Atrophy

• looks suspicious for adenocarcinoma at first glance.
• the nuclei are small and hyperchromatic.
• No prominent nucleoli are seen.
• Some glands are lined by obviously benign flattened atrophic epithelium.
• The immunostain for high molecular weight cytokeratin can be helpful in distinguishing between atrophy (fragmented basal cell layer) from atrophic variant of prostatic adenocarcinoma (no basal cell layer).

Atypical adenomatous hyperplasia

• It may show the infiltrative architecture of cancer,
• lacks the cytologic features such as prominent nucleoli.
• The immunostain for high mol. wt. Cytokeratin will show fragmented basal cell layer in most cases.

Post-Atrophic Hyperplasia

• Post-atrophic hyperplasia architecturally mimics adenocarcinoma
• lacks the cytologic features.
• In difficult cases, the immunostain for high mol. wt. cytokeratin can be performed which would show at least a few basal cells in post-atrophic hyperplasia.

Sclerosing Adenosis

• small glands with infiltrative growth pattern in a cellular spindled stroma.
• The plump spindle cells in the stroma are nicely seen here.
• The lining acinar epithelial cells lack cytologic atypia – no significant nuclear or nucleolar enlargement is seen
• Myoepithelial differentiation in basal cells of the acini of Sclerosing adenosis is illustrated with the immunostain for muscle specific actin.

Cowper’s Glands

• They have a lobular configuration and are often associated with skeletal muscle fibers
• The glands are lined by goblet cells distended with mucin.
• The small hyperchromatic nuclei are pushed to the periphery.
• Sometimes ducts lined by cuboidal cells are present in the center of the lobules.

Mucinous Metaplasia

• Mucinous metaplasia is seen in about 1% of prostates.
• It may occasionally resemble prostatic adenocarcinoma. However, it lacks prominent nucleoli and the does not show immunoreactivity for PSA and PAP.
• The cells are positive for PAS, mucicarmine and Alcian blue.

Prostatic xanthoma

• Prostatic xanthoma is an uncommon benign lesion that may mimic high-grade prostatic adenocarcinoma.
• It consists of lipid-laden macrophages that may be arranged in small circumscribed nodules or infiltrating cords extending into the stroma
• diffusely positive for CD68 (shown here), and negative for CAM5.2, PSA, and PSAP.

Alan Schiller (Mount Sinai) gave us a two-hour primer/review on cartilage tumors and David Klimstra from MSKCC gave an in-depth update on cystic neoplasms of the pancreas and peri-ampullary lesions.

Tomorrow (Saturday) morning, Jonathan Epstein is lecturing on practical GU topics and Elizabeth Montgomery addresses small bowel and esophageal pathology (both Johns Hopkins) and Jeffrey Myers (Michigan) goes into pulmonary lymphproliferative disorders and interstitial lung disease.

Finally, on Sunday Nour Sneige (MD Anderson) covers nonpalpable and spindle cell  breast lesions.  These were just our guest lecturers…we also have a great lineup of our own faculty, of course.

I feel lucky as a resident to be able to attend this conference so close to home.  To hear some of the pathologists speak who also write the textbooks I read is quite humbling.  At the same time, I realize just how difficult pathology is.  I have learned it’s not always the obviously unusual cases that are worrisome.  Those cases that will skip by me without my noticing the subtle (or not-so-subtle) pathology are the ones that really worry me.  Of course, my goal is to become a well-taught pathologist so those cases are few and far between.  Still, I suspect when my name goes on the signature line in the not-to-distant future, I will lose some sleep.

If you live in the Midwest or are interested in good Surg Path conferences for next summer/fall, I encourage you to check out the 2010 Midwestern Conference.  Information will be posted on our MCW department website (http://www.mcw.edu/pathology/MidwesternConference.htm).  For residents and fellows, especially, the deal is unbeatable.  $50 registration fee for all three days.  Hope to see you next year if you’re not already attending this weekend!

Click here to view the embedded video.

Have seen this story on a number of sites and with 2.0 technologies others are going to add their opinions such as here.

The stories are short on details as suit just filed but emphasizes importance of pathology and need for public to understand what pathologists do and for us in pathology to realize our patients expect no less than 100% from us if in fact there was an error made here.  Some may act without questioning the diagnosis or obtaining other opinions prior to initiating therapy.

