Surgical Pathology Case Study: A 2.5 Year Old Male Who Presents with Jaundice and Pruritus

Case History

The patient is a 2.5 year old male who is being evaluated for a liver transplant versus biliary diversion surgery. The patient was born at 2 kilograms and went home with mom one week after birth. The patient was readmitted back to the hospital for evaluation of jaundice and since then the patient has been intermittently hospitalized for episodes of worsening jaundice, acholic stools, scleral icterus, and pruritus. At 5 months of age, the patient was diagnosed with progressive familial intrahepatic cholestasis, type 2, and was placed on the liver transplant list. As a result of the liver failure, the patient has developed coagulopathy, hypocalcemia resulting in seizures, and pruritus. The family history is significant for no known congenital liver diseases.

Table 1. Pertinent lab findings.

The father was worked up for living donation and was found to be a suitable donor, and is donating the left lateral segment of his liver.

Diagnosis

Received in the Surgical Pathology laboratory is a 700 gm, 23.5 x 14.5 x 3.5 cm explanted liver with an attached 4.5 x 1.2 x 0.4 cm gallbladder. The liver specimen has a smooth, green-red liver capsule without any grossly identifiable nodules or lesions (Image 1). The gallbladder has a yellow-pink external surface and is opened to reveal a 1.5 x 0.7 x 0.4 cm dark brown stone with a small amount of brown-yellow bile fluid. The liver is sectioned to reveal a smooth green-red cut surface (Image 2). No lesions are identified and minimal hilar structures are included with the specimen. Portions of the specimen have been taken for electron microscopy and frozen for future diagnostic purposes. Submitted sections include:

Cassette 1 and 2:   Hilar structures

Cassettes 3-15:   Representative sections of liver parenchyma

Cassette 16:   representative section of gallbladder

Image 1. Posterior aspect of green-tinged liver
Image 2. Cut section of liver

On microscopy, the trichrome stain highlights the presence of portal and centrilobular fibrosis, with focal bridging. However, regenerative nodule formation is not evident. The portal tracts contain sparse mononuclear cell infiltrates. Significant bile ductular proliferation is also evident, as confirmed by a CK7 immunostain. However, the native bile ducts appear unremarkable. There is also considerable hepatocellular and canalicular cholestasis in the centrilobular regions. Occasional multinucleated hepatocytes are also seen within the centrolobular zones. No steatosis is evident.

This constellation of histologic features is consistent with the clinical history of progressive familial intrahepatic cholestasis, type II.

Discussion

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders that affects bile formation and results in cholestasis of the liver, usually beginning in infancy and childhood. There are three types of PFIC, each related to a mutation in the liver transport system genes that are involved in bile formation. PFIC type 1 (PFIC1), which is also referred to as Byler disease, is due to impaired bile salt secretion related to a ATP8B1 gene that encodes the FIC1 protein. PFIC type 2 (PFIC2), which is referred to as Byler syndrome, is due to impaired bile salt secretion (similar to type 1), but is related to the ABCB11 gene that encodes the bile salt export pump, or BSEP. PFIC type 3 (PFIC3) is due to impaired biliary phospholipid secretion that is related to a defect in the ABCB4 gene that encodes the multi-drug resistant 3 protein, or MDR3.

PFIC is suspected to be the cause of cholestasis in 10-15% of children, and is also the underlying cause of liver transplants in 10-15% of children. The exact prevalence remains unknown, but is estimated to be between 1 in every 50,000-100,000 births. PFIC1 and PFIC2 account for 2/3 of all PFIC cases, with PFIC3 making up the other 1/3. PFIC is present worldwide, and there does not appear to be a gender predilection.

