Surgical Pathology Case Study: A 3 Year Old Male with a Suspicious Lesion on Imaging Following an Injury

Case History

The patient is a 3 year old male with no significant past medical history who presented to the ED with left lower extremity pain for 24 hours after falling while playing with family members. The patient’s mother was present at bedside providing the history, but was not present at the time of the fall. It is unclear how the patient injured his ankle, but family members noticed the child grabbing his ankle and suspected that he may have twisted it. After the fall, the patient was unable/unwilling to ambulate on the ankle. There is no history of fractures or cancer.

An x-ray and subsequent MRI were ordered of the ankle which demonstrated an expansile lytic lesion involving the metaphysis of the distal tibia measuring approximately 3.4 x 2.2 cm (Figure 1 and 2). The margins of this lesion are indistinct, and there is cortical irregularity at the anterior and lateral aspect of the distal metaphysis of the tibia, likely representing a pathologic fracture. The differential diagnosis includes infection, aneurysmal bone cyst, nonossifying fibroma, osteoblastoma and histiocytosis.

The patient and family then followed up with Orthopedics, who proceeded to perform a biopsy of the lytic lesion in order to determine the nature of the lesion. The results are below.

Figure 1. Xray of the distal tibia demonstrating the lesion.
Figure 2. MRI demonstrating the lytic lesion involving the metaphysis of the distal tibia.

Diagnosis

Received fresh for intraoperative consultation is a 1.1 x 0.6 x 0.5 cm aggregate of white-tan soft tissue fragments. Half of the tissue fragments are frozen and read out as “spindle cell proliferation. Consideration of low-grade vasoformative lesion. Defer to permanent,” with 3 pathologists consulting on the diagnosis. The remainder of the tissue not submitted for frozen section, as well as the entirety of a second container from the same lesion, is submitted for routine processing.

On microscopy, the biopsies demonstrate a moderately cellular proliferation of fasciculated spindle cells in a collagenous to myxoid stroma. Nuclei are predominantly oval with variably fine to granular chromatin. Many cells have moderate amounts of tapering eosinophilic cytoplasm, resembling strap cells. Inflammatory cells and osteoclast-like giant cells are admixed (Figure 3 and 4). Immunohistochemical stains demonstrate lesional spindle cells to be positive for CD31, ERG, and FLI1. AE1/AE3 and CAM5.2 highlight rare lesional spindle cells. SMA stains some stellate spindle cells, favored to represent associated myofibroblasts. Desmin, MDM2, CDK4, ALK, and S100 are negative in plump lesional cells (Figure 5 and 6). Overall, the features are consistent with pseudomyogenic hemangioendothelioma, a rare vascular tumor. Although more commonly present in soft tissue, primary bone cases have been reported. These neoplasms have some risk for local recurrence, but only rarely distant metastasis. A portion of tissue was sent to the University of Nebraska Medical Center to evaluate for a characteristic gene rearrangement (SERPINE1-FOSB) that is present in at least a subset of pseudomyogenic hemangioendotheliomas. This was negative.

The lesion was then curettaged by the surgical team.The patient and his family had two follow up office visits with the Orthopedics department. The first one, a week after surgery, was unremarkable. The second visit, two weeks after surgery, was notable for the patient developing a cutaneous rash on both arms and chest. Due to literature citing that these tumors generally arise in the soft tissue, the clinician suggested that the patient and family follow up with pediatric dermatology to ensure that this new rash is not related to the pseudomyogenic hemangioendothelioma. Unfortunately due to insurance, the patient and family had to see a dermatologist at a different institution, and no further visits have taken place.

Figure 3. Photomicrograph of the strap-like cells with tapering eosinophilic cytoplasm , and osteoclast-like giant cells.
Figure 4. Higher power photomicrograph demonstrating the appearance of the strap-like cells with tapering eosinophilic cytoplasmFigure 4.

Discussion

Pseudomyogenic hemangioendothelioma (PHE) is a rare vascular tumor that most commonly arises in the skin and soft tissues of the extremities. It is usually multifocal, appearing in multiple tissue planes, such as the mucosa, dermis, subcutis and skeletal muscle, in a variety of different anatomic sites. Although even less common, PHE can also involve bone (such as this case). PHE has a male predilection, typically appearing in the second to fourth decades of life. Of the most common symptoms that the patient presents with, pain appears to top the list, although it should be stated that only about half of the patients experience pain.

Grossly, skin and soft tissue PHE tumors appear firm, ill-defined and gray-white. When they involve bone, they appear as multiple discrete, pink-tan to dark brown hemorrhagic tumors with surrounding sclerosis, ranging from 0.1 to 6.5 cm in greatest dimension.

Histologically, PHE demonstrates plump spindle and rhabdomyoblast-like cells with densely eosinophilic cytoplasm that grows in sheets and fascicles. The cells can be mistaken as rhabdomyoblasts because of the eosinophilic cytoplasm that pushes the nucleus to the periphery of the cell. Immunohistochemical studies are very helpful in order to determine a diagnosis of PHE. AE1/AE3, ERG, FLI-1 and CD31 are positive, whereas CD34, desmin and S100 are negative. Karyotyping has revealed a fusion of genes SERPINE1-FOSB that corresponds to the recurrent translocation t(7;19)(q22;q13). In this case, the SERPINE1-FOSBgene rearrangement was negative, but could possibly be due to a variant fusion gene.

Making a histologic diagnosis can be difficult for a Pathologist, due to the wide variety of differential diagnoses that will need to be excluded first.