From http://www.wbbm780.com/pages/4501411.php:

A Niles (IL) couple filed a lawsuit against NorthShore University HealthSystem (IL) and a doctor Friday after they allegedly misdiagnosed a woman with breast cancer and removed her right breast only to discover that the woman did not have breast cancer.

The suit, filed by Niles residents Ranna and Rajesh Dave, claims that Ranna Dave went to her gynecologist complaining of swelling, irritation and discharge of her right nipple on August 1, 2007.

Her doctor suggested she undergo a right nipple biopsy, and a specimen was sent to a lab and analyzed by Dr. Robert Goldschmidt, the suit alleges.

Dr. Goldschmidt issued a pathology report; diagnosing Ranna Dave with “invasive breast cancer” and her doctor, relying on the accuracy of the pathology report, recommended she undergo a right mastectomy.

On August 24, 2007, Ranna Dave’s right breast was removed at Rush North Shore Medical Center in Skokie and another pathologist analyzed a surgical specimen, the suit alleges.

“A pathology report was issued by Rush North Shore Medical Center indicating that the surgical specimen was negative for malignancy,” the suit said. An independent review of the findings by the hospital confirmed that Ranna Dave did not have breast cancer.

The Dave’s are suing Dr. Goldschmidt and NorthShore University HealthSystem, accusing them of medical negligence, improper diagnosis of cancer, personal injury, loss of consortium and institutional negligence.

Rush North Shore Medical Center and Dr. Steven Sandler are also listed in the suit as respondents in discovery, “as they have information essential to the determination of who should properly be named as additional defendants” in the case, the suit said.

Ranna Dave claims the incident left her with injuries of a “personal and pecuniary” nature, and her husband has lost affection, comfort, services and consortium of his wife.

In this particular instance, inflammatory bowel disease can be difficult to diagnose and manage as the biology and causes are still poorly understood.  Histologically, the findings may be non-specific and granulomas are actually rarely present on endoscopic biopsies (less than 30% of cases and perhaps much less than that).  And not all granulomas are Crohn’s disease.  Nonetheless, Jessica became an active participant in her health care and is clearly a bright student who now has some answers to questions long unanswered.

Perhaps Jessica Terry is a future pathologist with a keen eye for detail that is required.  I think the article also points out opportunities for pathologists to engage high school students and educate them about medicine and pathology.  It also points out the power and effectiveness of direct pathologist-patient communication, as in this case, with the power of second consultation with “fresh eyes”.

In our case, the presentation was quite classic as described in the literature and was recognized quickly by our hepatologist.  Her ceruloplasmin level (the copper carrying protein) was slightly low but was likely elevated due to an acute phase reaction.  Her urine and plasma copper were quite high (24 hour urine collection was 27180 mcg [normal 3-35 mcg]).  She underwent 4 consectutive days of plasma exchange with FFP as the replacement product and underwent an uncomplicated liver transplantation.  The following chart shows the drop in creatinine following plasmapheresis (extending the span of the red bracket) and the date of liver transplant (black arrow).

Her INR and bilirubin dropped similarly, although not quite back to normal before the transplant.  Because the clinical team suspected ongoing hemolysis and coagulopathy, she received a new liver when one became available.  As you can see in the H&E and trichrome stains of the native liver, there is clear cirrhosis.  Her hepatic parenchymal copper content (by ICP/MS) was 1103 mcg/g dry weight, which is “strongly suggestive of Wilson’s disease.”  A level of <40-50 mcg/g dry weight almost always excludes the disease.

I came into contact with this case on my Blood Bank rotation because we were asked in consultation to assess her for plasmapheresis.  Wilson’s disease is not included as an indication in the ASFA (American Society for Apheresis)’s recommendations for therapeutic apheresis, but a few case series have shown its effectiveness, especially in cases showing fulminant liver failure and hemolytic anemia.  Thus, it should probably be a category III indication (diseases with anecdotal benefit but for which there is limited data or conflicting results from published clinical trials).  The thought is that excessive copper accumulates in hepatocytes due to inherited autosomal recessive mutations in a copper transport gene, ATP7B, that codes for a P-type ATPase.  When this accumulation reaches some threshold, the liver begins to fail as hepatocytes die and release copper into the circulation, which damages erythrocytes through membrane damage or enzyme disruption.  This is thought to be the mechansim behind the hemolysis partly because of the strong, direct association of levels of serum copper and the severity of hemolysis.