The main clinical manifestation in all forms of PFIC, hence the name, is cholestasis, and will usually appear in the first few months of life with PFIC1 and PFIC2. Recurring episodes of jaundice are also present in PFIC1, whereas permanent jaundice and a rapid evolution to liver failure are characteristic of PFIC2. In PFIC3, cholestasis is noted within the first year of life in 1/3 of all cases, but rarely will be present in the neonatal period. PFIC3 can also present later in infancy, childhood or even early adulthood, with gastrointestinal bleeding due to portal hypertension and cirrhosis being the main symptoms that the patient would present with. Pruritus is severe in PFIC 1 and 2, but has a more mild presentation in PFIC3. There have been multiple cases reported of hepatocellular carcinoma that are associated with PFIC2, but there so far have not been any cases of hepatocellular carcinoma reported that are associated with PFIC3. Other signs and symptoms that may be present in PFIC1 include short stature, deafness, diarrhea, pancreatitis and liver steatosis. When examining clinical laboratory results, patients with PFIC1 and PFIC 2 will have normal serum gamma-glutamyltransferase (GGT) levels, but patients with PFIC3 will have elevated GGT levels. PFIC1 and PFIC2 can be differentiated from each other by the higher transaminase and alpha-fetoprotein levels that are found in PFIC2. When analyzing the biliary bile salt concentrations, PFIC1 will have mildly decreased levels (3-8 mM), PFIC2 will have drastically decreased levels (<1 mM), and PFIC3 will have normal levels. In addition, the biliary bile salt:phospholipid ratio and the cholesterol:phospholipid ratio will be approximately 5 times higher in PFIC3 than in normal bile, due to the biliary phospholipid levels being dramatically decreased (normal phospholipid range = 19-24%, PFIC phospholipid range = 1-15%).

Histologically, PFIC1 and PFIC 2 will have canalicular cholestasis, an absence of true ductular proliferation, and periportal biliary metaplasia of the hepatocytes. In PFIC2, these manifestations are much more worrisome with more marked lobular and portal fibrosis, and inflammation, as well as having much more pronounced necrosis and giant cell transformation (Images 3 and 4). PFIC3 will show portal fibrosis and true ductal proliferation, with a mixed inflammatory infiltrate. In addition, cholestasis can be present in the lobule and in some of the ductules that contain bile plugs. Cytokeratin staining can help confirm the ductular proliferation within the portal tract. Mild or absent canalicular staining with BSEP and MDR3 antibodies will help to diagnose PFIC2 and PFIC3, respectively.

Image 3. Photomicrograph demonstrating cholestasis, centrilobular necrosis, lobular inflammation, and giant cells (H&E)
Image 4. Photomicrograph demonstrating portal, centrilobular and bridging fibrosis (Trichrome)

A diagnosis of PFIC is based on the clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis (such as biliary atresia, Alagille syndrome, cystic fibrosis and alpha-1 antitrypsine deficiency). Ultrasonography of the liver will be normal with the exception of a possible dilated gallbladder. At the time of the liver biopsy, a portion of tissue can be submitted for electron microscopy, which in the case of PFIC, can show canalicular dilatation, microvilli loss, abnormal mitochondrial internal structures, and varying intra-canalicular accumulations of bile. PFIC1 will have coarsely, granular bile on electron microscopy, whereas PFIC2 will have a more amorphous appearance. If biliary obstruction is noted on the liver biopsy, a cholangiography will need to be performed to exclude sclerosing cholangitis. If a normal biliary tree is observed, as in PFIC, bile can be collected for biliary bile salt analysis (which was discussed earlier in the laboratory results section). Differentiating between PFIC1, PFIC2 and PFIC3 can be quite troublesome, but luckily Davit-Spraul, Gonzales, Baussan and Jacquemin proposed a fantastic schematic for the clinical diagnosis of PFIC, which is presented as Figure 1.

Figure 1. Schematic proposed for the clinical diagnosis of progressive familial intrahepatic cholestasis

Ursodeoxycholic acid (UDCA) therapy should be considered in all patients with PFIC to prevent liver damage and provide relief from pruritus. Rifampicin and Cholestyramine can help in cases of PFIC3, but have been found to provide no improvement in PFIC1 or PFIC2. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. The total caloric intake should be around 125% of the recommended daily allowance. Dietary fats should come in the form of medium chain triglycerides, and care should be taken to check the patient’s vitamin levels to look for signs of vitamin deficiency. Patients with PFIC2 should be monitored for hepatocellular carcinoma, beginning from the first year of life. Ultimately, most PFIC patients develop fibrosis and end-stage liver disease before adulthood, and are candidates for liver transplantation. Diarrhea, steatosis and short stature may not improve after liver transplantation, and could become aggravated from the procedure. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy are possible alternative therapies for PFIC, but will require more research and studies to determine whether they are viable options.