The differential diagnosis for a cutaneous tumor includes:

  • Cellular benign fibrous histiocytoma (lacks rhabdomyoblast-like cells and neutrophilic infiltrates, contains mitotic figures, and is negative for cytokeratin and CD31)
  • Spindle cell squamous cell carcinoma (usually in sun-damaged skin, with nuclear atypia and negative endothelial markers)
  • Epithelioid sarcoma (negative INI1, positive EMA and CD34, and a nodular architecture with central necrosis and more nuclear atypia)

The differential diagnosis for soft tissue tumors include:

  • Epithelioid sarcoma (see above)
  • Epithelioid hemangioendothelioma (usually intracytoplasmic vacuoles, positive CD34 and CAMTA1, and a t(1;3)(p36.3;q25) translocation resulting in WWTR1-CAMTA1 gene fusion)
  • Epithelioid angiosarcoma (vasoformative architecture with sheet-like pattern, nuclear atypia, high nuclear grade, frequent mitosis and irregular vascular channels)

 The differential diagnosis for bone tumors includes:

  • Epithelioid hemangioma (lacks rhabdomyoblast-like cells)
  • Giant cell tumor (lacks rhabdomyoblast-like cells and fascicles of spindle cells)
  • Osteoblastoma (lacks rhabdomyoblast-like cells and fascicles of spindle cells)

In a study by Inyang et al, when PHE involved bone, imaging would demonstrate multiple to innumerable discontinuous tumors throughout the affected bone, involving the cortex and/or medullary cavity of the epiphysis, metaphysis, or diaphysis. On x-ray and computed tomography, the lesions appeared as well circumscribed, lobulated and lytic, with a sclerotic rim on some of the lesions. On magnetic resonance imaging, T1-weighted images would appear dark, and T2-weighted images would appear hyperintense.

PHE has a tendency to recur locally, but rarely develops distant metastases. Since PHE presents as a multifocal disease and can be easily confused for a distant metastasis, care needs to be taken to ensure that a diagnosis of PHE is not overlooked.

Surgical ablation and excision is the standard treatment for a patient with PHE, with a few cases noted of patients being treated with radiotherapy and/or adjuvant chemotherapy, in addition to surgery. Everolimus and sirolimus have recently been found to be effective in cases of patient with PHE that had metastatic and relapsing multifocal PHE.

Figure 5. Immunohistochemical stains (part 1 of 2)
Figure 6. Immunohistochemical stains (part 2 of 2)

References

  1. Hornick JL, Fletcher CDM. “Pseudomyogenic Hemangioendothelioma: A Distinctive, Often Multicentric Tumor With Indolent Behavior.” Am J Surg Pathol. 2011; 35: 190201.
  2. Inyang A, et al. “Primary Pseudomyogenic Hemangioendothelioma of Bone.” Am J Surg Pathol. 2016; 40: 587598.
  3. Pradhan D. “Pseudomyogenic hemangioendothelioma of skin, bone and soft tissue; a clinicopathological, immunohistochemical, and fluorescence in situ hybridization study.” Hum Pathol. 2018; 71: 126134.
  4. Sugita S, Hirano H, Kikuchi N, et al. Diagnostic utility of FOSB immunohistochemistry in pseudomyogenic hemangioendothelioma and its histological mimics. Diagn Pathol. 2016;11(1):75. Published 2016 Aug 11. doi:10.1186/s13000-016-0530-2

-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.

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.

I Had a Blast

Hi again everyone!

Welcome back. Last month I talked about a colleague of mine, a fellow student who’s pursuing a career in pathology. The month before that I wrote a bit about Just Culture and how those of us in laboratory medicine ought to act as leaders for patient advocacy—especially when it comes to putting the needs of patients first. And in the spirit of progressing career timelines and fortuitous transitions, this month I want to talk about a place where Just Culture is tangible, where “patient come first” is a mission statement, and where I just spent the last month rotating in their Department of Laboratory Medicine and Pathology: The Mayo Clinic.

Image 1. Commemorative statue of the Mayo brothers in a park in front of the main building of the downtown campus at Mayo Clinic in Rochester, MN.

Before I go any further, if you haven’t seen the PBS Ken Burns’ documentary, I highly suggest you do; it’s fantastic. There are also a few excellent books on the hospital’s history and vision here and here. But back to the rotation: I can’t express how lucky I feel having spent time there or convey how much of a privilege it was to see pathology in a uniquely Mayo way. What I can do is try to talk a little bit about my experience and what that translates to regarding a culture of advocacy and collaboration; and I’ll share a case conference I presented on my last day in a topic I find fascinating.

Image 2. Ken Burns presents The Mayo Clinic: Faith, Hope, and Science on PBS, which aired September 2018.

Mission, Vision, and Values

As with any hospital, academic center, clinic, etc., you’re always going to have a driving philosophy that anchors the values of that particular institution. Some of my experiences in larger academic centers tout their strides at the forefront of medicine and translational research, others advertise that they treat the whole person body and spirit. Community hospitals sometimes lean into their integral part of, well, their communities as a center for trust and health. Sometimes institutions have specific populations to cater to or work intensely with industry and boast strong contributions to medical science. At the Mayo Clinic you’d be hard pressed to miss the message (in various forms) that “The Patients Come First”—in fact that line from many years ago comes from Dr. William Mayo delivering a commencement speech at a Rush Medical College graduation. (I was so happy to see so many Chicago-Mayo Clinic connections!)

Image 3. Dr. W. Mayo articulated the concept of patients’ “needs come first” in a graduation speech at Rush Medical College in Chicago on June 15, 1910.

It becomes very obvious that this culture of advocacy permeates into the daily proceedings there. The hospital makes a strong point to celebrate outreach, education, and research; and clinicians are given a cultivated environment in which to flex muscles of compassion for patient outcomes. It makes you a better clinician, and I argue, person. Everyone at this hospital has a voice and a seat at the table. I was continuously encouraged to interact with staff, clinicians, residents, fellows, and patients and contribute what I thought would benefit patient care. A unique perspective as a visiting medical student with previous MLS experience was both noted and celebrated.

