Shabnam Momtahen

Epidermotropic B-Cell Lymphoma: A Unique Subset of CXCR3-Positive Marginal Zone Lymphoma.

Background:Epidermotropic B-cell lymphoma is a very rare entity that has primarily been reported in the literature as anecdotal case reports. The majority of the reported cases exhibit a diffuse skin rash affecting middle-aged to older adults with a male predominance. The exact mechanism of marginal zone B-cell localization to the epidermis is unclear. Material and Methods:To describe a very rare subset of cutaneous B-cell lymphoma and explore potential pathogenetic mechanisms for the epidermotropic tendency, the hospital database and literature review was conducted to isolate cases of epidermotropic B-cell lymphoma. Routine hematoxylin and eosin stain followed by selective phenotypic studies. Results:Two of the cases were encountered in the hospital database, whereas 5 cases have been previously reported; material was requested on previously reported cases and was received on 3 of them. In one of the 2 cases encountered in our database, the patient presented with a progressive skin rash over 7 months resembling pityriasis rosea. Subsequent to a diagnosis of B-cell lymphoma, further staging revealed bone marrow involvement. The other patient, an elderly female, presented with isolated nodules. The biopsies of both cases showed areas of superficial band-like lymphocytic infiltration with large monocytoid appearance and an epidermotropic pattern of lymphocyte migration into the epidermis. Neoplastic cells were extensively positive for CD20, CD79a, and BCL-2 and negative for CD10 and BCL-6. Of interest, a similar pityriasis rosea–like presentation was encountered in the cases reported in the literature. All patients were elderly males with established bone marrow, peripheral blood, and spleen involvement several months to years after the initial cutaneous presentation in 3 of them. None of the patients to date have died of lymphoma. CXCR3 epidermotropic B cells were detected in both our cases and in 3 of the 3 previously published cases. Conclusions:Epidermotropic B-cell lymphoma represents a subset of marginal zone lymphoma characterized by a papulosquamous rash most frequently resembling pityriasis rosea, occurring almost exclusively in older males. We speculate that aberrant expression of CXCR3 in marginal zone lymphoma of the skin is associated with migration of lymphoma cells to the epidermis and could lead to an epidermotropic pattern given the known role of CXCR3 expression in neoplastic T cells in the localization of mycosis fungoides to the epidermis. There is a tendency toward bone marrow, spleen, and peripheral blood involvement.

Role of the skin biopsy in the diagnosis of atypical hemolytic uremic syndrome.

Introduction:Atypical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. In the absence of complement inhibition, progressive clinical deterioration occurs. The authors postulated that a biopsy of normal skin could corroborate the diagnosis of aHUS through the demonstration of vascular deposits of C5b-9. Materials and Methods:Biopsies of normal skin from 22 patients with and without aHUS were processed for routine light microscopy and immunofluorescent studies. An assessment was made for vascular C5b-9 deposition immunohistochemically and by immunofluorescence. The biopsies were obtained primarily from the forearm and/or deltoid. Results:Patients with classic features of aHUS showed insidious microvascular changes including loose luminal platelet thrombi, except in 2 patients in whom a striking thrombogenic vasculopathy was apparent in biopsied digital ulcers. Extensive microvascular deposits of the membrane attack complex/C5b-9 were identified, excluding 1 patient in whom eculizumab was initiated before biopsy. In 5 of the 7 patients where follow-up was available, the patients exhibited an excellent treatment response to eculizumab. Patients without diagnostic clinical features of aHUS failed to show significant vascular deposits of complement, except 2 patients with thrombotic thrombocytopenic purpura including 1 in whom a Factor H mutation was identified. Conclusions:In a clinical setting where aHUS is an important diagnostic consideration, extensive microvascular deposition of C5b-9 supports the diagnosis of either aHUS or a subset of thrombotic thrombocytopenic purpura patients with concomitant complement dysregulation; significant vascular C5b-9 deposition predicts clinical responsiveness to eculizumab.

