Sebastian Fernandez-Pol, MD

View details for DOI 10.1182/bloodadvances.2020002371

View details for PubMedID 33560388

Abstract

Patients with lymphoproliferative disorders following hematopoietic stem cell transplant (HSCT) most commonly present with fever and lymphadenopathy within the first 5months of transplant. Pulmonary post-transplant lymphoproliferative disorder (PTLD) is a particularly aggressive and rapidly progressive disease, with high morbidity and mortality. There are a very limited number of reported pulmonary PTLD cases following HSCT in patients with acute myeloid leukemia (AML). Early diagnosis and detection of pulmonary PTLD is critical given its high lethality. However, variable clinical presentations and nonspecific radiographic findings make pulmonary PTLD difficult to distinguish from other more common causes of pulmonary disease in AML patients.Here, we describe a 68-year-old Caucasian man who presented for salvage induction therapy following relapse of his AML after a haploidentical allogeneic HSCT 10 months earlier. He developed recurrent fevers, dry cough, and hypoxemia, with chest computed tomography (CT) showing bibasilar consolidations and increased nodularity without increased lymphadenopathy. His symptoms initially improved with antibiotic and antifungal therapy, but his follow-up chest CT showed progression of disease despite symptomatic improvement. Epstein-Barr virus (EBV) was detected in his blood by polymerase chain reaction (PCR), and a lung biopsy revealed monomorphic PTLD with B cells positive for EBV. Unfortunately, the patient's condition rapidly deteriorated, and he passed away prior to treatment initiation.To our knowledge, this is the first reported case of an AML patient developing pulmonary PTLD relatively late in his post-transplant course in the setting of relapsed disease and salvage therapy. Pulmonary PTLD, a rare but highly lethal disorder, can imitate the symptoms and radiographic findings of pneumonia, a common diagnosis in immunocompromised AML patients. This case illustrates the importance of considering pulmonary PTLD in the differential diagnosis for pulmonary disease in AML patients with a history of HSCT, especially in the setting of progressive radiographic findings despite broad antibacterial and antifungal therapy. Further, our case demonstrates the importance of biopsy and uninterrupted EBV DNA monitoring in the definitive diagnosis of PTLD, given nonspecific symptomatology and radiographic findings.

View details for DOI 10.1186/s13256-021-02744-2

View details for PubMedID 33773605

View details for Web of Science ID 000600556200003

Abstract

Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES.

View details for DOI 10.1097/PAS.0000000000001604

View details for PubMedID 33060403

Abstract

BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas for which diagnosis can be challenging given the potential for overlap with inflammatory dermatoses. Current diagnostic criteria for CTCL incorporate clinical and histopathologic findings as well as results of T-cell receptor (TCR) gene sequencing. Molecular interrogation of TCR genes, TRG and TRB, has provento be a critical tool for confirming diagnoses of CTCL and for disease tracking after initiation of therapy or after stem cell transplant. Methods for confirming a diagnosis of lymphoma in the absence of TCR gene clonality are lacking. We present two patients with CTCL with pathogenic somatic mutations in the absence of TRG and TRB clonality.CASE PRESENTATIONS: Case 1: A 38-year-old male had a 19-year history of a diffuse skin rash with papulosquamous, granulomatous, and verrucous features and progressive ulcerated plaques and tumors demonstrating an atypical CD4+ T-cell infiltrate with expression of cytotoxic markers CD56, TIA-1, granzyme, and perforin on histopathology. No definitive evidence for T-cell clonality was detected by conventional PCR of 6 biopsies or by next-generation sequencing (NGS) of 14 biopsies. Somatic mutational profiling of a skin biopsy revealed pathogenic mutations in PIKC3D and TERT promoter hotspots, confirming the presence of a clonal process. Case 2: A 69-year-old male with a 13-year history of progressive, diffuse hypertrophic and eroded plaques showed an atypical CD4+ T-cell infiltrate with subset expression of TIA-1 and granzyme on histopathology. No TCR clonality was detected by TCR-NGS of 6 biopsies. Somatic mutational profiling of a skin biopsy detected a pathogenic mutation in TP53, confirming the presence of a clonal process.CONCLUSIONS: These cases highlight how detection of pathogenic somatic mutations can confirma diagnosis of lymphoma in a clinically and histopathologically suspicious cutaneous lymphoid proliferation without detectable TCR clonality.

