8,000 bladder cancer cells. It takes about 24 hours for our cell to divide into two cells. Normal cells only divide until they detect external signals which tell the cells to divide. Normal bladder cells divide every 40 days.
One of the hallmarks of cancer cells is that they do not stop dividing. So, 1 cancer cell becomes 2 in one day and 4 in two days, and 10,000 by 20 days. Technically speaking in perfect condition, a bladder cancer call grows to the size of a grain of salt in just 20 days. In reality, not that fast. I read also that cancer cannot grow more than the size of a grain of salt without getting the nutrition and oxygen from the blood. It will require a process called angiogenesis, in which new blood vessels are created to feed the cancer cells. Incidentally, the MERCK website says that we see blood in urine when the new blood vessels break due to contraction and expansion of the bladder. I do not know how long it will take for new blood vessels to grow to feed bladder cancer cells. There are also genes that influence
the creating of the new blood vessels, but I have not looked into it yet. Still, cancer cells need to compete for resources with normal cells and among themselves, and that might affect too.

Joe, Thanks for taking the time to provide me with such a thorough response. I did go to a major cancer center to get a second opinion. This doctor wants to do another cystoscopy to see the bladder himself and if red spot is as described by the first dr. He will send me for bcg treatments for 6 weeks.....starting right after the cysto. If he see's a larger spot or tumor then he will do another turbt prior to bsg treatment. I think he is very thorough and doesn't want to strictly rely on another uro's notes. I also wonder how long it takes for CIS to grow? Does it always grow into the muscle? Can it stay as is for a long period? I was lucky they found mine. I went to a uro for BPH treatment and he finally did a cystoscopy and seen the spot and then we biopsied it. If not for bph I would have never known I had an issue. There are probably allot of folks with these problems that don't know until they have serious problems. I asked the dr if I could have had this for years but he said there is no way to tell. I also read the BCG effectiveness is boosted by maintenance treatments. Of course it is a concern if the bcg doesn't work. Then you have some tough decisions on how much more time you have to try other therapies before the CIS grows into the muscle or worse.

Sorry, I forgot to attach Genomic analysis of muscle-invasive bladder cancer. Among muscle-invasive bladder cancer patients, over 40 patients had mutations (some deleted) of P53 - tumor suppressor gene. CIS cancer cells also often show mutations of P53. Papillary low-grade cancer cells rarely have mutations of P53. It is noted that P53 is not only the cause of progression. Analyzing pathways and cell environment which contribute to progression is so complex and I do not understand it though mcuh researches have been done.

Hi Clyde,

Do you have the pathology report from the initial TURBT? It's good to make a file for all the medical records.
From what you described what you saw "a small red spot" what the urologist described "superficial and caught early", I think your prognosis looks good.

I too have a habit going down a rabbit hole to find relevant information over the internet. There are so many sites and there are many research papers on bladder cancers, sometimes with conflicting results. I will be careful not just taking in some number or a statement straight as it may confuse you more. I usually first refer to the American Urology Association guidelines to urologists for the treatment of NMBIC (non-muscle-invasive bladder cancers). Treatment is based upon the Risk Stratification as shown in table 4. Most NMIBCs are papillary type, which grows up into the lumen (empty area) of the bladder. The stages of NMBIC for papillary type has T0, Ta and T1, depending on how deep it has progressed. The grade for papillary type NMIBC is LG(low grade) and HG (high grade). The grade indicates how much cancer cells look different from normal cells. CIS has its unique stage and grade, which is Tis.

Link to AUA www.auanet.org/guidelines/bladder-cancer-non-muscle-invasive-guideline

Table 4 categorizes NMBICs into low risk, intermediate-risk, and high risk. All CIS is high risk, accordingly the recommended treatment is BCG. T1HG is high risk, accordingly the recommended treatment is also BCG. TaHG, if it is not recurrence, is intermediate risk, so the recommended treatment is intravesical chemotherapy or BCG but shorter period than high risk.

Attached are the histology of normal bladder and CIS. In the normal bladder, all cells look uniformed. Umbrella cells (top layer) stretched out to protect urine to come inside. There is a think layer called the basement membrane just below the basal cell (bottom layer). This is like a glue between epithelial cells and lamina propria (connective tissue).

Another picture is CIS. Notice that cells are very abnormal-looking compared to normal bladder cells. But, if you look below the basal cells (bottom layer), they have not crossed the basement membrane into lamina propria (the connective tissue). This is the typical feature of CIS. But, CIS is known to progress to the Lamina propria layer and into the muscle layer. I assume that when your urologist said that your CIS was early stage and superficial, the urologist meant that your CIS had not crossed the basement brane.

So, the question is why when the behavior of CIS tends not to go up like a papillar type and not go under beyond the basement membrane to lamina propria (T1 area), but indeed if not treated it tends to progress to lamina propria and muscle layer. A clue is found by its genomic analysis. P53, which is known as a tumor suppressor gene is often found in muscle-invasive cancers. P53 is rarely mutated Low-Grade NMIBCs but P53 mutation is often found in CIS. It is also noted P53 mutation is also found in high-grade papillary type bladder cancers.
See gene mutations of MIBC.

In terms of the treatment for CIS, there have been several studies. The largest random study was done in 2005
by the European Organization for the Research and Treatment of Cancer. pubmed.ncbi.nlm.nih.gov/15947584/

203 of 293 (68.1%) patients who received Intravesical BCG had a complete response.
158 of 203 (51.5%) patients who received Intravesical chemotherapy had a complete response.

Because every cancer is different even among CIS and every patient is different, Some patients do not respond well to BCG treatment. In such a case, there is an option of early cystectomy or several options for bladder preservation treatment.

Thanks for the response Sara.Anne. Your experience is encouraging. Hopefully I can get the same results. The more I read about CIS the scarier it sounds.