Leadership in Pathology

In many of my pieces on this blog, I frequently discuss how we should champion active roles in testing stewardship, policy advocacy, and promoting positive patient outcomes. Granted, when you find yourself in larger, resource-rich, tertiary academic centers you can really push the envelope for progress. But generally, those of us on the ‘scopes operate in this margin between clinical medicine and translational research. Where does our leadership come in? What does it look like? I think it comes in the form of prolific contributions to societal guidelines and interdisciplinary work. Nowhere have I seen this more than my month in Rochester.

So many of their residents contributed abstracts and presentations at this year’s USCAP conference, some winning awards. The academic cycle of producing something great requires strong support from your home institution and that’s exactly what I saw. Not only were folks supported for their trips to conferences per usual, they were celebrated—hallway handshakes, accolades at morning conference, discussions post-meeting, and social media shares. Which, by the way, social media is now a leadership staple. You can’t go far in the present day without utilizing technology both inside and out of your practice. The Pathologist recently celebrated their first #TwitterPathAward for residents like Dr. Tiffany Graham at UAB for contributions to medical education and advocacy in pathology. Mayo clinicians, including residents, consultants, pathologist’s assistants, and more share case studies, educational material, and cutting-edge pathology news in terabytes! I now find myself increasingly active on social media representing pathology and interests within our field.

Image 4. A spring 2015 issue of The Pathologist discussed the increasing presence of pathology in social media and the trends of utilization for medical laboratorians abound.

Side note: I’ve followed a number of these social media pages about cases in pathology for a while, and when I was fortunate enough to be part of ASCP’s Top 40 Under Forty 2017, I connected with lots of awesome laboratorians. Some of which I got to meet this month! Including a fellow blogger on this site, some celebrated path assistants, and a prolific parasite-discussing clinical microbiologist.

Case Conference

So, my presentation was intense! I’ve given plenty of case reports and conference discussions before, but this was an opportunity for me to explore quite a rare case in genetics and connect it with my interests in hematopathology. This was a case of a patient with Li-Fraumeni Syndrome (LFS) who developed therapy-related Acute Myeloid Leukemia. It’s not a current case and has since been signed-out and closed, but I’ll only be talking about the pathologic entities involved.

Image 5. Remember that power of social media I mentioned earlier? Well, what better way to share information for other medical students interested in pathology and interested in visiting Mayo Clinic! Having my presentation grab an honorable mention amidst their productive and busy residents was great! #path2path #hemepath #lablogatory

Essentially, this patient was found to have Li-Fraumeni after the second manifestation of an acute sarcoma—the first being osteosarcoma in her teenage years and the second breast cancer in her 30s. Both cancer diagnoses were treated accordingly, and this patient was going through routine work-up for anemia before being referred to the Mayo Clinic. By the time the patient reached there, the clinical investigation included a battery of testing for causes of anemia—all within normal limits—so a bone marrow examination was performed which revealed a significant, though not acute (<20% blasts), myelodysplastic process. A follow-up in-house bone marrow collection revealed hypercellular marrow, now in acute myeloid proliferation, with abnormal myeloid cell maturation and very complex cytogenetics. She had a very complex karyotype and several detectable mutations which were consistent with the WHO’s classification and description of therapy-related myeloid neoplasm as a sequale to the treatments she received for her prior cancers. In the setting of a patient with LFS, it is almost impossible to avoid malignancy. The following slides are a (very abridged) summary taken from my presentation of this patient’s case:

Figure 1. Official LFS and AML discussion. As mentioned, this is the case of a patient with a history of osteosarcoma and breast carcinoma, both treated, now presenting status-post initial work-up for evaluating possible causes for anemia. Ultimately, when reaching a bone marrow examination, certain myelodysplastic features were discovered, referring this case for close investigation and expanding the differential to include various hematologic malignancies.
Figure 2. This bone marrow biopsy was evaluated at an outside institution and was reported to this patient’s case at Mayo Clinic. Note the presence of myeloid lineage blasts cells in the peripheral blood (PB) and bone marrow (BM) evaluations, however, at less than 20% this would not immediately indicate any acute myeloid crisis. There is a definitive left-shift in maturity with myeloid dysplasia.
Figure 3. This bone marrow evaluation was done about a month after the previous reported one. Note the significant increase in myeloid blasts present in both peripheral and bone marrow specimens. This time, there was significant dysplasia noted in multiple lineages as well as particular changes in granulocytic lines including left-shift and pseudo Pelger-Huet cells present. This diagnosis was upgraded from myeloid dysplasia to acute myeloid leukemia in the setting of myelodysplasia. The blast count has now crossed the 20% threshold and there are marked changes to morphology in several cell lines. Hypercellularity and cytogenetic testing were also highly contributory in this diagnosis. Not included in this slide but CD34+ cells that previously expressed CD15, CD33, and CD38 were now negative for those three markers. This indicates decrease in maturity and a poorer prognostic and clinical assessment of this malignancy.
Figure 4. A peripheral blood smear at the time of the second bone marrow specimen. In almost every field photographed, there were myeloid blast cells present. No Auer rods were seen, but many blasts had granules. There was left shift, and some immature granulocytes were present. Erythroid immaturity was demonstrated with morphology and circulating nucleated RBCs. Abnormalities in granulocytic lineages were present with hypogranular neutrophils and pseudo Pelger-Huet morphology.
Figure 5. At nearly any age, this bone marrow needle core biopsy on H&E stain would qualify as hypercellular. At low to medium power this is clearly evident. At higher powers, note the presence of predominantly immature granulocytes (with very few, if any, mature PMNs) as well as numerous blasts—on H&E blasts appear differently, but appreciate the increased number of cells with active nuclei, condensing chromatin, and prominent nucleoli.
Figure 6. Back to traditional hematology staining, you can still appreciate this bone marrow aspirate’s hypercellularity. There is a labeled megakaryocyte (which appears slightly abnormal) to scale against the numerous, immature and left-shifted granulocytes which overrun the fields. Myeloid blasts are seen in high numbers, with granules and prominent nucleoli. Increased levels of mitotic activity, abundant (and some abnormal) myeloid precursors, and a highly proliferative picture is appreciated.
Figure 7. Li-Fraumeni Syndrome (LFS) is a rare genetic predisposition to soft-tissue sarcomas. It is a germline mutation of either TP53 or CHECK2, more often the former. The mutation usually has an autosomal dominant inheritance pattern and has very high penetrance, more so in females (possibly due to the fact that the most common presentation of tumor formation in LFS is breast cancer). Note that this patient had a clinical history significant for both breast carcinoma and osteosarcoma which were treated with chemotherapy and radiation.
Figure 8a. Patients with LFS often have a germline mutation in p53, a very significant tumor suppressor gene, which is implicated in a wide host of cellular functions. Located on the short arm of Chromosome 17, when mutated this gene affects a myriad of pathways including cell senescence, growth cycle response, proliferation, DNA damage repair from mutations, epigenetic, or exogenous causes, and programmed cell death. If this downstream protection against severe DNA compromise is lost, this becomes a highly pre-cancerous environment for Knudsen’s “second hit” to negatively affect cells and ultimately lead to a vast array of malignancies.
Figure 8b. I mean just look! P53 is a serious player in cell survival and DNA damage recovery. It is the archetype example of a tumor suppressor gene and is implicated in an ever-growing number of cell survival and growth cycle pathways—of course a loss of p53 function would set the stage for high-risk.
Figure 9a. The World Health Organization (WHO) and its updated guidelines for diagnosing and addressing hematologic malignancies now includes a lot of new data regarding the molecular biology of cancer. Its applications to diagnostics in hematopathology are growing daily. In these guidelines, the WHO classify AML into seven general categories. For reasons relating to her clinical history of cancers and treatment, as well as the timeline she presented with, t-MN or therapy-related myeloid neoplasm would be an appropriate diagnosis.
Figure 9b. The American Society of Hematology (ASH) and the College of American Pathologists (CAP) co-wrote guidelines for the diagnosis of AML and published a number of recommendations in The Hematologist in 2017-2018. Essentially, proper laboratory test utilization and incorporation with significant clinical history is crucial. Staying organized and operating within WHO guidelines for hematologic malignancy diagnosis is just as important. The ASH/CAP guidelines tell diagnosticians to think about several key questions when approaching AML which further underscores the values of consistency, efficiency, and appropriate utilization.
Figure 10a. The reason for establishing a diagnosis of therapy-related AML is a significant one. The use of Topoisomerase II inhibitors, alkylating agents, antimetabolites, and radiation therapy all affect the genetic components relating to this particular leukemia. To correlate further, the patient had a 5q deletion, a complex karyotype, a history of receiving all treatments related to this entity, and a presentation of myelodysplasia which rapidly progressed to AML.
Figure 10b. LFS can cause leukemia on its own, AML can present as a hematologic malignancy on its own too; but this patient’s clinical history and treatment history lean the diagnosis away from de novo cancer to a myeloid process in response to a latent treatment effect.

Why All of This Matters

There are two main reasons why all of this is important enough to discuss in a case conference. First, as clinicians from the bench to the bedside we should all strive to talk through the toughest diagnoses and share with each other what best practices, lessons, and goals we can reach together. In the setting of Li-Fraumeni Syndrome it becomes critical to evaluate new onset (especially myeloid) neoplasms. TP53 mutations are associated with the lowest survival rates in acute myeloid leukemia, which has its own diagnostic and prognostic classifications set forth by the World Health Organization. Furthermore, understanding appropriate patient history, clinical information, and what appropriate lab investigation means is crucial. It not only keeps the needs and interests of the patient first, but also translates to the proper utilization of resources for the best results in the best timelines. Potential future implications of concurrent ongoing work in hematopathology and molecular genetics may yield therapeutic and diagnostic benefits we are not yet aware of—we must constantly include updates as we practice.

Second, this was an opportunity to share insights into the diagnosis and discussion of AML that came from my clinical experiences before rotating there. I previously mentioned the demonstrated value of including clinical viewpoints for the benefit of patient care outcomes, so appropriately I incorporated these topics into this case conference and included the following points to consider:

  • Hematologic premetastatic niches

When I was in graduate school at Rush University in Chicago, I did some research in hematopoietic responses to various therapies in the context of proliferation and understanding mobilization for transplant and engraftment. In this work, I became familiar with the concept of a reactive stroma and a “pre-metastatic niche.” There are small microenvironments in which hematopoietic, mesenchymal, and endothelial cell lines in the bone marrow thrive and develop which are full of cytokines and cell-cell interactions. My work focused on mobilizing all three lines with a CXCR4 target, but the concept holds true when considering germline and somatic mutability. In effect, those cells with pre-malignant mutations can cluster and affect the environment of other cells maturing in the same setting. The same way invasive cells can break through barriers to metastasize and spread past their in situ conditions, the same mobilizing spread can grow from pre-metastatic clusters. This, again, opens the discussion for treatment targets in future LFS and/or AML patients as molecular pathology expands.