View details for DOI 10.1186/s13000-020-01022-x

View details for PubMedID 32988392

Abstract

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for six months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case demonstrates that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may demonstrate histologic features of leukemia cutis on skin biopsy. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/cup.13780

View details for PubMedID 32588467

Abstract

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary cutaneous T-cell lymphoma that is challenging to distinguish from other neoplastic and reactive panniculitides. In an attempt to identify somatic variants in SPTCL that may be diagnostically or therapeutically relevant, we performed both exome sequencing on paired tumor-normal samples and targeted sequencing of hematolymphoid-malignancy-associated genes on tumor biopsies. Exome sequencing was performed on skin biopsies from 4 cases of skin-limited SPTCL, 1 case of peripheral T-cell lymphoma, not otherwise specified with secondary involvement of the panniculus, and 2 cases of lupus panniculitis. This approach detected between 1 and 13 high-confidence somatic variants that were predicted to result in a protein alteration per case. Variants of interest identified include 1 missense mutation in ARID1B in 1 case of SPTCL. To detect variants that were present at a lower level, we used a more sensitive targeted panel to sequence 41 hematolymphoid-malignancy-associated genes. The targeted panel was applied to 2 of the biopsies that were evaluated by whole exome sequencing as well as 5 additional biopsies. Potentially pathogenic variants were identified in KMT2D and PLCG1 among others, but no gene was altered in >2 of the 7 cases sequenced. One variant that was notably absent from the cases sequences is RHOA G17V. Further work will be required to further elucidate the genetic abnormalities that lead to this rare lymphoma.

View details for DOI 10.1097/PAI.0000000000000683

View details for PubMedID 31702703

View details for Web of Science ID 000540191100190

Abstract

Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (2cm) and raised (4/5). Histologically, the tumors were paucicellular, comprised of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/cup.13686

View details for PubMedID 32187703

Abstract

The diagnosis of lymphomas and leukemias requires hematopathologists to integrate microscopically visible cellular morphology with antibody-identified cell surface molecule expression. To merge these into one high-throughput, highly multiplexed, single-cell assay, we quantify cell morphological features by their underlying, antibody-measurable molecular components, which empowers mass cytometers to 'see' like pathologists. When applied to 71 diverse clinical samples, single-cell morphometric profiling reveals robust and distinct patterns of 'morphometric' markers for each major cell type. Individually, lamin B1 highlights acute leukemias, lamin A/C helps distinguish normal from neoplastic mature T cells, and VAMP-7 recapitulates light-cytometric side scatter. Combined with machine learning, morphometric markers form intuitive visualizations of normal and neoplastic cellular distribution and differentiation. When recalibrated for myelomonocytic blast enumeration, this approach is superior to flow cytometry and comparable to expert microscopy, bypassing years of specialized training. The contextualization of traditional surface markers on independent morphometric frameworks permits more sensitive and automated diagnosis of complex hematopoietic diseases.

View details for DOI 10.1038/s41591-020-0783-x

View details for PubMedID 32161403

View details for DOI 10.1111/cup.13727

View details for PubMedID 32342514

Abstract

Recurrence of breast cancer is a predominant fear for patients who were treated for breast cancer. Acute and late dermatologic effects of radiotherapy are not uncommon and could have similar characteristics to breast cancer recurrence. Thus, it is important to highlight key differences between the clinical and histologic presentations of radiation effects and recurrence. Herein, we present two patients who presented with late dermatologic effects of radiotherapy months to years after treatment, neither of whom had workup consistent with cancer recurrence. We provide clinical and microscopic descriptions of each case and provide a review to differentiate various dermatologic conditions. This report aims to outline potential late dermatologic effects of radiation treatment and emphasise that changes in the breast do not always signal breast cancer recurrence.

