Clinical Chemistry - Consultations & Lab Capacity

Background:
Clinical chemistry is usually the busiest section of a hospital laboratory.  To give you a sense of scale, a busy institution might handle 50,000+ surgical pathology cases each year.  Sounds like a lot, right, but clinical chemistry performs 1,000,000+ tests every year.  Most of the basic labs you (or someone you know) has ever received have gone through the clinical chemistry section: electrolytes, glucose, kidney function, liver function tests, and markers of a heart attack (E.g., troponin) are likely the tests with which you're most familiar; although the list of all tests offered is much, much longer.

The clinical chemistry section in Kijabe Hospital is no different.  So I wanted to share a call I received from the an Internal Medicine doc in the ED (also visiting from UWMC) that's a common call for lab med residents at home, highlights some important issues around how the laboratory here functions, and provides a nice segue to showcase the clinical chem resources here.

Lab Med Consultation:
The doc who called me noted that they were treating a number of patients for high serum potassium levels.  Potassium is a critical electrolyte for regulating the electrical potential across cell membranes, and thus really important for cardiac function: if potassium gets too low or too high, the patient can have a cardiac arrest.  The electrical potential is generated because positively charged potassium ions are highly concentration inside of cells, but relatively low in the circulating fluid (serum).  The doc asked, quite rightly, if the potassium levels could have been elevated because of red blood cell (RBCs) breakdown ("hemolysis"). 

At home, we wouldn't rely on a potassium from a hemolyzed sample because it may be falsely elevated because of RBCs having dumped their contents into the sample.  Treating this falsely elevated potassium can have disastrous consequences for the patient, so we always check for a pink hue to the sample after we centrifuge the RBCs to the bottom of the tube.  If the top, acellular section of the specimen is pink it's (usually) due to hemoglobin left behind from ruptured cells and we request a new specimen.  The hemolysis gets reported in the medical record and/or called to the clinical team!

Resolution:
I  asked the laboratory staff about our procedures for hemolyzed samples here and, not surprisingly, their procedure is the same: they won't report a potassium from a hemolyzed sample for fear of providing false information.  I was able to reassure my colleague that, in fact, they were getting truly elevated potassium concentrations.  That's basically the same as back home, but here's where things change.  Here, it's the laboratory staff that performs the blood draw.  So instead of requesting a new blood sample, the lab staff here draws another from the patient.  From what I could gather, the clinical team is NOT contacted directly in these circumstances.  And of course, there is no electronic medical record here.

How do we check lab values?
So how do we actually determine potassium concentrations?  I'll stay away from the detailed physical chemistry, but we use ion selective electrodes.  Usually this is a resin that selects for potassium ions, which changes the electrical potential across the resin, which we can detect.  For a platform, we use the HumaStar600 - this covers our electrolytes, as well as liver and kidney function tests. It looks like this:

Test Utilization
One question I've been asked is to evaluate test mal-utlization (over- or under-).  I think this is a really hard question to get at for a few reasons.  First, we don't have electronic records!  So I don't how to gauge what's being ordered.  Second, there are some different incentives here as compared to the US - namely, patients have to pay for their care (in cash, often prior to being seen), and lab capacity is somewhat lower.  In pathology we do get lots of PSA values; whether that's being over-utilized or not is up for debate, even in the US.  

In some upcoming blog posts I'll try to address some more of this process, including a first hand look from the patient's perspective in a foreign hospital.  Stay tuned!

Access to healthcare prevents deaths.

Cervical cancer (invasive carcinoma) is a mostly preventable disease, but only if people have access to regular health care. The use of Pap smear screening has already dramatically reduced the incidence of cervical carcinoma in countries with robust health care systems. The introduction of the HPV vaccine adds a second, extraordinary public health tool that promises to further reduce this form of cancer!  Sadly, despite these interventions there are a significant number of preventable deaths from cervical cancer.  

Today’s New York Times reported new estimates of deaths from cervical carcinoma (I’ve not been able to find a working link to the e-publication, but will post when available). The cited study, which excluded women with hysterectomies (and men), demonstrates mortality from cervical carcinoma at 4.7 per 100,000 white women and 10.1 per 100,000 for black women.  The study did not investigate the cause of the disparity, although previous work (also cited by the NYT and available here) indicates that deaths from advanced cervical cancer are associated with a lack of access to care, particularly for poor and non-white women.  

In Kenya, we’ve already seen quite a bit of invasive cervical carcinoma (see explanatory images and a discussion of “cancer” in this related post).  Kenyan women have limited access to routine screening with Pap smears, tend to present with more advanced disease, and have low survival compared to Western countries; these trends are associated with poverty and lack of access to care (Reference). Alarmingly, the death rate from cervical cancer for black women in the US (10.1 / 100,000 women) was comparable to that seen in low-income countries, just like Kenya.  Nicole is working on a similar project, tracking how the type and severities of cases we see in the Kijabe Hospital Pathology Department has changed overtime; she and Rochelle hope to compare these to a similar set of cases at our home institution.