  • Acute Myeloid Leukemia and Myeloid Sarcoma

In a recently published paper in Histopathology, I was part of a team at the UAB hospital’s department of pathology which discussed their experience with patients diagnosed with myeloid sarcomas (MS). The point was to look for correlations with MS to connect the entity with age, sex, location of tumor, AML status, genetics, etc. Ultimately, what became the highest predictor of disease was a complex karyotype, consistent with other concurrent literature. With respect to this patient, what if there was another soft tissue (or other location) sarcoma alongside her myelodysplastic picture. What if she had a low blast count, or hypocellular bone marrow, or necrosis/fibrosis, or had received G-CSF? Would AML with myeloid sarcoma be considered in this diagnostic setting, would myeloid sarcoma be something to worry about in her future or in her clinical history as a misdiagnosis? The take-home message would be to pay close attention to patient clinical history and stay both focused on the current diagnostic work-up but also open enough to avoid pitfalls in diagnostic challenges.

  • Misdiagnosis in clinical settings

In a case report from 2017 I discussed a patient who had bilateral lung nodules several years after being treated for breast carcinoma. It was initially thought to be relapse but was later correctly diagnosed as de novo peripheral T-cell lymphoma (PTCL). This could have very well been the same clinical scenario, with a different cell lineage. The lesson gleaned here is the same as those ASH/CAP guidelines: stay organized, consistent, and purposeful with your testing and investigation. What came down to a few immunohistochemical markers in this PTCL case could make all the difference in another case. Missing the clinical history and specific genetic mutations present in this LFS/AML patient could have led to a diagnosis of a myelodysplasia related AML instead of a therapy-related one, especially in the setting of such a severe germline pre-disposition.

  • Future plans for this patient

I thought it was ultimately important to discuss the patient’s future plans with the audience. In pathology we often sign-off after we sign-out. So, in order to make sure we emphasize the patient’s best interests moving forward from a poor prognostic diagnosis, we discussed her enrollment in a trial aimed at improving bone marrow donor matching based on HLA and KIR combination typing. This a relatively new and promising concept in the literature which I hold high hopes for.

If anything, this was something I learned last month: in order for you to call the quality of care the highest possible, you have to uphold many standards, both clinical and non-clinical. Clinically we all have to share with each other the latest and greatest in modern literature and advances in interdisciplinary or translational research. Aside from this, however, we have to keep each other human and connected to our patients. I never like to hear the stereotypes in pathology that place us in lab medicine miles away from patient care; instead, we do things every day that impact our patients’ lives greatly. And when we keep ourselves connected to that fact, like the philosophy at the Mayo Clinic, then we can boast our quality of care—from small community hospital to academic trauma center. Because its not the size of the lens on the scope, it’s the vast scope of impact we look through in a lens of compassion.

There you have it. That’s my month at Mayo and a case conference in a nutshell. It was a fantastic experience and I have to say it—I had a blast!

Thanks for reading, I’ll see you next time!

And have a Happy Lab Week 2019!

–Constantine E. Kanakis MSc, MLS (ASCP)CM graduated from Loyola University Chicago with a BS in Molecular Biology and Bioethics and then Rush University with an MS in Medical Laboratory Science. He is currently a medical student actively involved in public health and laboratory medicine, conducting clinicals at Bronx-Care Hospital Center in New York City.

Gastric Cancer: A Multidisciplinary Approach

Maryam Zenali1*, Dmitriy Akselrod2, Eric Ganguly3, Eswar Tipirneni4 and Christopher J. Anker5*

1 Department of Pathology, 2 Department of Radiology, 3 Division of Gastroenterology, and 5 Division of Radiation Oncology, The University of Vermont Medical Center (UVMMC), Burlington, VT and 4 Department of Hematology Oncology, Central Vermont Medical Center (CVMC), The University Of Vermont Health Network, Adult Primary Care, Berlin, VT

*corresponding authors

A 57 year old woman with a personal and family history of breast cancer presented with early satiety and dysphagia for 5 months. Her abdominal computed tomography (CT) scan (Image 1 A) showed marked thickening of an apparently featureless gastric wall (A, blue arrows indicating the mucosal [rightward pointing] and serosal [leftward pointing] aspects of the gastric wall). Prominent gastrohepatic lymph nodes were noted as well. Her fluoroscopic upper GI study (Image1 B), following administration of barium and effervescent crystals (a double contrast effect to allow for mucosal evaluation), showed thickened rugal folds (B red arrow) and pooling of barium within an antral ulcer (B blue arrow). A subsequent CT scan (Image 1 C) after administration of intravenous and enteric contrast, confirmed marked diffuse gastric wall thickening (C blue arrows again indicating the mucosal [rightward pointing] and serosal [leftward pointing] aspects of the gastric wall) (Image 1, composite radiographs A-C).

The gastric body distended poorly with insufflation and demonstrated thickened, erythematous, edematous folds with erosions (Image 2, endoscopy image). On endoscopic ultrasound, the total thickness of the stomach was 12 mm with expanded wall layers in the proximal stomach to the antrum and a thickness of 3.5 mm in spared areas. Biopsies were obtained; the corresponding H&E and keratin stains are provided (Image 3, composite photomicrographs A-B).

Image 1. Composite radiographs.
Image 2. Endoscopy image.
Image 3. Composite photomicrographs.

Based on the original radiographic imaging that led to the biopsy, what are the differential diagnoses?