View details for DOI 10.1111/iwj.13350

View details for PubMedID 32227450

View details for DOI 10.1097/PAI.0000000000000644

View details for Web of Science ID 000479114600005

View details for PubMedID 30819837

View details for PubMedID 29866887

Abstract

Here, we utilize a high throughput sequencing panel that covers several genes known to be recurrently mutated in certain T-cell lymphoma subtypes as well as genes frequently mutated in other hematolymphoid malignancies, including myeloid neoplasms. This panel was applied to formalin-fixed, paraffin-embedded tissue from 84 biopsies from 78 patients selected for this study. The biopsies included ones a with a diagnosis of T-cell lymphoma (n=79), including peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n=26) and angioimmunoblastic T-cell lymphoma (AITL; n=13), as well as 5 cases of atypical T-cell proliferations. KMT2C and KMT2D, which code for proteins involved in histone modifications, were the 2 most frequently mutated genes in our cohort and were altered across a range T-cell lymphomas. Mutations in TET2 and DNMT3A, which are involved in regulating DNA methylation, were also found in a variety of T-cell lymphoma categories. The RHOA G17V mutation that is frequently found in AITL was identified 5 of 13 (40%) cases of AITL and in 3 of 26 (12%) cases of PTCL-NOS, but not in biopsies involved by other T-cell proliferations. Our study adds to the already significant evidence from other investigators that, among T-cell lymphomas, the RHOA G17V variant is specific for AITL and PTCL-NOS. In contrast, variants in epigenetic modifier genes do not appear to be particularly specific for T-cell lymphoma subcategories evaluated in our study.

View details for PubMedID 29629950

Abstract

Infection with Scedosporium species is associated with a significant morbidity and mortality and is becoming increasingly common, especially in immunocompromised patients. We describe the presentation and successful management of an immunocompromised patient with Scedosporium apiospermum infection of the upper urinary tract system, a rare disease manifestation. The current literature on urinary tract scedosporiosis is further reviewed with emphasis on treatment options and limitations of current antifungal therapy.

View details for PubMedID 29111602

View details for PubMedCentralID PMC5871223

Abstract

PAX7 has been recently demonstrated to be a highly sensitive marker for Ewing sarcoma, and thus far has only been shown to label a relatively small set of other mesenchymal neoplasms. Because the processing of bone marrow core biopsies can often hinder the performance of immunohistochemical stains, we set out to determine if our laboratory's PAX7 staining protocol effectively detects Ewing sarcoma in Bouin's fixed, decalcified bone marrow core biopsies. We stained ten core biopsies involved by Ewing sarcoma, nine non-involved core biopsies, and 13 core biopsies involved by histologic mimics of Ewing sarcoma. Only the ten biopsies involved by Ewing sarcoma and four biopsies with rhabdomyosarcoma showed strong nuclear PAX7 staining. None of the other tumors demonstrated PAX7 expression. This study demonstrates that the PAX7 staining protocol used in our laboratory is a useful marker for Ewing sarcoma and other PAX7-positive tumors in decalcified bone marrow core biopsies.

View details for PubMedID 30014288

Abstract

Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a CD30+ lymphoproliferative disorder (LPD) of the skin with a relatively good prognosis in the absence of high-stage disease. CD30+ LPDs comprise approximately 25%-30% of primary cutaneous lymphomas and as a group represent the second most common clonal T-cell neoplasm of the skin behind mycosis fungoides. Diagnosis of PC-ALCL relies strongly on clinicopathologic correlation given the potential morphologic, clinical and molecular overlap with the other cutaneous CD30+ LPD, lymphomatoid papulosis, and more aggressive hematolymphoid neoplasms.

View details for DOI 10.1111/cup.12937

View details for PubMedID 28342276

Abstract

In this study, we evaluate the expression of p53 in core biopsies with acute myeloid leukemia and correlate the level of expression with acute myeloid leukemia subtype, TP53 mutation status, karyotype, and survival. Of the 143 cases evaluated, 71 fulfilled the WHO 2016 criteria for acute myeloid leukemia with myelodysplasia-related changes, 40 were acute myeloid leukemia-not otherwise specified, 25 were acute myeloid leukemia with recurrent genetic abnormalities, and 7 were therapy-related acute myeloid leukemia. By immunohistochemistry, 17% showed p53 expression in >5% of the cells. Of the 24 cases with >5% p53-positive cells, 17 were acute myeloid leukemia with myelodysplasia-related changes, 5 were acute myeloid leukemia-not otherwise specified, 1 was acute myeloid leukemia with recurrent genetic abormalities, and 1 was therapy-related acute myeloid leukemia. In cases for which data was available, expression of >5% p53-positive cells was significantly associated with genotype (n=67) and/or karyotype (n=130). Among the 115 cases for which clinical follow up was available, the overall survival of cases with p53 expression >15% (Median=102 days) was significantly shorter compared with cases with p53 expression 15% (Median=435 days). Within the acute myeloid leukemia with myelodysplasia-related changes group, this association remained significant, with cases with 15% p53-positive cells having a median overall survival of 405 days versus 102 days for cases with >15% p53-positive cells. Among acute myeloid leukemia with myelodysplasia-related changes cases with a complex karyotype, the finding of >15% p53-positive cells was significantly associated with worse overall survival. The poor prognosis associated with more than 15% p53-positive cells was independent of age and karyotype. In acute myeloid leukemia with myelodysplasia-related changes, p53 expression may be useful to infer TP53 mutation status, complex karyotype, and/or poor prognosis in situations where other modalities are not readily available.

