Sunday, September 25, 2016

CAP16 Scientific Plenary Session - The Immune Checkpoint Revolution in Cancer Treatment: "Moonshot" or "Pie in the Sky"

I'm attending the scientific plenary session at the 2016 annual meeting of the College of American Pathologists in Las Vegas. The discussion is being led by Dr. Lynette Sholl (pathologist), Dr. Christopher Lathan (medical oncologist), and Barry Nelson (lung cancer patient).  Although not directly related to neuropathology, the discussion of the role of biomarkers as a means of directing treatment impacts every area of surgical pathology -- including neuropathology. Mr. Nelson recounted his journey through immunotherapy. Dr. Sholl talked about the paradigm shift that has occurred in cancer therapy by virtue of harnessing T-cell mediated immunity, particularly related to PD-L1. Dr. Lathan, who is Mr. Nelson's physician, talked about his relationship with both the cancer patient and the pathologist. It was pointed out that everything starts with the diagnostic tissue; and the pathologist, as custodian of that tissue, is at the foundation of every patient's battle against cancer.  Importantly, Dr. Lathan pointed out that Mr. Nelson is a outlier. Most patients, at this point in our understanding of treatment, do not respond to immunotherapy. Finally, Mr. Nelson pointed out that he does not consider himself cured, but rather "healed". Thanks to immunotherapy, he lives with cancer rather than being cured from it. That relationship with cancer in itself is a paradigm shift, much like the one we have already gotten used to with regard to AIDS.

Thursday, September 22, 2016

A case of recurrent ligneous conjunctivitis in an adult

Massive fibrin deposition in a case of recurrent ligneous conjunctivitis in an adult

I recently signed out a case of ligneous conjunctivitis, a rare form of chronic pseudomembranous conjunctivitis that is marked by a massive accumulation of fibrin. The term ligneous (from the Latin term for "woody") refers to the firm consistency of the large masses of fibrin that comprise the pseudomembranes. Ligneous conjunctivitis typically occurs in children but may recur in adults. Treatment is often challenging because the inflammation is persistent and the pseudomembranes often recur rapidly after excision. Histopathology shows two components: granulation tissue and sheets of intensely eosinophilic acellular amorphous material, which has been shown to be composed predominantly of fibrin. The mass of fibrin also incorporates other serum components such as immunoglobulin. Lesions that resemble those found in the conjunctiva can affect other mucous membranes including the larynx, vagina, and ear. Ligneous conjunctivitis is an autosomal recessive trait caused by mutations in the gene for plasminogen on chromosome 6q26.

Reference: Eagle, Ralph C. Eye Pathology: An Atlas and Text [2nd edition] page 55.

Wednesday, September 21, 2016

CAP16 Abstract Highlights - BRAF Mutational Status in Desmoplastic Infantile Astrocytoma/Ganglioglioma

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Ashley Greer and colleagues at the University of Colorado in Poster #194 discuss the BRAF mutational status of DIA/DIG.



Context: Desmoplastic infantile astrocytoma/gangliogliomas (DIA/DIGs) are rare, massively cystic tumors usually found in superficial cerebral hemispheres. They are characterized by prominent desmoplastic stroma, interspersed neoplastic astrocytes, and fewer, if any, neoplastic ganglion cells. While BRAF mutation is found in up to 50% of pediatric gangliogliomas, 2 recent studies found it was rare in DIA/DIGs. We sought to assess BRAF mutation in our DIA/DIGs.

Design: Review of departmental files from 2000–2016 was performed to identify DIA/DIGs, with review of clinical outcome, neuroimaging features, immunohistochemistry (IHC) for astrocytic and neuronal markers, and BRAF VE1. BRAF mutational assessment was undertaken in IHC+/equivocal cases, with additional next generation sequencing whenever possible.

Results: All 6 cases were cerebral-hemispheric, with overlapping neuroimaging features (Figure 76, A and C) and favorable clinical outcomes, although histologic differences were noted. Five of 6 tumors contained a predominantly neoplastic astrocytic population (Figure 76, B), while DIA/DIG from the oldest child (12 months) showed exceptionally large nodules of neoplastic ganglion cells (Figure 76, D). This was the only case to show either BRAF VE1 IHC+ and/or mutation (rare c1799_1800TG.AT; p V600D). Next-generation sequencing on this case, and a comparison astrocytic-dominant DIA/DIG, showed only mutation in BRAF, and not in 26 other commonly mutated genes.

Conclusions: Five of 6 classic DIA/DIGs were negative for BRAF mutation. Previous publications found mutation in 2 of 18 and 1 of 14 cases; 2 of 3 reportedly mutated cases were unusual in that they were in atypical anatomic locations (suprasellar, fourth ventricle), and 1 was in an older child (24-month-old). DIA/DIGs with unusual features may be more likely to show BRAF mutation similar to ganglioglioma.