Plasmapheresis effectively removes the toxic levels of copper in the circulation to disrupt the hemolytic cycle, most importantly sparing the kidneys of irreversible damage.  In some cases in the literature, plasmapheresis has been used effectively to obviate the need for liver transplantation, but in most of the cases it serves as a bridge to stabilize the patient in anticipation of a donor liver.  Many of these patients are female and have fit into an age range of 16-21, as was true in our case.

Random fact:  if you are looking for copper in your diet, you may find it in these foods: shellfish, nuts, chocolate, mushrooms, organ meats…among others.  See, you learn something new every day!

For my first post I’ll share an interesting case that my Blood Bank team last month was involved with, but is interesting from an Anatomic Pathology point-of-view too.  It’s identical to my post on my original blog (geniculating.blogspot.com) but I still haven’t posted the answer.  I’ve also changed some of the information to protect the patient’s privacy.

Case:

A 21-year-old female presented with a 5 week history of fatigue, anorexia, and mild jaundice. She was previously healthy with no past medical history, no medications, and no drug or medication use. The initial workup showed a normochromic, normocytic anemia (Hgb 11.5) and increased liver function tests and was negative for infectious mononucleosis and viral hepatitis. Just a few days after this basic workup her course worsened and she became more severely jaundiced and developed dark urine and right upper quadrant pain. She was admitted to a referring institution before being transferred to Milwaukee and the workup showed the following:

Afebrile and vital signs stable
Scleral icterus, jaundice, splenomegaly, and RUQ pain on exam

WBC: 13.5 H
Hgb: 6.5 L
Plt: 178
Creatinine: 2.2 H

ALT: 13
AST: 147 H
Alk phos: 17 L
Tbili: 42.9 H
Dbili: 12.6 H

INR: 3.1 H
Albumin: 2.3 L

LDH: 659 H
Haptoglobin: undetectable L
Retic: 11.79 H
Direct antiglobulin: neg.
Blood type: O+, Ab screen neg.

Peripheral smear: see image

ANA: within normal limits
Serum pregnancy test: neg.

Does anyone have a diagnosis? I’ll say that the peripheral smear is just of interest, not crucial to the diagnosis.  I thought it was just nice to see an image associated with the case.  I’ll post the diagnosis in a week with follow up photos in a new post and/or comment.

1) Molecular profiling may help determine patient’s response to cancer therapies, research suggests.

A pilot study of molecular profiling of tumors, helped to identify therapies that ultimately had an impact on the disease.The University of Texas MD Anderson Cancer Center and the Memorial Sloan-Kettering Cancer Center are “striving to profile individual tumors so that therapy can be personalized, which means that it has a better chance of working because it targets specific mutations found in that tumor. This also prevents patients from being exposed to drugs that have a limited chance of success, eliminating toxicity and improving quality of life.

2 )Scientists developing new techniques for detecting CTCs in cancer patients’ blood (Medscape Report)

Measuring “circulating tumor cells (CTCs) in the blood of cancer patients” gives “an indication of whether or not the patient is responding” to treatment.” Presently, “there is only one commercially available product to measure CTCs — CellSearch (Veridex LLC).” Now, one device in development “promises to be cheaper and faster,” say University of California-Los Angeles researchers. The “new technique is based on a microfilter device.”

3) Bladder cancer cells may have two distinct genetic patterns, research suggests.

Bladder cancer cells have two distinct genetic patterns, depending on whether they are invasive or not, say University of Southern California-Los Angeles scientists. The “discovery opens the possibility of monitoring the disease by a simple urine test,” which would enable clinicians to sidestep “invasive procedures.”

4) Immune cells could be reprogrammed to attack prostate cancer, scientists say.

Reprogrammed immune cells could become targeted ‘killing machines’ against prostate cancer.” In fact, “these reprogrammed T cells sharply reduced the levels of prostate specific antigen (PSA) in two patients with metastatic prostate cancer,” scientists at the Roger Williams Medical Center said. But first, the team had to “isolate a patient’s T cells from a blood sample and use genetic engineering techniques to make them sensitive to a molecule that only occurs in prostate cancer — prostate specific membrane antigen, or PSMA.”

5) Researchers say presence of certain variants in MC1R gene may increase melanoma risk.