References

  1. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4(1). doi:10.1186/1750-1172-4-1
  2. Evason K, Bove KE, Finegold MJ, et al. Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol. 2011;35(5):687–696. doi:10.1097/PAS.0b013e318212ec87
  3. Srivastava A. Progressive Familial Intrahepatic Cholestasis. J Clin Exp Hepatol. 2013;4(1):25-36. doi: 10.1016/j.jceh.2013.10.005

-Cory Nash is a board certified Pathologists’ Assistant, specializing in surgical and gross pathology. He currently works as a Pathologists’ Assistant at the University of Chicago Medical Center. His job involves the macroscopic examination, dissection and tissue submission of surgical specimens, ranging from biopsies to multi-organ resections. Cory has a special interest in head and neck pathology, as well as bone and soft tissue pathology. Cory can be followed on twitter at @iplaywithorgans.

Sex Hormones in Competitive Athletics

Image 1. Photo from NBC News.

Given my previous work in lab value changes in transgender individuals on hormone therapy, I was recommended to consider discussing the case of Olympic mid-distance runner, Caster Semenya. Although she is not transgender, this professional runner from South Africa has won her last 30 races and been scrutinized for her muscular build as having potentially higher levels of testosterone, a condition called hyperandrogenism. The International Olympic Committee’s (IOC) regulations require testosterone levels to be below a certain threshold for female athletes. 

While no competitor can achieve great victories without hard work and practice, there are certainly examples of outliers whose genetics give them an advantage. However, I don’t think we would endorse shortening Michael Phelps’ arms or lobotomizing chess master Bobby Fisher to decrease their inborn advantages for a level playing field.

But this gets into an area of ethics that I’m not an expert on, so instead I will stick to my area of science and examine what evidence may exist to support the IOC’s policy. Then I will extrapolate the results from our study of transgender individuals to see if hormone regulation may impact contributions to athleticism. The most strongly shifted lab values in hormone therapy for transgender individuals are red blood cells (including oxygen-carrying hemoglobin) and creatinine (byproduct of muscle used to monitor kidney function, but also reflects total muscle mass).

Once looking more closely at this topic, I realized there is a lot to say about the contributions of 1) muscle mass and 2) red blood cells to athleticism. So, I will discuss muscle mass this month and wait until next month to discuss hemoglobin levels (including athletic performance by blood removal/ doping).

Mid-distance running, which is Caster Semenya’s sport, is a mix of anaerobic and aerobic activity. This means having more muscle would be advantageous. This is supported by a study that was commissioned by the IAAF (International Association of Athletics Federation), which shows a 1.8-2.6% increased competitive advantage in short distance track events (400m, 800m and, 400m hurdles)1. However, this study had several limitations. First, the sample size was quite low with only 22 female athletes. Next, they use a p-value of 0.05 for significance without correction for multiple hypothesis testing (21 hypotheses tested representing each event), which increases the likelihood of a false positive result by chance.

What makes me curious is whether following the International Olympic Committee’s recommendations of lowering testosterone levels would even have a meaningful impact and improve competitiveness?

From my research, I know that adding testosterone to individuals assigned female at birth to transition to transgender males (TM ) does substantially increase creatinine (p<0.005, Figure 1)2 to male levels (baseline TW). This is likely not due to changes in kidney function (although this has not yet been proven), but rather due to increased muscle mass.

Figure 1.

However, the inverse is not quite true for transgender women who take combinations of estrogen for feminization and spironolactone to block the effects of testosterone. In these patients, we see a slight decrease in the creatinine (TW). While this decrease is statistically significant, the range is not clinically different from male creatinine levels. This concurs with the observations that musculature in transgender women does not change substantially upon taking hormone altering medication.

A more rigorous examination of muscle mass, performed by MRI measurement, determined that after 1 year of hormone therapy testosterone increased muscle mass in transgender men to biological male levels3, similar to our observations of creatinine. Further, they saw a significant reduction in muscle mass from baseline of transgender women on hormone therapy for 12 months, but it was still much higher than the muscle mass of biologic females4.

Therefore, were Casten Semenya to take testosterone blocking medication, I suspect there would be little impact on her overall muscle mass. Which is one of, if not the explicit purpose of taking testosterone lowering medicine. The strength of my conclusions is limited by the fact that we don’t know Casten Semenya’s testosterone levels, and furthermore a hyperadrogenic female is not the same as a male-to-female transgender woman.

As mentioned above, I will continue this discussion next month with an exploration of how testosterone lowering therapy could affect red blood cell levels, which would affect athletic performance differently.