Tuesday, September 20, 2016

CAP16 Abstract Highlights - Astrocytoma With a Distinct Molecular Signature: MYB Rearrangement and EGFR Amplification

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Doan V. Lai and colleagues at Oklahoma University and St. Jude's in Memphis in Poster #184 describe a combination of low- and high-grade molecular features in a pediatric diffuse astrocytoma.

Diffuse gliomas are uncommon in children but cause significant morbidity and mortality. Unlike diffuse gliomas in adults, pediatric low-grade tumors rarely progress to high-grade disease. Molecular studies are playing an increasingly large role in classifying and predicting therapeutic response in these tumors. MYB rearrangements are common in pediatric diffuse low-grade astrocytomas. EGFR amplification, which occurs in high-grade gliomas, however, is not reported in low-grade gliomas. We report the first case of a pediatric astrocytoma with both MYB rearrangement and EGFR amplification. A 3-year-old boy was found to have a T2 hyperintense, nonenhancing mass in the
left temporal lobe after minor head trauma. Histology showed a diffuse astrocytic tumor with low cell density and bland cytology. Mitotic figures were present, albeit focally, prompting a diagnosis of anaplastic astrocytoma. No necrosis or microvascular proliferation was identified. The Ki-67 labeling index, while generally low, rose to approximately 20%, corresponding to regions of mitotic activity. Interphase fluorescence in situ hybridization analysis showed both rearrangement of MYB in two-thirds of cells and amplification of EGFR in approximately one-quarter of cells. This combination of low- and high-grade molecular features in a pediatric diffuse astrocytoma is so far unique and may
represent the molecular correlate of the rare clinical scenario where a pediatric diffuse astrocytoma, with MYB rearrangement, progresses to high-grade disease.

Saturday, September 17, 2016

CAP16 Abstract Highlights - Naegleria fowleri: Understanding the Clinical Presentation and Autopsy Findings of a Rare and Almost Universally Fatal Central Nervous System Infection

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Alexander T. Damron and colleagues at Baylor College of Medicine in Houston discuss Naegleria fowleri CNS infection in Poster #114:


Naegleria fowleri is a free-living ameba known to cause primary amebic meningoencephalitis (PAM). Moreover, PAM is an acute, fulminating, and hemorrhagic infection that occurs in healthy young children with fresh water exposure in warm climates. It is postulated that Naegleria fowleri enters through the nasal passages and crosses the cribriform plate, where it reaches the subarachnoid space and disseminates into the olfactory lobes. Visvesvara et al (2007) performed a retrospective study of all reported N fowleri infections in the United States from 1937 to 2013 and found 3 survivors in 142 reported cases. Only 27% of the 142 cases were diagnosed before patient death. We present a case of a previously healthy 14-year-old boy who presented with fever, headache, vomiting, and altered mental status 8 days after swimming in a warm freshwater lake. Cerebrospinal fluid studies showed organisms consistent with amoeba (Figure 265, C). Despite neuroprotective measures and antimicrobial medications, the patient was pronounced brain dead 9 days after admission. Autopsy revealed the cause of death to be PAM from infection with N fowleri with cerebral edema and tonsillar herniation (Figure 265, D). Microscopic examination of the central nervous system revealed amoebic organisms infiltrating the meninges and diffusely involving the brain parenchyma in a perivascular distribution (Figure 265, A and B). The most critical aspect in treating patients with PAM is early detection and prompt initiation of multiple antimicrobials and neuroprotective measures.Despite current recommendations, the high mortality rate of these infections (97%–98%) suggests that an effective treatment for PAM is not yet known.

Friday, September 16, 2016

CAP16 Abstract Highlights - Heterotopic Cutaneous Meningioma: An Unusual Presentation Occurring in a Patient With a History of Intracranial Meningioma

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. I'll be attending the meeting this year. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Chibuike L. Enwereuzo and Jean Henneberry at Baystate Medical Center/Tuft University School of Medicine, in Springfield, Massachusetts  discuss an unusual case of cutaneous meningioma in a patient with a history of intracranial meningioma (Poster #106):

Meningioma is a neoplasm of the meninges and typically occurs in intracranial sites. Extracranial meningioma has been reported most frequently in the sinonasal tract and skull bone, most often as extension of intracranial meningiomas. Isolated heterotopic meningioma without contiguous intracranial lesion is extremely rare. A 56-year-old woman presented in December 2015 with 2 firm subcutaneous scalp masses: one in the left lateral and the other in the left superior regions. The clinical impression was that of lipoma. Pathologic examination revealed
an ill-defined proliferation of fairly uniform meningothelial cells, infiltrating a fibroblastic stroma with interspersed adipose tissue. The 2 excised lesions had similar histologic features. Immunohistochemical stains were performed, and the tumor cells were positive for epithelial membrane antigen and negative for S100. A diagnosis of atypical meningioma, World Health Organization (WHO) grade II, was made. The patient’s medical history was significant for intracranial meningioma of the frontal lobe in October 2007, which was diagnosed as atypical meningioma, WHO grade II. Comparison of the scalp masses to her prior meningioma revealed a distinctly different morphologic pattern. Considering the 8-year interval between the scalp tumors and intracranial meningioma, it is unlikely that her most recent tumors represent a recurrence or metastasis of the intracranial tumor.