Surgical Pathology Case Study: A 42 Year Old Woman with an Enlarging Mass of the Forearm

Case History

A 42 year old female with a history of neurofibromatosis, hypertension and Hashimoto’s thyroiditis had noted a mass on her forearm approximately 15 years ago. According to the patient, the mass did not change in size and did not cause her any discomfort during that time. Approximately 6 months prior to presenting to her primary physician, the mass began to increase in size and caused discomfort and pain. Upon examination with the Orthopedic Surgery department, a 20 x 20 cm firm, smooth mass on her forearm with mild pain on palpation was noted (Image 1). On MRI, the mass appeared to partially surround the radius and ulna, and encased the median, radial and ulnar nerves. A needle core biopsy was subsequently performed on the mass revealing a high grade malignant peripheral nerve sheath tumor (MPNST). A CT scan of the chest showed no evidence of metastatic disease. During her clinical visit, the use of neoadjuvant chemotherapy and chemoradiotherapy were discussed, but based on the large size of the mass, tumor response would have to be significant in order to allow for limb conserving surgery. At the time that the patient was seen, MPNSTs were not known to be chemosensitive and the chances of significant tumor response was very low (clinical drug trials have since shown some improvements in this area). In light of the poor response to systemic therapy of these tumors and the potentially toxic side effects of chemotherapy, the decision was made to proceed with amputation of the arm through the humerus.

Diagnosis

Frozen sections were sent from all the major peripheral nerves, including the ulnar, radial and median nerves. There was no evidence of any tumor consistent with a high-grade MPNST, although there was evidence of neurofibromas. There were atypical cells with hyperchromasia in the ulnar nerve margin, however, this was not considered to be consistent with a high grade MPNST. Received in the surgical pathology lab was an above elbow amputation consisting of a 30.0 cm long distal arm, an attached hand measuring 17.0 cm in maximum length., and a 4.5 cm long exposed humerus. The specimen is covered by grossly unremarkable skin, with a palpable mass in the mid-portion of the forearm. Sectioning reveals an 18.0 x 12.0 x 11.0 cm well-circumscribed mass composed of bulging, myxoid, white-tan tissue with central areas of hemorrhagic degeneration and yellow-tan friable tissue (Image 2). The bulging white-tan tissue is mainly found peripherally and encompasses approximately two-thirds of the mass. The mass is confined to a thin translucent lining and does not grossly invade neighboring soft tissue or overlying skin. The radial, median and ulnar nerves are adjacent to but not invaded by the mass, although the distal aspect of the mass shares a translucent, myxoid-like tissue with the peripheral nerve sheath of the ulnar and median nerves.

In addition to the standard bone and soft tissue margins that are taken, representative sections of the mass with the closest approach to the overlying skin are submitted. Sections demonstrating the relationship of the distal mass to the radial, median and ulnar nerves are submitted in separate cassettes. Lastly, representative sections sampled from various areas of the mass are submitted in an additional 15 blocks.

Histologically, the tumor consisted of spindle cells arranged in a fascicular pattern with intermittent whorled areas. The cells contained pleomorphic, hyperchromatic nuclei and intervening myxoid hypocellular areas. Mitotic figures were observed with sparse areas of necrosis and hemorrhage. S-100 was ordered on the prior biopsy of the mass, which was weakly positive. Based on these findings, the specimen was signed out as a malignant peripheral nerve sheath tumor.

Image 1. Above elbow amputation with a large forearm mass.
Image 2. Longitudinal cross section of arm demonstrating a bulging, white-tan mass with areas of hemorrhage and necrosis.

Discussion

Malignant peripheral nerve sheath tumors (MPNST) are locally invasive tumors that are associated with medium to large nerves (as opposed to cranial or distal small verves) and commonly recur with eventual metastatic spread. Common sites for metastatic spread include lung, liver, brain, bones and adrenals. They are usually found in adults between the second and fifth decades of life, and account for only 5% of malignant soft tissue tumors. Approximately half of MPNSTs will occur sporadically, with the other half generally arising in the setting of neurofibromatosis type 1 (such as in this case). There is a high clinical suspicion for MPNST if the patient has a history of neurofibromatosis type 1 or if the tumor arises within a major nerve component.

Grossly, MPNST will present as a large, poorly defined, fleshy tumor that runs along a nerve and involves adjacent soft tissue. Often, these tumors will have areas of hemorrhage or necrosis and can track along the length of a nerve. Histologically, the tumors are composed of monomorphic spindle cells arranged in fascicles, palisades and whorls, with compact comma-shaped, wavy or buckled hyperchromatic nuclei with alternating hypocellular foci. (Image 3 and 4). Mitotic figures and necrosis are common, and although S-100 is considered the best marker for MPNST, there is a lack of specificity and sensitivity for immunohistochemical markers. Due to the lack of immunohistochemical markers and molecular findings, as well as the variability associated with the cells, it has traditionally been difficult to diagnose MPNST. The differential diagnosis includes fibrosarcoma, monophasic synovial sarcoma, desmoplastic melanoma, and pleomorphic liposarcoma. Goldblum et al put forth the idea that a diagnosis of MPNST can be made if the tumor falls into any one of the following three categories:

  1. The tumor arises along a peripheral nerve
  2. The tumor arises from a pre-existing benign nerve sheath tumor, such as a neurofibroma
  3. The histologic features are consistent with a malignant Schwann cell tumor

Unfortunately, due to the aggressiveness of the tumor and high recurrence rate, MPNST has a poor prognosis with a 2 year overall survival rate of around 57% and a 5 year survival rate around 39%.

Image 3. Low power photomicrograph showing a spindle cell neoplasm arranged in a fascicular pattern.
Image 4. High power photomicrograph demonstrating spindle cells with hypercellular nuclei in a whorled arrangement and adjacent myxoid hypocellular areas.