Histiocytoid Sweet's Syndrome: A localized cutaneous proliferation of macrophages frequently associated with chronic myeloproliferative disease

BackgroundHistiocytoid Sweet’s syndrome was originally described as cutaneous lesions of Sweet’s syndrome where the infiltrate is mostly composed of histiocytoid mononuclear cells. The putative cell has been interpreted as an immature neutrophil based on the intense expression of myeloperoxidase.MethodsThe study comprised eight men and five women aged from 23 to 80. There was a significant association with underlying myeloproliferative disease. In particular, five patients had underlying myelodysplastic syndrome. One patient had unspecified chronic myeloproliferative disorder and another hadAML.Two cases were triggered by drug therapy (Cox-2 inhibitors). One patient had familial Mediterranean fever. The eruption was asymptomatic and an aggressive clinical course was not observed in most cases. Skin biopsies were composed of striking angiocentric and intersititial mononuclear cell infiltrates, often accentuated in the deeper dermis and subcutaneous fat. There was marked leukocytoclasia. Neutrophils were sparce or absent. These cells were strongly positive for CD163 and either expressed CD16 or myeloperoxidase. Variable positivity for myeloid dendritic cell markers including CD11c, BDCA-3, TCL1 oncogene, MXA and CD123 was observed.ResultsThe study comprised eight men and five women aged from 23 to 80. There was a significant association with underlying myeloproliferative disease. In particular, five patients had underlying myelodysplastic syndrome. One patient had unspecified chronic myeloproliferative disorder and another hadAML.Two cases were triggered by drug therapy (Cox-2 inhibitors). One patient had familial Mediterranean fever. The eruption was asymptomatic and an aggressive clinical course was not observed in most cases. Skin biopsies were composed of striking angiocentric and intersititial mononuclear cell infiltrates, often accentuated in the deeper dermis and subcutaneous fat. There was marked leukocytoclasia. Neutrophils were sparce or absent. These cells were strongly positive for CD163 and either expressed CD16 or myeloperoxidase. Variable positivity for myeloid dendritic cell markers including CD11c, BDCA-3, TCL1 oncogene, MXA and CD123 was observed.ConclusionsThe histiocytoid cells of histiocytoid Sweet’s syndrome define a novel subset of activated monocytes. This variant of Sweet’s syndrome has a significant association with underlying myeloproliferative disease.

Current Chemotherapy and Potential New Targets in Uterine Leiomyosarcoma

A variety of chemotherapeutic agents have been used for treating recurrent or advanced stage uterine leiomyosarcoma (ULMS). The response rates of these current agents are disappointing, with partial response rates varying from 0% to 33%, and complete response rates varying from 0% to 8%. Recent studies have documented many molecular changes in ULMSs. Prominent amongst these are gains of growth factors C-MYC, Bcl-2, K-ras, and Ki-67, and losses in tumor suppressors p16, p53, Rb1, ING2 and D14S267. Various techniques that have been used to target these molecules are presented. Targeting specific therapies at these underlying molecular changes could potentially yield better response rates with fewer side effects.

Differential Nfatc1 Expression in Primary Cutaneous Cd4+ Small/medium-sized Pleomorphic T-cell Lymphoma and Other Forms of Cutaneous T-cell Lymphoma and Pseudolymphoma.

Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (PCSTCL) has recently emerged as a distinct clinicopathological entity. Because of a considerable degree of overlap with pseudolymphoma, the diagnosis is often challenging. Preliminary studies suggest that nuclear upregulation of calcineurin/nuclear factor of activated T cells (NFAT) may play a role in lymphomagenesis. Design: 137 cases (70 males and 67 female, mean age = 55) of various forms of cutaneous T-cell and B-cell infiltration were evaluated for NFATc1 expression. The study comprised 18 cases of PCSTCL, 45 cases of mycosis fungoides (MF), 5 cases of lymphomatoid papulosis (LyP), 5 cases of anaplastic large-cell lymphoma (ALCL), 8 cases of other forms of peripheral T-cell lymphoma, not otherwise specified, 12 precursor lesions of MF (ie, cutaneous T-cell dyscrasias), 35 cases of pseudolymphomas, 8 primary cutaneous B-cell lymphoma, and 1 chronic lymphocytic leukemia. The number of cells exhibiting a nuclear stain was counted per 10  high-power field and 2-tailed statistical analysis was used for comparison of nuclear NFATc1 expression between primary PCSTCL and all other groups. A P-value <0.05 was considered to indicate statistical significance. Results: All cases of PCSTCL showed nuclear staining for NFATc1 (mean = 296 ± 236) with no cases in which an exclusive cytoplasmic stain was observed. The cells exhibiting this staining pattern were oftentimes larger manifesting other features of a follicular helper T-cell phenotype, such as variable positivity for PD1, ICOS, CXCL13, and BCL6. In comparison, an exclusively cytoplasmic stain was observed in 29 cases of MF; in few cases, rare nuclear staining cells were observed averaging less than 10 per high-power field (P = 0.0001). These positive staining cases were not only limited to tumor-stage MF but also encompassed patch- and plaque-stage lesions and follicular variants of MF. The same pattern was observed in cases of T-cell dyscrasia (mean = 3 ± 3, P = 0.0001) and pseudolymphoma (mean = 2 ± 3, P = 0.0001), both revealing a dominant cytoplasmic staining pattern. In pseudolymphomatous folliculitis, a greater extent of nuclear staining for NFATc1 was observed compared with other forms of pseudolymphoma. No significant difference was seen between MF and T-cell dyscrasia or pesudolymphomas excluding pseudolymphotous folliculitis. Anaplastic large-cell lymphoma cases showed an almost exclusive cytoplasmic staining pattern with rare nuclear staining (mean = 55 ± 102, P = 0.0001); similar results were observed in LyP (mean = 17 ± 15, P = 0.004). Cutaneous B-cell lymphomas showed a similar extent of staining as that noted for PCSTCL. The greatest extent of staining was observed in chronic lymphocytic leukemia. A significant difference was noted between the extent of nuclear staining in PCSTCL and other forms of primary cutaneous T-cell lymphoma, type unspecified (mean = 22 ± 43, P = 0.0002), although not between PCSTCL and B-cell lymphoma. Conclusion: NFAT signaling plays a critical role in peripheral T-cell activation after T cell receptor engagement. When assessing T-cell–rich infiltrates where the differential diagnosis is largely between a PCSTCL and pseudolymphoma, a significant degree of nuclear staining of lymphocytes would be more in keeping with a diagnosis of PCSTCL. Upregulation of the NFAT pathway is not a feature of tumor progression in the setting of MF.

Cutaneous myeloid dendritic cell dyscrasia: A cutaneous clonal monocytosis associated with chronic myeloproliferative disorders and peripheral blood monocytosis

Monocytes are critical components of the innate immune system and they can differentiate into dendritic cells (DCs). Cutaneous neoplasms of dendritic cell origin are uncommon and mostly represented by histiocytic lesions derived primarily from Langerhans cells. The myeloid DC (mDC) while recognized in the immunology literature does not have a well-defined neoplastic cutaneous counterpart. Eleven patients with a diagnosis of cutaneous mDC dyscrasia were evaluated. Routine hematoxylin and eosin stain were performed followed by selective phenotypic studies. The patients were older without a gender predilection and exhibited an asymptomatic papular skin rash with a waxing and waning course. The biopsies demonstrated a dermal based monomorphic small mononuclear cell infiltrate. The cells expressed CD14, CD11c, HLA-DR, as well as granzyme and lysozyme that defines terminally differentiated monocyte/dendritic cells. Expression of BDCA-3 (CD141) by the tumor cells indicated that they were myeloid dendritic cells (mDC2). Each patient had a prior or subsequent diagnosis of an abnormal bone marrow biopsy that included myelodysplastic syndrome, myelofibrosis, chronic myelomonocytic leukemia, and acute myelogenous leukemia. We propose the term cutaneous mDC cell dyscrasia for distinctive infiltrates of differentiated mDCs reflective of underlying myeloproliferative disease. The clinical course is variable and can be indolent although it is strongly correlated with myelodysplastic syndrome that included leukemia.