Thursday, September 15, 2016

CAP16 Abstract Highlights - Extraventricular Neurocytoma: A Diagnostic Pitfall Mimicking Oligodendroglioma

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. I'll be attending the meeting this year. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Xinhai Zhang and colleagues at Loma Linda University in California discuss in Poster #198 discuss the problem of distinguishing extraventricular neurocytoma from oligodendroglioma:

Context: Extraventricular neurocytoma (EVN) mimics oligodendroglioma in terms of location and morphology. Oligodendrogliomas usually progress, while EVNs, other than atypical EVNs, typically do
not.

Design: We retrospectively analyzed studies encompassing 155 EVN cases published since 2000 for distinguishing features.

Results: Summarized differentiating features include the fact that EVNs have a peak incidence in the third and fourth decade of life, whereas the peak incidence of oligodendrogliomas is from the fourth to sixth decade. EVNs can have small areas of nucleus-free neuropil as well as thickened hyalinized blood vessels, features not seen in oligodendrogliomas. Immunohistochemically, oligodendrocyte lineage transcription factor 2 (OLIG2) is immunopositive in oligodendroglioma but negative in EVNs. In addition, EVNs are consistently positive for synaptophysin but rarely positive for GFAP, whereas oligodendrogliomas are variably positive for synaptophysin and more often positive for GFAP. Many oligodendrogliomas show loss of heterozygosity on
chromosomes 1p and 19q. These changes are not seen in EVNs except for atypical EVN with MIB-1 proliferation indices greater than 3%. IDH1/2 mutations are present in many oligodendrogliomas but not EVNs. Ultrastructurally, EVN tumor cells demonstrate numerous neuritelike cell processes as well as cell bodies with dense-core neurosecretory granules, whereas oligodendroglioma cells show plump and rounded cytoplasm without forming cellular processes, synaptic structures, or dense-core granules. Rare hypothalamic neurocytomas express TTF1 and vasopressin.

Conclusions: While clinicopathologic features are diagnostically helpful, additional molecular analyses are needed to better characterize the spectrum of EVNs and their distinction from oligodendrogliomas.

Wednesday, September 14, 2016

CAP16 Abstract Highlights: Accuracy of Central Nervous System Intraoperative Consultation Among Neuropathologists and General Pathologists

The 2016 annual meeting of the College of American Pathlologists (CAP16) is coming up September 25-28 in Las Vegas. I'll be attending the meeting this year. In this series of posts, I'll be featuring poster abstracts of particular interest to neuropathologists.

Timothy Harcom and Patrick Malafronte of the Walter Reed National Military Medical Center address in Poster #202 the accuracy of CNS intraoperative consultation:

Context: The reported accuracy of central nervous system (CNS) intraoperative consultation approaches 90%. Many of these studies, however, only include analysis by neuropathologists. The accuracy of diagnoses among general pathologist has not been extensively studied.

Design: All CNS intraoperative consultations during a consecutive 5-year period were evaluated. The consultations were separated into 2 groups: those consultations evaluated by a neuropathologist and those evaluated by a general pathologist. Four categories of frozen-permanent concordance were created: complete concordance, partial concordance, discordance, and deferral of diagnosis beyond the appraisal of adequate diagnostic tissue.

Results: A total of 170 CNS intraoperative consultations were identified: 91 cases with neuropathology evaluation and 79 cases with general pathologist evaluation only. The results (numbers of cases) were as follows, respectively: total concordance of 43 and 25; partial concordance of 39 and 31; discordance of 5 and 6; deferral of diagnosis of 4 and 17. Two of these comparisons produced statistically significant results (P< .05), complete concordance, showing a 72% increase, and deferral of diagnosis, showing a 76% decrease when the cases were evaluated by a neuropathologist.

Conclusions: The increased reliance on deferral of diagnosis and a reduced concordance rate among general pathologists points to a potential learning deficit that could be overcome through targeted education programs, similar to the ThinPrep Pap Proficiency Test, with the aim of increasing the quality of information provided during CNS intraoperative consultation.