References

  1. Case of the week #443. Pathology Outlines. http://www.pathologyoutlines.com/caseofweek/case443.htm. Published November 15, 2017. Accessed March 10, 2019.
  2. Frosch MP, Anthony DC, De Girolami U. Malignant Peripheral Nerve Sheath Tumor. In: Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran Pathologic Basis of Disease, 8th edition. Philadelphia, PA: Elsevier, Inc. 2010: 1341-1342
  3. Guo A, Liu A, Wei L, Song X. Malignant Peripheral Nerve Sheath Tumors: Differentiation Patterns and Immunohistochemical Features – A Mini-Review and Our New Findings. J Cancer. 2012; 3:303-309. http://www.jcancer.org/v03p0303.html. Accessed March 9, 2019.
  4. Hirbe AC, Cosper PF, Dahiya S, Van Tine BA. Neoadjuvant Ifosfamide and Epirubicin in the Treatment of Malignant Peripheral Nerve Sheath Tumors. Sarcoma. https://www.hindawi.com/journals/sarcoma/2017/3761292/cta/. Accessed March 10, 2019.
  5. Ramnani, DM. Malignant Peripheral Nerve Sheath Tumor. WebPathology. https://www.webpathology.com/case.asp?case=499. Accessed March 9, 2019.
  6. Shankar V. Malignant peripheral nerve sheath tumor (MPNST). Pathology Outlines. http://www.pathologyoutlines.com/topic/softtissuempnst.html. Revised September 12, 2018. Accessed March 9, 2019.

-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.

Hematopathology Case Study: A 39 Year Old Woman Presenting with Persistent Cough and Pericardial Effusion

Case history

The patient is a 39 year old woman presenting with a persistent cough. Upon work up, a pericardial effusion is noted. Pericardiocentesis is performed and a smear made from the pericardial fluid reveals atypical lymphoid cells.

Cytology of the Pericardial Fluid

Image 1. Pericardial fluid cytology showing reactive mesothelial cells surrounded by benign small lymphocytes and atypical large lymphocytes.

Additional imaging reveals an anterior mediastinal mass measuring 12.6 cm. Excision of the mediastinal mass is performed. Sections of mediastinal mass show a variable population of lymphoid cells ranging from small to medium lymphocytes and some atypical large lymphocytes. These atypical large lymphocytes have irregular nuclear contours with abundant cytoplasm, vesicular chromatin and prominent nucleoli. These atypical large lymphoid cells are consistent with Hodgkin Reed-Sternberg cells. Abundant eosinophilic and scattered neutrophilic infiltration are noted within the nodules. These nodules are surrounded by dense collagen bands.

Image 2. H&E sections showing small to medium sized lymphoid cells with scattered large Hodgkin Reed-Sternberg cells infiltrating through fibrosis (frozen section A) and inflammatory cells predominantly eosinophilic infiltration (B) Fascin (C) and CD30 (D) are positive for atypical lymphoid cells.

Immunohistochemistry studies are performed, atypical large lymphoid cells are positive for CD30, Fascin and PAX5, while rare small to medium sized lymphocytes are positive for CD20, however, large atypical lymphoma cells are negative for CD20. Tumor cells are negative for CD3, CD5, CD15, LCA, ALK and EBER ISH. CD3 and CD5 highlight the reactive T cells in the background.

Image 3. PAX5 is positive in some tumor cells.

Overall, the case is consistent with nodular sclerosis classic Hodgkin lymphoma.  The presence of sheets of large lymphoma cells is suggestive of the syncytial variant.

Discussion

Nodular sclerosis classic Hodgkin’s lymphoma (NSCHL) subtype has a distinct epidemiology, clinical presentation and histology. NSCHL is more common in females with peak aged between 15 and 34 years. The risk is higher in high socioeconomic status. The patients are presenting with particularly mediastinal mass and 40% B symptoms.

NSCHL can be distinguished from the other subtypes of Hodgkin’s lymphoma (HL) with characteristic histologic features. There is a nodular growth pattern and the nodules are surrounded by collagen bands representing nodular sclerosis.  The lymphoma is composed of variable number of Hodgkin Reed-Sternberg (HRS) cells, small to medium sized lymphoid cells and non-neoplastic inflammatory cells, predominantly eosinophils, neutrophils and histiocytes. HRS cells have multinucleated or binucleated with irregular nuclear contours and prominent nucleoli. HRS cells induce fibroblastic activity by expressing IL-13 and the fibrosis begins in the lymph node by invaginating into the lymph node along vascular septa.

Immunophenotypically, the lymphoma cells are mostly positive for CD30 and 75-85% positive for CD15. Association with EBV can be demonstrated with EBER in-situ hybridization.  The malignant lymphocytes in NSCHL are variably expressing CD20, PAX5 and CD79a, however, T cell antigen markers, particularly CD4 and CD2 are aberrantly expressed in NSCHL.

NSCHL is classified mostly as grade 2 and the prognosis is better than the other subtypes of HL.  Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is the most frequent induction regimen for NSCHL patients with over 70% response rate.

Patients with Syncytial Variant Nodular Sclerosis Classic Hodgkin Lymphoma experience a lower than expected rate of complete therapeutic response with shorter progression-free than non-SV NSCHL treated with standard therapy. Syncytial Variant NSCHL should therefore be recognized as a high-risk subgroup within the otherwise traditionally docile NSCHL classification. This case fits the classic presentation for syncytial variant with presentation as bulky (mediastinal) disease.

References

  1. Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin’s Lymphoma. Cancer J. 2009 Mar-Apr;15(2):129-37.
  2. Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (Revised 4th Edition). IARC: Lyon 2017.
  3. Sethi T, Nguyen V, Li S, Morgan D, Greer J. Differences in outcome of patients with syncytial variant Hodgkin Lymphoma compared with typical nodular sclerosis Hodgkin Lymphoma. Ther Adv Hematol 2017, Vol. 8(1):13-20.