This phenomena is not isolated to non-white women, or women in the developing world.  Poverty and lack of access to medical care are scourges that ignore color, race, and religion.  In some of the poorest areas of the US, in Appalachia, death rates from all forms of cancer are ~8% greater than the rest of the country (Reference).   The 13 states analyzed in this study, and their most Appalachian counties, were significantly more white (90.6% vs 71.8%), ~20% poorer, and had fewer high school graduates (22.2% vs 19.9%) than the non-Appalachian controls (37 states and the District of Columbia).  

I draw these distinctions because deaths from cancer cut across the lines that separate us: race, class, education, and language or nation of origin.  That said, poverty, living in rural areas, or otherwise lack of access to medical care puts people at higher risk of death.  Not just illness, but death.

So what is cancer?

So what is cancer, anyway?

By Josh & Rochelle

As Pathologists we deal with this question every day and while this might seem like a straightforward question, it requires some careful consideration.  Like any good question, trying to answer “what is cancer” leads us to a series of additional, equally interesting questions.  Before reading on, take a minute and fix a definition of cancer in your mind.  

Got one?  Ok, good. 

Cancers – and I emphasize the plural, because there are a great many different diseases that are all “cancer” – are a type of something that we generically call neoplasms (neoplasia simply means “new growth”). But not all neoplasms are cancers – so what’s the difference? 

I think most people would agree with us in saying that neoplasm is an uncontrolled, clonal proliferation of cells carrying a mutation in their genetic material (a “somatic mutation”) and that this uncontrolled growth may damage the patient.  That’s a good start, but let’s dig a little deeper.  This process starts from some precursor cell with the potential to divide that acquires genetic changes.  These changes (mutations) allow the cell to divide and give rise to daughter cells that keep dividing, all ignoring the usual signals that tell them to stop and/or die when they should.  We usually talk about “two hits” being required for this process called “transformation.” 

So when does a neoplasm become cancer?  We argue that “cancer” identifies a neoplasm that is locally destructive and/or can metastasize (spread to a different site).  It is these two features – local destruction and metastatic disease – that are clinically so very dangerous for patients.

Pre-Cancer vs Cancer

The body has stem cells to replenish damaged or shed normal cells at the end of their lives.  The gut and skin, for example, routinely and rapidly turn over new cells in predictable, genetically-regulated cycles that ensure we have an intact covering over our body to prevent infections, retain moisture, and absorb nutrients.  But the body has stem cells ready to replenish essentially every part of itself! 

Overtime, these stem cells can acquire transforming mutations either by chance, because the person has inherited a defective copy of the genetic proof-reading machinery, or due to an infection.  These cells can start to grow, ignore boundaries and stop signals, and produce a change that we can see with our eyes or a microscope.  These growths are also neoplasms!  Often, the body’s immune system can find a way to kill these misbehaving cells – especially when helped by a doctor cutting out this neoplasm. 

When neoplasms occur in the colon, the gastroenterologist typically sees polyps.  In the cervix (think HPV infection), a gynecologist finds discolored or eroded tissue.  In the breast, we might call this “ductal (or lobular) carcinoma in situ.” In the colon we call these “adenomas” and in the cervix we call this “intraepithelial neoplasia.”  The difference between each of these three processes is only in the spelling. These processes are all neoplasms arising from the lining of the body (mucosal surface or “epithelium”) and at the time of detection have not “invaded” into the underlying tissue.  Invasion is a complex process that requires eating and/or squeezing through some sophisticated networks of proteins that the body builds to separate its different compartments. 

The above examples – adenoma, carcinoma in situ, and intraepithelial neoplasia – are all types of “pre-cancers.”  This means they all have the potential to invade, but right now they are contained.  It’s like a misbehaving child who is grounded and stays in the house.  Catching these lesions early is precisely the goal of screening programs, like getting a Pap smear.  If left to their own devices, these lesions may (many do not) invade and from their spread throughout the body and wreak havoc. 

Examples in Pictures:

Colon: Normal, Intraepithelial, and Invasive 

Panel A shows normal colonic epithelium.  Part B shows an overgrowth of cells confined to the surface, an intra-epithelial neoplasm.  Part C shows glands running around beneath the surface; this is an invasive neoplasm (cancer), or in this case, an adenocarcinoma which indicates the cancer arose from gland-forming epithelium.  Panel A & C are from a case in Kijabe.

Breast: Intraepithelial and Invasive

Panel A shows a hypercellular duct, but all this new cells growth is contained within the duct.  If you look closely, you can see thin, spindled cells lining the duct and separating the glandular cells (in the duct) from the pale, pink, whispy supportive tissue (stroma).  Panel B is quite different, with duct-like structures invading throughout the stroma.  Unfortunately I don't have a great picture of normal breast epithelium to share, but it's basically a much smaller, less cellular version of Figure A with some glands hanging off the end.  Both of these figures are from a case we had recently in Kijabe.