References

  1. Bermon S and Garnier P. Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes. British Journal of Sports Medicine. 2017; 51(17): 1309-1314.
  2. SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.
  3. Gooren LJ, Bunck MC. Transsexuals and competitive sports. Eur J Endocrinol. 2004; 151(4): 425-9.
  4. Jones BA, Arcelus J, Bouman WP, Haycraft E. Sport and Transgender People: A Systematic Review of the Literature Relating to Sport Participation and Competitive Sport Policies. Sports Med. 2017;47(4):701-716.

-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and advancing quality in molecular diagnostics.

Safety Mistakes Your Lab Vendors Are Making

Laboratory professionals work with vendor representatives on a regular basis, and it is important to develop a good working relationship with them to ensure continued smooth operations in the department. They provide analyzers, products, equipment, and services. However, lab managers and employees may sometimes need to pay special attention to the actions a representative will take in the department or to some of the information they may provide. They should be experts about their products and processes, but they may not always be well-versed in your lab-specific process and the regulations.

One common safety mistake representatives make has to do with proper use of personal protective equipment (PPE). Not all vendors provide adequate PPE training, and many of the representatives may not have a laboratory background. Check to make sure vendors wear lab coats and gloves when working in the lab, and offer face protection if they open up instruments for repairs or diagnostics. Some reps bring their own lab coats and use them in different settings where they work. This is common, but it is also a violation of OSHA’s Bloodborne Pathogens standard. PPE used in a lab should never be taken out of the department (except as waste). Don’t let your vendor roll up his used lab coat and place it into his work bag for his next stop. Let him know about the regulations and offer him a new disposable coat upon each visit.

Another common issue with lab vendor reps is the use of laptop computers and cellphones in the laboratory. In some cases, they must use their computers to connect to instruments or to the company control center, but they should be decontaminated before removal from the department, especially if they were set on top of a lab counter or analyzer. Can reps use lab phones instead of their cell phones? It’s a worthwhile question, especially if cell phone use is against your lab policy (it should be), and if allowing vendor use of the cell phone will be a detriment to your lab’s safety culture. Again, as with PPE use, this safety knowledge may not be known by the vendor company, and certainly they need education about local policies as well.

Laboratory vendors that manufacture analyzers or that design testing processes know their products inside and out, but their set-up work and lab staff training should be monitored, particularly if the information pertains to local or state regulations. For example, some lab analyzers are put in place using an extension cord for power because the analyzer cord doesn’t reach the outlet. In many locales, the permanent of an extension cord is not permitted. Often a vendor will train staff to incorrectly dispose of bio-hazardous or chemical waste. That can lead to large citations and fines if the mistakes are not caught and corrected. If a new process or analyzer generates a new waste stream, be sure all waste regulations are being followed. For example, if an instrument waste line is tied to a drain, contact your local wastewater treatment center to obtain approval for drain disposal.

Labs need vendors and their representatives, they play a vital role making sure the department can provide quality patient testing and care. Be sure these valuable team members understand your operations, and provide lab safety training in order to prevent injuries or even lab-acquired infections. Ask questions, and communicate with the vendor to ensure that all lab safety procedures are being followed and that safety regulations are not violated. Keeping that eye on safety when dealing with vendors will help to ensure that the important relationships created with them will last.

Dan Scungio, MT(ASCP), SLS, CQA (ASQ) has over 25 years experience as a certified medical technologist. Today he is the Laboratory Safety Officer for Sentara Healthcare, a system of seven hospitals and over 20 laboratories and draw sites in the Tidewater area of Virginia. He is also known as Dan the Lab Safety Man, a lab safety consultant, educator, and trainer.

Microbiology Case Study: A 90 Year Old Male with Acute Appendicitis

Case History

A 90 year old male is transferred from his nursing care facility to the hospital for management of acute appendicitis. He had acute onset of right lower quadrant abdominal pain the morning prior to admission with fevers, rigors and drenching sweats. Imaging showed ruptured appendicitis with a fecalith surrounded by small pockets of fluid. His past medical history included dementia, heart disease, hyperlipidemia, hypertension, and glucose intolerance. He denied having any prosthetic joints or valves. Blood was obtained for microbiological analysis.

Laboratory Identification

Blood culture bottles flagged positive. Gram stain of the blood culture bottles showed medium to long gram negative bacilli (Image 1). The blood culture media was plated on blood, chocolate, and MacConkey agar. Aerobically, yellow colonies grew on the blood and chocolate agar. The yellow colonies turned red when exposed to 10% KOH (Image 2). Definitive diagnosis of Chryseobacterium gleum was obtained by MALDI-TOF.