Ayse Irem Kilic is a 2nd year AP/CP pathology resident at Loyola University Medical Center. Follow Dr. Kilic on twitter @iremessa.

Kamran M. Mirza, MD, PhD, MLS(ASCP)CM is an Assistant Professor of Pathology and Medical Education at Loyola University Health System. A past top 5 honoree in ASCP’s Forty Under 40, Dr. Mirza was named to The Pathologist’s Power List of 2018. Follow him on twitter @kmirza

Just Say Know! From Mentoring to High Performance: A Resident Perspective

As pathologists, we are responsible for increasingly intricate anatomic pathology and clinical laboratory services in a continually changing healthcare landscape that requires us to integrate emerging technologies for improved quality of medical care while also being hypervigilant to cost control and efficiency. Hospital systems working under managed care business models seek to expand their coverage networks and boost the number of patients served, and as such, it is going to be very critical for the next generation of pathologists to develop and implement the management skills and techniques necessary to effectively advocate for investment in their departments and meet such goals.

The problem, however, is that we are largely shielded from these issues during our undergraduate and even graduate medical education experiences. We focus, of course, on the basic sciences and clinical skills, which are undeniably important; however, we get significantly less instruction or discussion on functioning within our health care system, addressing quality issues, or general leadership training that is indispensable and highly valuable for practicing physicians.

Earlier in the summer, I saw a number of pathology folks on Twitter promoting and strongly encouraging residents to apply for the two-day “Just Say Know! From Mentoring to High Performance” program, formed through collaboration between ASCP and USCAP, on an approach to leadership, management, and business for pathology. I was highly intrigued and had a feeling this program was the sort of experience for which I had been looking. Traveling to Palm Springs in the middle of the Chicago winter was not a bad deal either!

Drs. Blair Holladay and David Kaminsky assembled an impressive collection of speakers for the weekend, which was divided into four focus areas: leadership, management, business and policy, and change. After an engaging introduction by Drs. Holladay and Kaminsky, current trainees Drs. Kabeer Shah and Melissa Hogan set the stage by highlighting the increasing importance of “management” and “leadership” as reflected in the ACGME milestones as well as recent literature suggesting expectations for newly-trained pathologists include these very skills (Post et al. Arch Pathol Lab Med 2017;141: 193-202).Above all, they encouraged all of the thirty residents and fellows in attendance to “be honest, be open, and be vulnerable,” and ask the tough questions of themselves to gain the most from the weekend.

Lotte Mulder from ASCP led an enlightening discussion on the differences between emotional intelligence (EI) and conventional IQ, as well as the critical need to be self-aware of how our emotions can affect our performance and to understand the extent of our own abilities, strengths, and weaknesses. Dr. Karen Kaul followed with a very timely overview of strategies for identifying mentors. She discussed how our mentorship needs will evolve over the course of our careers and that fulfilling the mentor role for another junior individual while having your own mentors is key to the professional development necessary in leadership positions.

 After lunch, Dr. Dan Milner from ASCP took us through some very interesting global health case studies that forced our group to think critically about the role of pathology and the clinical laboratory in underserved settings as well as the major obstacles and economic disparities that must be considered. There were a number of important teaching points from Dr. Milner’s international cases that will be equally helpful for understanding the disparities we encounter right here in our backyard.

Dr .Yael Heher led off the afternoon management focus series with a really comprehensive look into how she has championed quality improvement and patient safety reviews at her institution to address root causes for laboratory errors, followed by a well-timed interactive session in which we divided into groups to use the six sigma methodology to work in concrete steps through a real-life laboratory error. It was a great opportunity to see people from different institutions and backgrounds bring unique perspectives to a common problem. The first day of the program concluded with a very unique session on art and leadership in which Dr. Kaminsky led us into Downtown Palm Springs to view the Palm Springs Babies art installation set up by David Cerny. Our powers of observation as pathologists were put to the test as we were asked to describe and interpret the meanings behind the exhibit in the same way that we often use visual evidence in our day-to-day work.

The second day of the program focused on business and policy with talks by Dr. Gary Procop on how pathologists can help integrate interventions into the laboratory to improve system-level metrics and by Khosrow Shotorbani on how laboratory data can be used to optimize laboratory services in the model of the rideshare service, Uber. The morning also included an interactive session on negotiation skills, in which each of us assumed the roles of departmental chair and owner of a private practice group negotiating with newly-hired pathologists. The weekend concluded with Dr. Nathan Johnson’s 18 steps to make change a part of an organizational culture, which was based on his experiences in academic research, military operational theory, and real-life lab experiences.

The weekend provided an incredibly impactful and high-yield array of discussions, so much so that I am already finding myself applying many of the strategies and techniques described over the weekend in my role as chief resident as well as to some of the changes and initiatives that I am hoping to bring to our department. Most important, though, were the opportunities to interact with my peers from around the country. We all face similar challenges as residents, and the opportunity to learn each other’s perspectives and approaches to similar issues was just as illuminating as the structured portions of the program. I hope that the ASCP and USCAP continue to offer the Just Say Know! Program and enthusiastically join all those pathology folks on social media promoting the program last summer with my own strong recommendation to challenge yourself and be open to new ways of learning by considering participating in this event!

From Twitter, @Blair_Holladay, December 12, 2018
Photo by Imran Uraizee

-Imran Uraizee, MD, is currently chief resident and a third-year anatomic and clinical pathology resident at the University of Chicago. He also manages the Department of Pathology Twitter account, @UChicagoPath. He majored in Biology at Duke University before earning his MD at the University of Rochester School of Medicine and Dentistry. Dr. Uraizee can be followed on Twitter at @IUraizee3MD.