This was indeed a case of hepatosplenic T-cell lymphoma (HSTL), gamma-delta type.  Characteristically, lymphadenopathy was absent and there was no peripheral involvement at presentation.  Interestingly, however, the typical intrasinusoidal marrow involvement was a minor feature second to an interstitial process.  Perhaps it was just caught at a progressed stage.  The immunophenotype was fairly typical: CD2+, surface CD3+, CD4-, CD5-, CD7 partial dim, CD8 partial dim, CD16+, and CD56/CD57-.  One reader pointed out that these lymphomas are usually CD4- and CD8-.  This is true; but a solid subset will express partial CD8+ as this case did.  Another interesting feature of this T-cell lymphoma is its predilection for expression of multiple KIR isoforms, for those of you keen on flow cytometry.  Cytogenetic studies also showed the characteristic isochromosome 7q and associated trisomy 8.  The spleen was also removed after diagnosis and representative images are shown below.

While it was more specifically named hepatosplenic gamma-delta T-cell lymphoma in the REAL classification, the WHO 2001 and 2008 classification calls this entity simply hepatosplenic T-cell lymphoma, as alpha-beta rearranged TCRs are found in a minority of cases.  From my perspective, the main differential diagnoses here are:

1) gamma-delta T-large granular lymphocytic leukemia: often a very difficult distinction to make, though g-d T-LGLLs are quite rare (alpha-beta T-LGLs much more common).  From my reading, T-LGLLs will often express some CD5 and/or CD57 (rather than CD56 in many HSTLs) and have the activated cytotoxic phenotype of TIA-1+, granzyme B+, and perforin+ by IHC.  HSTLs would be TIA-1+ but granzyme M positive rather than granzyme B.  Also, the isochromosome 7q/trisomy 8 associations are not classic for T-LGLLs.  Probably most importantly, though, is the clinical picture: T-LGLLs will be relatively indolent and involve the peripheral blood.

2) peripheral T-cell lymphoma (NOS): if classical HSTL features are not present

3) aggressive NK cell leukemia/lymphoma: Asian females, EBV-associated, surface CD3 neg by flow cytometry

I suppose in some respects an adult T-cell leukemia/lymphoma might also be on the differential but one would need a different clinical and immunophenotypic picture (patient from Caribbean, Japan, or Africa; positive HTLV-1 status; more atypical lymphocytes [flower cells], CD4+, CD7-, CD8-, CD25(strong+), CD26+.

Another important aspect to point out with regard to hepatosplenic T-cell lymphomas is their association with chronic immune suppression and/or antigenic stimulation.  The entity is also one type of post-transplant lymphoproliferative disorder (PTLD) – but of T cells.  Patients with inflammatory bowel disease or following renal transplantation are especially at risk for this complication, especially those treated with the TNF-alpha blocking agents and immune suppressing drugs like infliximab and azathioprine, respectively.

In Dr Foucar’s 3rd edition of Bone Marrow Pathology – a must-read – it is also emphasized that HSTLs may also present with an exuberant myelomonocytic proliferation, sometimes mimicking a chronic or juvenile myelomonocytic leukemia (CMML or JMML, respectively).

While there is much more to be said of gamma-delta T cells, my space is limited!  Suffice it to say, they are a minor subset of circulating and epithelial T cells involved in the innate immune response and the normal counterpart of primary cutaneous gamma-delta T-cell lymphomas, the other relatively well-described site for these cells to go mad.

Unfortunately for this patient, hepatosplenic T-cell lymphomas are very aggressive and median survival is <2 yrs.  It is ultimately difficult to reach allogeneic stem cell transplant and none of the standard chemotherapeutic regimens work well for the disease.  Early splenectomy, novel antifolates, cladribine, and monoclonal antibodies (including anti-CD52) have been employed with some effect but the optimal therapy is still years away at best.  The post-solid organ transplant cases have a particularly dismal outlook and unlike other PTLDs these immunosuppressive agents cannot simply be withdrawn.  These patients are treated with HyperCVAD and other extremely intensive chemotherapeutic regimens for any hope of survival.

Hope this was helpful!  Below are some helpful references…I highly recommend the Tripodo review from Nature Reviews Clinical Oncology.  And just for completeness, I have no financial disclosures regarding this case.

Belhadj K et al. Hepatosplenic T-cell lymphoma is a rare clincopathologic entity with poor outcome: report on a series of 21 patients. Blood 2003;102(13):4261-9.

Jaeger et al. Hepatosplenic gammadelta T-cell lymphoma successfully treated with a combination of alemtuzumab and cladribine. Ann Onc 2008; 19(5):1025-6.

O’Conner OA et al.  Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. BJH 2007;139:425-8.

Tey SK et al. Post-transplant hepatosplenic T-cell lymphoma successfully treated with HyperCVAD regimen. Am J Hemat 2008;83:330-3.

Tripodo C et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol 2009;6:707-717.

Vega F, LJ Medeiros, and P Gaulard. Hepatosplenic and Other γδ T-Cell Lymphomas. AJCP 2007;127:869-80.

The patient is a 44 yo M with a history of end-stage renal disease secondary to hypertensive nephropathy who was awaiting transplant > 2 years and undergoing peritoneal dialysis.  Fatigue and anemia and thrombocytopenia developed in late 2009 and because the anemia was attributed to his renal impairment, the thrombocytopenia was felt to be immune thrombocytopenic purpura (ITP) and he was treated with oral prednisone.  As you might expect, his fatigue persisted – as did the anemia and thrombocytopenia.  In addition, on review of systems in January he complained of drenching night sweats, fevers, a 30# weight loss and occasional nose bleeds.  Of significance he also had left upper quadrant cramping.  A physical exam at the time showed a palpable spleen and did NOT uncover any lymphadenopathy.