Image 1. Gram stain from the blood culture bottle shows gram negative bacilli.
Image 2. Growth of the organism on chocolate agar with addition of 10% KOH solution (circled in black).

Discussion

Chryseobacterium gleum is a gram negative bacillus. They form yellow colonies that grow on blood and chocolate agar. They rarely grow on MacConkey agar and are non-fermenters when they do grow. Species of Chryseobacterium will turn red with addition of 20% KOH due to a pigment protein called flexirubin. Interestingly, our lab had only 10% KOH and the colonies turned red with this as well. Other key biochemical and physiologic characteristics of Chryseobacterium include being indole and oxidase positive and they are non-motile.

Chryseobacterium species are found in the environment and are usually not part of normal flora, therefore infection requires exposure of the bug to a debilitated patient in order to colonize the respiratory tract. However, infection of other body sites that may or may not have preceded respiratory tract colonization have been reported. These organisms can survive in chlorinated tap water. They are an emerging cause of hospital associated infections. No virulence factors have been studied. Risk factors for infection include immunosuppression, trauma, surgery, burns, foreign body implants and infused fluids. Of note, the patient was thought to obtain his Chryseobacterium bacteremia from his ruptured appendicitis.

For therapy, there are no definitive guidelines due to lack of understanding of resistance mechanisms. These antibiotics have been reported to have potential activity: Ciprofloxacin, rifampin, clindamycin, trimethoprim/sulfamethoxazole and vancomycin (reportedly for C. indologenes). Our patient was given Piperacillin/tazobactam, Ceftriaxone and metronidazole for two days, Cefepime for one day, Vancomycin for a day. Infectious disease recommended continuing piperacillin/tazobactam and starting trimethoprim/sulfamethoxazole and discontinuing vancomycin.

Antimicrobial susceptibility testing was performed and showed resistance to meropenem, aztreonam, gentamicin, and tobramycin. The organism was susceptible to piperacillin/tazobactam and trimethoprim/sulfamethoxazole.

References

  1. Tille P. Bailey & Scott’s Diagnostic Microbiology. Fourteenth Edition. Elsevier; 2017.
  2. Murray P. Medical Microbiology. Seventh Edition. Elsevier; 2013.
  3. Jain V, Hussain NAFA, Siddiqui T, Sahu C, Ghar M, Prasad KN. Simultaneous isolation of Chryseobacterium gleum from bloodstream and respiratory tract: first case report from India. JMM Case Rep. 2017;4(10):e005122. Published 2017 Oct 16. doi:10.1099/jmmcr.0.005122

-Angela Theiss, MD is a 3rd year anatomic and clinical pathology resident at the University of Vermont Medical Center.

-Christi Wojewoda, MD, is the Director of Clinical Microbiology at the University of Vermont Medical Center and an Associate Professor at the University of Vermont.

Hematopathology Case Study: A 71 Year Old Man with a History of Multiple Myeloma

Case History

A 71 year old man with a history of multiple myeloma presented with urinary incontinence and confusion and was found to have hyperkalemia with renal failure. Imaging showed extensive inguinal lymphadenopathy with concern for new lymphoma.

Excisional Lymph Node Biopsy

H&E 40x

Diagnosis

Sections show an enlarged lymph node with complete effacement of the normal lymph node architecture by sheets of medium and large plasmablastic cells. The cells have round nuclear contours, large prominent nucleoli and moderate amounts of amphophilic cytoplasm. Frequent apoptotic cells and scattered mitoses are seen.

Immunohistochemical stains show that the neoplastic cells are immunoreactive for CD138, CD38, CD19 (dim) and MUM1. They are negative for CD20, which highlights only small admixed B-cells. The cells are kappa restricted by kappa and lambda immunostain. The Ki-67 proliferation index is greater than 90%.

Taken together, the morphologic and immunophenotypic features are of a high grade plasmablastic neoplasm. The differential diagnosis includes plasmablastic myeloma and a plasmablastic lymphoma. Given the patient’s history of a kappa restricted plasma cell dyscrasia, plasmablastic myeloma is favored.