The distinctive histopathology of hydralazine-associated ANCA positive vasculitis: in vivo demonstration of NETosis

The least common variant of drug-induced vasculitis occurs within the context of anti-neutrophilic cytoplasmic antibody (ANCA)-mediated small-vessel vasculitis; the implicated drugs include minocycline, the TNF alpha inhibitors, as well as carbimazole [1, 2]. The mechanisms of ANCA+ vasculitis are complex but a component of the vascular injury represents at least one mechanism mediated by antibodies targeting antigens, namely intracytoplasmic neutrophil granules containing myeloperoxidase (MPO) [...]

The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential

BACKGROUND FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma. METHOD 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6. RESULTS The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis. CONCLUSION Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.

Primary cutaneous spindle cell B cell lymphoma: A report of three cases and review of the literature

Primary cutaneous spindle cell lymphoma is a rare variant of primary cutaneous B-cell lymphoma (PCBCL). Herein, we present 3 cases of primary cutaneous spindle cell B cell lymphoma, 2 males and one female (age range 66-76years). The patients presented with solitary skin lesions, distributed in the head and neck area and chest. The dominant cell size was in the intermediate to large cell size range. While the main cell type was a spindled one, other cells with a nuclear morphology quite typical for a centroblast were noted and as well careful inspection in the three cases revealed a focal residuum of germinal center-like structures. The spindled cells exhibited a B cell follicle center cell phenotype as revealed by expression of CD20, CD79a, BCL6, and CD10. BCL2 was negative in two cases and positive in one case. The proliferation index exceeded 80%. In one case the neoplastic cells were CD30 positive. Subsequent to a diagnosis in each case of follicle center cell lymphoma, the patients underwent complete excision with no known recurrence. In our review of the literature, a total of 42 other cases were reported showing a similar male predominance with the commonest sites of involvement being the head and neck area and upper back. Other than one patient who died of progressive disease due to treatment refusal and one patient who developed metastatic disease to the liver all patients are alive and well without recurrent or metastatic disease. In summation, our experience along with the reported cases suggest the categorization of primary cutaneous spindle cell B cell lymphoma as a variant of primary cutaneous indolent follicle center lymphoma. It is a neoplasm of middle aged to older adults with a predominance in males which can be treated locally in most cases whereby recurrent and metastatic disease following complete removal is uncommon.

Osteopontin expression in biopsies of calciphylaxis

BackgroundCalciphylaxis combines features of vascular thrombotic occlusion and endoluminal calcification. In this study we examine the expression of osteopontin as a diagnostic marker and its role in lesional pathogenesis.Methods25 formalin-fixed, paraffin embedded skin biopsies of 20 females and 5 males (mean age of 60 years) with a diagnosis of calciphylaxis were assessed for osteopontin expression.ResultsLower extremities were the most commonly involved areas; however a truncal and genital distribution was also noted in 3 cases. Renal failure was present in 21 of 25 cases. One patient had myeloproliferative disorder and one patient had advanced colon cancer. The dominant pathology was localized to the subcutaneous fat, characterized by mural calcification and luminal thrombosis affecting capillaries, venules, arterioles and small arteries. In 2 cases, a subcutaneous thrombogenic vasculopathy without calcification was noted. Osteopontin expression was confined to the subcutis, being most striking in calcified vessels but also apparent in vessels without calcification, including mineral poor variants of calciphylaxis.ConclusionCalciphylaxis represents a unique calcific thrombogenic vasculopathy, not limited to renal failure. Ectopic osteopontin expression may define a critical and initial event in the calciphylaxis pathogenesis. Therapeutic agents designed to reduce osteopontin expression may be of value in its treatment.