Researchers from the University of Pennsylvania “analyzed 779 patients with melanoma and compared them to 325 healthy people.” The investigators found that the “presence of certain variants in the MC1R gene was linked with at least a twofold increased risk of melanoma, and was largely confined to those people who would not normally be considered at increased risk.”

Posted by Dr.Prashant A.Jani M.D.FRCPC

Global Digital Pathology Leader Further Expands Its Patents Portfolio Enabling New Forms of Image Query

Vista, CA – April 28, 2009 – Aperio Technologies, Inc., (Aperio), a global leader in digital pathology for the healthcare and life sciences industry, announced today that the United States Patent and Trademark Office has issued the company patent No. 7,502,519, covering systems and methods for image pattern recognition using vector quantization (VQ). This is Aperio’s second patent on the use of VQ for pattern recognition applications.

As pathology labs, hospitals, biopharma companies and educational institutions increasingly adopt digital pathology, they generate vast libraries of digital slides that play a critical role in disease management, medical research, and education. These libraries have historically been indexed for access with text-based labels such as tissue type, patient age, or primary diagnosis.

Now, Aperio’s VQ technology enables content-based image retrieval (CBIR) to allow pathologists and researchers to search libraries of digital slides using image data, and to efficiently retrieve similar images from a large image archive. The ability to search image archives using image regions of interest in addition to text-based searches represents a significant advancement in image query.

Vector quantization is a breakthrough technology providing a novel way to perform content-based image retrieval,” said Dirk Soenksen, CEO of Aperio. “The image pattern recognition technology covered by this patent is unique in that it does not rely on prior knowledge of image-based features, but involves statistical comparisons to imagery data that exhibit characteristics of interest.”

In addition to providing an efficient way to search large libraries of digital slides for image regions that match a given image, vector quantization also allows searching for exceptions, such as regions of an image which are different from previously characterized images.

Aperio’s patent portfolio encompasses all of the elements that comprise a digital pathology system, including digital slide creation, data management, advanced visualization, and image analysis. Aperio holds over 30 issued patents and pending patent applications world-wide and is the digital pathology leader in the global market with an installed base of more than 500 systems in 32 countries.

About Aperio
Aperio is digitizing pathology. We provide systems and services for digital pathology, which is an environment for the management and interpretation of pathology information that originates with the digitization of a glass slide. Aperio’s award-winning ScanScope® slide scanning systems and Spectrum™ digital pathology information management software improve the efficiency and quality of pathology services for pathologists and other professionals. Applications include education, remote viewing, archival and retrieval, basic research and image analysis. Aperio’s products are FDA cleared for specific clinical applications, and are intended for research and education use for other applications. For clearance updates and more information, please visit www.aperio.com..

Pathological Findings
Gross examination of the wedge resection specimen showed a three-centimeter well-circumscribed, grey-white friable mass with central necrosis. The mass was sampled for frozen and permanent sections.

Low-power H&E of the mass.

Medium-power H&E of the mass.

Microscopic examination revealed that the mass was composed of a tangled network of septate hyphal elements. The inflammatory reaction in the surrounding tissue was sparse. Closer inspection revealed distinct acute angle hyphal branching, and occasional well-formed fruiting heads were seen.

A high-power view showing branching hyphae and two brown-pigmented conidia.

A single row of phialides cover the surface of the round vesicle (center).

Diagnosis
Mycetoma, favor Aspergillus species.

Discussion
Aspergillosis is a ubiquitous fungal organism which can sometimes be found in the sputum of healthy people. Depending on a variety of factors (like host immune status, for example) the organism can cause any of three main clinical syndromes: allergic pulmonary aspergillosis, invasive aspergillosis, and mycetoma (as seen in this case). The morphology in this case is consistent with Aspergillus species, but further categorization is probably best left to culture.

Mycetoma usually occurs in an immunocompetent host via colonization of a pre-existing cavitary lung lesion, particularly those related to tuberculosis. Fungal organisms proliferate to fill the cavity, forming a mass. There is sometimes a significant host inflammatory response, and necrotic fungal organisms and debris may be present. Patients with mycetomas sometimes present with hemoptysis or productive cough, but many remain asymptomatic and their lesions are discovered incidentally. If the host becomes immunosupressed (especially neutropenic) the infection can become invasive.

References:
1. DoctorFungus.org
2. Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis of Disease, 7th ed. 2007. Elsevier.