Discussion

Multiple myeloma is a neoplasm of clonal plasma cells that accounts for 10% of all hematologic malignancies. It is most commonly seen in adult and elderly patients with a male predominance. Plasma cells are generally characterized by the presence of a “clockface” nuclei and distinct perinuclear Hof or clearing of the cytoplasm containing a large number of Golgi bodies. The morphology of plasma cell tumors can range from small mature plasma cells to anaplastic or plasmablastic morphology. In this case, the cells showed plasmablastic (PB) morphology, which is characterized by a large nucleus, large nucleolus, fine reticular nuclear chromatin pattern, lack of nuclear Hof and less abundant cytoplasm than typical plasma cells.1

The differential diagnosis for cases with this morphology primarily includes PB lymphoma and PB myeloma with extramedullary involvement. PB lymphoma is seen more commonly in HIV positive patients or patients with other causes of immunodeficiency. It typically occurs in adults and has a male predominance. The tumor generally presents outside of nodes and is most frequently seen in the oral cavity/jaw. Patients tend to present with advanced stage and bone marrow involvement. While PB lymphoma is categorized as a distinct subtype of diffuse large B-cell lymphoma, PB myeloma is considered an atypical morphologic variant of multiple myeloma and is treated with therapy geared towards plasma cell neoplasms. 2

Making the distinction between these entities is difficult due to similarities in morphology and immunophenotype. Ultimately, the diagnosis is generally made based on the clinical context. In one series of “plasmablastic” neoplasms by Ahn, et. al., 6 out of 11 cases were called PB lymphoma, 2 out of 11 were called multiple myeloma and 3 were called indeterminate. Among the PB lymphoma patients, 4 were either HIV positive or had a history of immunosuppression. All 6 cases were positive for CD138 and negative for CD20 with EBV in situ hybridization positivity in 3 out of 6 cases. The multiple myeloma cases had evidence of end organ damage without lymphadenopathy. One indeterminate case had peritoneal nodules, lytic lesions and an EBV positive neoplasm in the bone marrow, which precluded a definitive diagnosis. 3

The immunophenotypic pattern seen in this case is typical of these neoplasms and is characterized by the expression of plasma cell antigens (CD138, CD38, MUM1) with either weak or negative expression of B-cell antigens (CD20). A study by Vega et. al. looked at the immunophenotypic profiles in nine cases of PB lymphoma and seven cases of PB myeloma. They found that the profiles were nearly identical.  All cases were positive for MUM1/IRF4, CD138 and CD38 and negative for CD20, consistent with a plasma cell immunophenotype. PAX5 and BCL6 were weakly positive in 2/9 and 1/5 PB lymphomas and were negative in all PB myelomas. A high Ki-67, overexpression of P53 and loss of p16 and p27 were present in both tumors. There was no evidence of HHV8 detected in either neoplasm. The presence of EBV-encoded RNA, was seen in all PB lymphoma cases tested and negative in all plasma cell myeloma cases. This was found to be statistically significant. 4

Unfortunately, both PB lymphoma and PB myeloma are aggressive high grade neoplasms with a poor prognosis. A study conducted by Greipp et. al. assessed the prognostic significance of plasmablastic morphology in a cohort of patients from the Eastern Cooperative Oncology Group Myeloma Trial E9486. They looked at bone marrow aspirates from 453 newly diagnosed multiple myeloma cases in a 5 year period. Of the 453 aspirates, 8.2% were classified as PB morphology.  The overall survival of patients with PB morphology was significantly shorter than patients with non-PB morphology with a median of 1.9 years compared to 3.7 years. There did not appear to be a relationship between PB morphology to other clinical or laboratory features such as age, sex, bone lesions or type of M-protein. 5

References

  1. M Srija, P Zachariah, V Unni, et. al. Plasmablastic myeloma presenting as rapidly progressive renal failure in a young adult, Indian Journal of Nephrology, Volume 24(1): 2014, Page 41-44.
  2. JJ Castillo, M Bibas, RN Miranda, The biology and treatment of plasmablastic lymphoma, Blood, Volume 125, 2015, Page 2323-2330.
  3. J Ahn, R Okal, J Vos, et. al. Plasmablastic Lymphoma vs Myeloma With Plasmablastic Morphology: An Ongoing Diagnostic Dilemma, American Journal of Clinical Pathology, Volume 144(2): 2015, Page A125.
  4. F Vega, CC Chang, LJ Medeiros, et. al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Modern Pathology, Volume 18: 2005, Page 806-815.
  5. PR Greipp, T Leong, J Bennett, et. al. Plasmablastic Morphology – An Independent Prognostic Factor With Clinical and Laboratory Correlates: Eastern Cooperative Oncology Group (ECOG) Myeloma Trial 39486 Report by the ECOG Myeloma Laboratory Group, Blood, Volume 91: 1998, Page 2501-2507.