Cervix: Normal, Intraepithelial, and Invasive

Panel A shows essentially normal epithelium (the layered, pink part that looks kind of like a basket weave at the "top" of the tissue in the image).  Panel B shows bigger, irregular cells in the epithelium with loss of the basket weave appearance.  Panel C shows destruction of the epithelium with those bigger, uglier cells invading the pink stroma in clusters and single cells. All of these images are from cases here in Kijabe.

Benign vs Malignant

These two terms, “benign and malignant,” are highly fraught and used quite imprecisely.  Benign means innocuous, but is an adenoma in the colon really innocuous?  How about ductal carcinoma in situ (DCIS) of the breast?  What about cervical intraepithelial neoplasia (CIN)?  None of them have invaded, all have the potential to invade and to go on and kill the person, but not all will progress. 

Many people – clinicians included – might call a colon adenoma “benign”, while deciding that DCIS is malignant – but biologically they are the exact same process.  Even the major US initiative that collects data on neoplastic diseases, the Surveillance, Epidemiology, and End Results program (SEER) run by the National Cancer Institute, includes DCIS as cancer but does not count colonic adenomas (non-invasive).  Many of us in pathology and the basic sciences object to this; why this distinction is made is an open question. 

Let’s ask the question one more time, but in a different way.  Are invasive colon cancer, invasive breast cancer, or invasive cervical cancer benign or malignant?  Of course they are malignant!  So perhaps the best thing we can say is that the pre-cancerous lesions “have the potential to invade and become cancers.”    

I'll add that "benign" doesn't necessarily mean "safe no matter what."  A couple of non-epithelial neoplasms demonstrate this nicely.  A meningioma is a "benign" brain neoplasm that doesn't infiltrate like a glioma and doesn't metastasize, but if in the wrong location can be fatal.  Similarly, uterine fibroids are a smooth muscle neoplasm called a leiomyoma. Usually the worst that accompanies a fibroid is pain or heavy periods, but someone with heavy bleeding from a fibroid could die from blood loss or secondary infection.   

Conclusions

I hope this has been a useful discussion of the terms “cancer,” “neoplasm,” “benign,” and “malignant.” These terms and diagnoses like those above carry enormous emotional impact for patients.  What we call these entities doesn’t necessarily reflect their biological behavior. For example, many people would consider DCIS to be “cancer” but wouldn’t be particularly perturbed by the diagnosis of a tubular adenoma in the colon.  However, they are fundamentally the same biological process. 

What is among us?

File under look-a-likes.

Histoplasma?  Platelets?

We went with platelet clumps.

Mt. Longonot

Saturday we set out for a 14.5 km hike from the Rift Valley floor to the top of a volcano with a collapsed caldera.

Just hitting the first little bit of steep stuff.  Nicole says this is one of the nicest photos I've ever taken.

After the first 3.1 km (including a few giraffe, gazelles, and a warthog) we came to the rim:

On the way, we passed lots of acacia trees covered in these funny little round things:

I wasn't trying to be artsy; I just accidentally had the camera in B&W mode.

These are little ant homes.  You can see them (as little black dot things) running along the sides of the "bulb."  The ants build these around the (massive) thorns on the acacias.  Thorns and ants provide extra defense against predators.  Sometimes the wind blows through them and makes a whistling sound, hence the "whistling acacia" or "whistling thorns." 

As we marched around the rim, we saw a neighboring crater (also a collapsed caldera).

The walls of the crater are really quite steep.  The views were tremendous, bordering on vertiginous.  Narrow paths, amazing views, and occasional hyena poop!

We elected NOT to descend.  Apparently some do... with equipment and guides.

Nonetheless, some pretty extraordinary views.  In the distance is Hell's Gate National Park.

Then we got to the top... and oh my, the view!  Plus refreshments and play time!

 Obligatory TAB.  I will be submitting these pictures to the manufacturer in a bid for a lifetime supply for our fearless leader/pathology attending extraordinaire.

Show offs.

Except for the red backpack in the background and the outmoded clothing, this could have been straight out of a martial arts movie.  "Rift Valley of Fury" or maybe "Enter the Rift Valley."

Then we set off for the rest of our circumambulation.

This also would fit in some classic martial arts movie.  Where's the Taoist Temple, Sifu?

There was just as much scrambling down as there was going up.

And yes, it was at least as dusty as it looks in the pictures...

Dirty feet.

 We all were quite pleased with ourselves at the bottom.  I had a refreshing, very cold, local ginger beer: Stoney Tangawizi.  It was amazing.  Too sweet and gingery for others... which worked for me!

Celebrate good times, c'mon!