View details for DOI 10.1038/modpathol.2016.206

View details for PubMedID 27934876

Abstract

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary cutaneous T-cell lymphoma that shares significant clinical, histopathologic and immunophenotypic overlap with lupus erythematosus panniculitis (LEP).We performed immunohistochemistry for the MYC oncoprotein on 23 cases of SPTCL (1 CD8 negative) and 12 cases of LEP to evaluate if there are quantitative or qualitative differences in protein expression of this marker in these entities.In SPTCL cases, the percentage of all cells that were c-Myc positive ranged from 0.8% to 16%, with a mean of 5.0% and a median of 4.4%. In contrast, in the LEP cases, the percentage of c-Myc-positive cells in the cases ranged from 0.34% to 3.7%, averaged 1.4% and the median was 0.8%. The difference between the means of these 2 diagnostic categories was statistically significant. Fluorescence in situ hybridization performed on 4 cases of SPTCL with a relatively high level of MYC immunohistochemical staining, however, failed to demonstrate evidence of MYC rearrangement or amplification.Our work demonstrates that MYC expression levels differ between these 2 histologic mimics and suggests that this important oncoprotein may play a role in the pathogenesis of SPTCL.

View details for PubMedID 28800143

Abstract

Histiocytic sarcoma is rare and difficult to distinguish from histologic mimics such as myeloid sarcoma due to its relatively nonspecific immunoprofile. A subset of histiocytic sarcomas are clonally related to synchronous or metachronous follicular lymphomas. Interestingly, the histiocytic tumor component has been shown to harbor BCL2 gene translocations that are identical to those found in the lymphoma. We present one case of histiocytic sarcoma and initially occult follicular lymphoma in which detection of a BCL2 gene translocation helped support the diagnosis. We also provide follow up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma. Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis. Testing for an IGH/BCL2 translocation should be considered in the diagnostic workup of difficult to characterize neoplasms with histiocytic/monocytic morphology and immunoprofile.

View details for DOI 10.1016/j.humpath.2016.04.004

View details for PubMedID 27134111

Abstract

In this study, we set out to evaluate the frequency of mutations in 20 myelodysplastic syndrome-associated genes in 53 individuals with pancytopenia in which bone marrow evaluation failed to meet standard criteria for a diagnosis of myelodysplastic syndrome. These idiopathic pancytopenia cases were associated with no specific cause for their pancytopenia (n=28), aplastic anemia (n=13), pancytopenia attributable to liver disease (n=4), pancytopenia associated with autoimmune disease (n=4), and pancytopenia attributed to drug effect (n=4). We also selected 38 bone marrow aspirates from patients presenting with pancytopenia and meeting criteria for a diagnosis of myelodysplastic syndrome (n=21) or acute myeloid leukemia (n=17) as malignant comparison cases. Targeted sequencing of the 20 genes was performed on all cases. The idiopathic pancytopenia group had a lower average age (46 vs 66 years, P<0.0001) and a lower number of mutations per case that were statistically significant (0.81 vs 1.18, P=0.045). The frequency of cases with at least one mutation was higher for cases with a diagnosable myeloid neoplasm (68 vs 38%, P=0.012). Except for mutations in U2AF1, which was mutated in 5 of the 38 malignant cases (13.2%) and in none of the idiopathic pancytopenia cases (P=0.011), the frequency of mutations in the genes evaluated was not significantly different between idiopathic pancytopenia and malignant cases. Median and mean clinical follow-up for the idiopathic pancytopenia group was available for 444 and 739 days, respectively. Over this time frame, none of the idiopathic pancytopenia patients was diagnosed with a myelodysplastic syndrome or an acute myeloid leukemia. These findings provide further evidence that identification of mutations in several genes associated with myelodysplastic syndromes should not be used alone to support a diagnosis of a myelodysplastic syndrome.Modern Pathology advance online publication, 3 June 2016; doi:10.1038/modpathol.2016.100.

View details for DOI 10.1038/modpathol.2016.100

View details for PubMedID 27255165

View details for DOI 10.1055/s-0034-1390722

View details for PubMedID 25926223