Chelsea Marcus, MD is a Hematopathology Fellow at Beth Israel Deaconess Medical Center in Boston, MA. She has a particular interest in High-grade B-Cell lymphomas and the genetic alterations of these lymphomas.

Working with Generation Z: How Other Generations Can Adapt

This generation is very new to the workforce. In fact, the majority has not had a job yet as they are all eighteen and younger at the time of this writing. However, it is important to know how to adapt to this generation as they are starting to enter the workforce and many people communicate with this generation daily on a personal level.

This generation experiences a tremendous amount of uncertainty in their early lives. From the economic downturn in the late 2000s and school and concert shootings, this generation cares about security. This security is important on both a physical but also on a professional level; they want to make sure that they have professional stability. They care about making a difference, but not to the extent of Generation Y, the Millennial Generation.

There is some concern about this generation’s ability to connect with people on a long-term social level, mainly due to technological and social media advances. However, they do have a preference for face-to-face communication, so even if they do not come with that skill to the workplace, they can learn and adapt to it. Additionally, they are competitive and good multitaskers. They also have an entrepreneurial and independent spirit; they want to be in charge of their own projects and start their own companies. They are also looking into different ways to get their education that do not involve higher education and student debt. They are an imaginative generation with an intellectual curiosity.

Generation Z is the most diverse and open-minded generation, which means that they bring a plethora of ideas, background, concepts, and experiences. Leaders can utilize their diverse base to foster diversity of thought, practice, and skills at organizations. Including this generation as interns and entry-level workers is a good start to begin the process of mentoring this generation while learning from everything they bring to the organizational table.

lotte-small

-Lotte Mulder earned her Master’s of Education from the Harvard Graduate School of Education in 2013, where she focused on Leadership and Group Development. She’s currently working toward a PhD in Organizational Leadership. At ASCP, Lotte designs and facilitates the ASCP Leadership Institute, an online leadership certificate program. She has also built ASCP’s first patient ambassador program, called Patient Champions, which leverages patient stories as they relate to the value of the lab.

Global Health Narratives Interview Series: Meet Dr. Ann Marie Nelson

Ann Marie Nelson, MD has been a long-time hero of mine from afar. If you don’t know who she is and what she has done, then after reading this interview – you will see why! She is brilliant, selfless, kind hearted, and is simply an inspiration!

Dr. Nelson is an anatomic and clinical pathologist with more than 30 years’ experience in global infectious disease pathology and is committed to improving health care by promoting timely and accurate diagnoses, especially in parts of the world where resources are limited. She is currently Infectious Disease Pathology Consultant at the Joint Pathology Center and Professor of Pathology (visiting) at Duke University. The focus of her work has been in HIV/AIDS pathology in the US and in sub-Saharan Africa. Currently she works on educational projects and capacity building in anatomic pathology, and linking anatomic pathology to ongoing clinical and epidemiologic research. She is a founding member of InPaLa (International Pathology and Laboratory Medicine), ASAP (African Strategies for Advancing Pathology) and serves as co-chair of the subcommittee on education for the ASCP Partners in Pathology initiative.

Recently, I had the good fortune of meeting her in person and we sat down to talk about her amazing life and career, and what she continues to do to contribute to the world.

Q: Your entire career has been focused on improving the lives of others, through helping people get the care they need by improving access, education, and opportunity. What inspired you to pursue a career in global health in the first place especially as it relates to working through pathology?

A: I’ve always had a desire to travel even since I was young – I thought I wanted to do something involving travelling – something like photography. When I was older, I worked as a medical technician and the pathologist I worked under advised me to pursue medical school. It was Vietnam war time though, so the odds of going to medical school were 30:1 in California – but an opportunity arose to go to medical school in Guadalajara, Mexico. I did, and this was my first time living outside of the country. While there, I would participate in medical outreach projects orchestrated by the medical school to serve the rural community members. Naturally, since I was a Med Tech, I would run the laboratory point-of-care diagnostics for the outreach. We would screen for parasites for example, and this got me interested in infectious diseases.