Labs showed the following:

WBC 6900 (normal diff), Hgb 8.6 L, MCV 101 H, Plt 37,000 L

BUN 66 H, Cr 6.35 H, Uric acid 15.9 H, LDH 1767 H (range 100-190), albumin 3.2 L, and slightly increased AST and ALT.  Calcium levels were normal.

A CT abdomen, bone marrow examination, and representative flow plots (with the population of interest painted red) showed the following.  Diagnosis?  Comments?

Below, you’ll find a list of links to some excellent Pathology-related websites from professional organizations, to study cases, to blogs.  These are all sites that I’ve found useful over the past three years as a resident at Albany Medical Center, and, hopefully, they can be of use to you as well!
(Note: none of the following links are sponsored; I just like them.)

Obviously, this list is far from comprehensive, and if you have more links that you find useful, please post them as a comment below, as I’m sure we are all always looking for additional great online resources!

Organizations:

• College of American Pathologists
• United States and Canadian Academy of Pathology
• American Society for Clinical Pathology
• American Board of Pathology

Journals:

• Modern Pathology (included with USCAP membership)
• Archives of Pathology (included with CAP membership)
• Journal of Pathology Informatics
• PubMed (for completeness’ sake)

Helpful Websites (not exclusive):

• Pathology Outlines (Great for IHC Stains/CD Markers, also COW)
• Pathology Links (Good link farm)
• Hopkins Unknown Conference (Registration required, free membership)
• PathMax (Another Pathology link farm, many links are out of date now, however)
• UPMC CP COM (Check AP case of the month too)
• TraQ Program (Case studies)
• USCAP (Excellent site for AP educations material)
• ASCP Journal Online (Electronic access included with American Society of Clinical Pathology membership, free for residents, good articles for rounds presentations and board preparation)
• May Clinic Online Labs (Free, registration required. Check hot topics and management strategies videos.)
• Derm 101 (Registration required. Some free, some not. One of the better derm sites)
• PathConsultDDx (Good site for differential)
• U of Utah (Gross images and tutorials)
• California Tumor Registry (Super anatomical pathology case of the month)
• Lab CE (MCQs for CP)
• Kansas State U Parasitology (Good tutorial for parasites)
• Cytology Stuff (for cytology study)
• UT Houston Coag Studies (cases for study coagulation)

Books with online resources (require purchase/registration):

• Sternberg’s Diagnostic Surgical Pathology
• Robbins Pathologic Basis of Disease
• Weedon (Dermatopathology):
• Rosen’s Breast Pathology
• Diagnostic Pathology: Genitourinary
• Gastrointestinal Pathology
• Flow Cytometry and IHC for Hematologic Neoplasms
• AFIP Fascicles

Identification?

Congratulations to Anonymous (x 3!), Kenneth, Chris, Victor, and Santoshpath who all got this correct! The keys to the diagnosis is the clinical history (location in nasal mucosa), exposure history (India), and histopathologic features of a polypoid mass containing mature sporangia (large, thick-walled spherical structures) and smaller internal sporangiospores (daughter cells). The sporangia stain with the fungal stains Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS), and may mimic the appearance of similar appearing fungi such as Coccidiodes immitis (as one viewer suggested) and Chrysosporium spp. (the agent of adiaspiromycosis). Myospherulosis, a non-infectious entity, is also in the differential diagnosis. The difference between these entities is in the size of the spherule/sporangia and the internal structures.

This organism was previously considered to be a fungus, but it is now considered to be an aquatic protistan parasite (classified under Mesomycetozoea, which includes parasites of fish and amphibians). Rhinosporidiosis is endemic in India, Sri Lanka, South America, and Africa.

Although the disease most commonly involves the mucosa of the nose, mouth, and conjunctiva, involvement of the skin, ear, genitals, and rectum has also been described. Disseminated infection has been described in 3 individuals.

Thank you all for viewing and writing in!

Thanks to everyone who wrote in for this case! This was, admittedly, a tricky case, since it is uncommon to see amastigote-type forms in peripheral blood. The reason these atypical forms were present is because this specimen was grown in culture and then innoculated in peripheral blood (artificial infection). Fortunately, the classic “C-shaped” trypomastigote forms with large kinetoplast were still abundant and allowed accurate identification. Although you wouldn’t expect to see a case like this in nature, this type of preparation may show up on proficiency test (since this material is typically grown in culture). Another important point of this case is that the forms on the thick smear resemble Plasmodium rings; thus, it is always important to examine BOTH the thick and thin smears!

Routine prophylaxis of tick-borne diseases is not generally recommended; instead, you should tell him to monitor himself for symptoms of a tick borne disease (e.g. headache, myalgia, fever, rash, influenza-like illness) and see a physician immediately should any symptoms appear.

The following insect was removed from the flank of a Medical Resident from Minnesota who had mistaken it for a ‘mole’ or ‘skin tag’. He notes that it had been present for at least 5 days. He is concerned that he is now at risk for an arthropod borne disease; specifically he is worried about Lyme disease. What should you tell him?

Click here to view the embedded video.

Here are some accompanying images to aid in identification.