I thought at first, I would pursue pediatrics, but pathology drew me in. In 1979, I took a course in ‘Parasites for Medical Technicians’ and met the folks in Tropical Medicine at UCLA.  I met Dr. Marietta Voge, who had written a book in Parasitology, and she became a mentor to me. Also, at the course, there was a pathologist named Dr. Daniel Connor, from the AFIP [Armed Forces Institute of Pathology], who was the editor of the ‘Atlas of Pathology of Tropical and Extraordinary Diseases’.  He gave a lecture on his fascinating work which took place all around the world, but at length in Uganda, and this was the inspiration for me.  I thought “that’s what I want to do!”. Dr. Connor would become like a father figure to me, and to this day my son calls him Grandpa. He has always been an important supporter and mentor throughout my career.

Fast forward, I finished my residency training in pathology and had the opportunity to spend four months at the AFIP working with the Infectious disease pathology department. A few months later, they invited me to take a job with them – which I did.

One of the hospitals in Africa that the AFIP supported was the Karawa hospital in the Ubangi territory in the former Zaire. I worked for a few months in the hospital there. While there, I met an African physician who had just returned from completing his master’s in public health at Tulane University. His name is Sambe Duale – I am now married to him. [She said this point with a smile and we both giggled at how charming this story was!]

Towards the end of my work at Karawa, I was asked to help bring pathology services to Kinshasa in a collaboration with the NIH, CDC, and the Tropical Medicine Institute of Antwerp to work on Project SIDA [the first project on AIDS in Africa]. I began working with Jim [James] Curran, Tom Quinn, and Peter Piot, who were some of the people leading the project. I worked at the Medical School in the Department of Pathology from the fall of 1986, and continued to work there until 1991 when we were evacuated out [by the US government due to the civil unrest that brought violence to the capital].

After that, I continued to work in infectious disease pathology in the US, waiting for my son to graduate from high school before considering working abroad again. In that time, I continued to be heavily involved in IAP [International Academy of Pathology], working to organize meetings, and contributing to building educational systems. I have given world-wide lectures in at least 23 countries, in all continents except for Antarctica. I retired from full time practice in 2015.

After my son graduated from high school, I decided to work in Africa again on a Fulbright in Tanzania and Uganda. Professor Nelson Sewankambo, who was the head of Makerere University College of Health Sciences, invited me to mentor the young pathologists at Makerere University. Robert Lukande was one of them – he is now Chair of the pathology department there. We worked and wrote several papers together, focusing on AIDS and autopsy. I gave lectures to multiple departments, mentored staff, and made connections. I went and built partnerships with everyone I could. You have to just go and talk to people, and ask them “What can we do?”

Q: You worked to conduct a landmark survey of African pathologists to determine the status of pathology resources in Sub-Saharan Africa. What were some of the key findings and how did you collect all this data?

A: The idea for the survey came when I was in Victoria Falls, South Africa for a pathology conference, when I was speaking with Martin Hale. The realization that most of the conference presenters were foreign pathologists, not African pathologists, struck us. We who had been working in Africa knew the answer as to why – there weren’t enough African pathologists. But there wasn’t any data, nobody knew how bad the situation really was. The idea evolved over the next decade, Dan Milner helped to put together an on-line survey that was translated into French and Portuguese.  When we finished the survey in 2014, there were less than 800 pathologists in Sub-Saharan Africa. The question then became, why aren’t there more African pathologists? How do you advocate for this to improve?

The data was largely based on person to person connections. We had to reach out individually, involving people who spoke multiple languages, made phone calls, sent emails…we worked for hundreds and hundreds of hours. You have to really just get out on the street and talk to people.

This was the starting point so that we could measure improvement. We are now working to update the survey and measure the progress that’s been made.

Q: I’ve heard you have the nickname “Mama” in and outside of Africa. How did this come about?

A: In 2006, it was the 100th anniversary of the IAP, and there was a pathologist from Nigeria who I had known, and he unofficially crowned me the “Mother of African Pathologists.” It stuck because people still refer to me as “Mama.” [Dr. Nelson told this story with a warm smile, and it was clear that this designation is an honor for her – I can easily tell that it is her kind soul and motherly nature that make people feel trust in her – “Mama” is absolutely a perfect fit.]


-Dana Razzano, MD is a Chief Resident in her third year in anatomic and clinical pathology at New York Medical College at Westchester Medical Center and will be starting her fellowship in Cytopathology at Yale University in 2020. She was a top 5 honoree in ASCP’s Forty Under 40 2018 and was named to The Pathologist’s Power List of 2018. Follow Dr. Razzano on twitter @Dr_DR_Cells.