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Primary Cutaneous Follicle Center Lymphoma.

By definition, primary cutaneous follicle center lymphoma (PCFCL) is a lymphoma of follicle center B cells without evidence of systemic/nodal involvement at the time of diagnosis. (1-5) It is a low-grade lymphoma with an excellent prognosis. Nonetheless, it can show a locally aggressive course if left untreated, (3,6,7) and rare transformation to diffuse large B-cell lymphoma has been suggested. (8,9) Its differential diagnosis is broad but primarily includes systemic/nodal follicular lymphoma secondarily involving the skin (FL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); reactive lymphoid hyperplasia (RLH); and primary cutaneous marginal zone lymphoma (PCMZL). This review highlights the clinical features, differential diagnosis, prognosis, and treatment of PCFCL and emphasizes how PCFCL can be separated from other considerations in its diagnosis.

EPIDEMIOLOGY AND CLINICAL FEATURES

Primary cutaneous follicle center lymphoma is the most-common primary cutaneous B-cell lymphoma. (4,10) It accounts for approximately 10% to 20% of all cutaneous lymphomas and comprises about 50% of primary cutaneous B-cell lymphomas. (2-4,10-12) Most commonly, patients are white men, 50 to 60 years old, although younger patients and women may also develop this lymphoma. (2,4,10,11,13-18) Patients with PCFCL typically present with one or more localized, erythematous papules, plaques, and/or tumors on the scalp/forehead or trunk (Figure 1, A and B). (2-4,10-16,19) Approximately 60% of patients will have more than one lesion; most commonly multiple lesions occur in a localized area (30%-40%), although a few patients have multiple dispersed skin lesions (10%-20%). (2-4,10,13,15,19)

PATHOLOGIC FEATURES

Histopathologically, PCFCL is characterized by often dense proliferations of neoplastic follicle center cells, which are separated from the epidermis by a grenz zone (Figure 2, A and B). Primary cutaneous follicle center lymphoma may show a follicular and/or a diffuse growth pattern. Neoplastic cells include enlarged centrocytes with cleaved/irregular nuclei and inconspicuous nucleoli and centroblasts with larger, rounder nuclei, more-open chromatin, and 1 to 3 peripheral nucleoli (Figure 2, C). Reactive T cells are often prominent. As with systemic/nodal FL, the neoplastic follicles in PCFCL show several features that distinguish them from reactive follicles. Specifically, abnormal follicles are often closely spaced and irregular. In addition, they have diminished or absent mantle zones, often do not include tingible body macrophages, and do not show polarized light and dark zones. Instead, in these abnormal follicles, centroblasts and centrocytes are intermixed throughout the follicle, and there is often a prominent stromal component. Some cases of PCFCL completely or partially lack a nodular architecture and are, instead, composed of sheets of centrocytes and centroblasts. In addition, centrocytes can be quite large in some tumors, and/or they may take on a spindled appearance. (6,8)

The neoplastic lymphocytes in PCFCL express B-cell markers (CD19, CD20, CD22, CD79a, PAX5) and at least one follicle center marker, which is usually BCL6 or, less commonly, CD10 (Figure 2, D and E). (2,3,12,13,17,20) BCL2 staining is usually absent. (4,12,13,17,18) Ki-67 may reveal a lower proliferation index than usual in reactive follicles and will not show the customary polarization of a reactive follicle. (15,17,21) Notably, some cases have a high proliferation index that, nonetheless, lacks polarization and may highlight the abnormal shape of the neoplastic follicles (Figure 2, F). (17,18) Additionally, [BCL6.sup.+] cells may extend beyond the follicular meshwork, the latter highlighted by CD21 and CD23, a finding that helps to exclude RLH. (21) Unlike PCDLBCL-LT, most cases do not express MUM1, FOXP1, p63, or immunoglobulin M (IgM). (4,17)

In difficult cases, in which the differential diagnosis rests between a reactive process and PCFCL, polymerase chain reaction can be used to examine the immunoglobulin heavy-chain and [KAPPA] light-chain genes. The presence of monoclonal B cells in the right clinical and pathologic context can support a diagnosis of PCFCL. However, many PCFCL do not have detectable monoclonal populations, (2,13,14,17,22) and false-positive results are also possible. (14,22) In addition, the DNA may be of insufficient quality for molecular analysis, particularly in formalin-fixed, paraffin-embedded tissue. (14,22) Follicular lymphomas, including PCFCL, frequently produce false-negative results. Polymerase chain reaction primers must anneal to the target gene sequence for gene rearrangement testing to be successful. Follicular lymphomas have undergone somatic hypermutation, a process by which nucleotides are randomly inserted and removed from the immunoglobulin genes to create immunoglobulin diversity, and primer binding may be affected. (22-24) False-negative results can also occur when the DNA in the sample is of poor quality. (22,24) Finally, false-positive results can occur when a B-cell population emerges as a dominant clone in RLH. (17)

In some instances, flow cytometry can be helpful in evaluating PCFCL. Flow cytometry is more likely to detect both CD10 and BCL2 expression and can assess light chain restriction in B cells. (14,25) Some studies have found flow cytometry to be a more-sensitive measure of clonality than immunoglobulin gene rearrangement studies by polymerase chain reaction. (14,25) Two important drawbacks in the application of flow cytometry to skin biopsies include small sample size limiting specimen adequacy (12,14) and laboratory inexperience with skin specimens; it may be technically difficult to obtain sufficient cells in small skin biopsies that are rich in stroma.

DIFFERENTIAL DIAGNOSIS

Please see the Table for a summary of the considerations in the differential diagnosis of PCFCL.

Systemic/Nodal FL

Systemic/nodal follicular lymphomas can involve the skin and are histopathologically indistinguishable from PCFCL. Clinical features, in particular, lymphadenopathy, B symptoms, or other evidence of systemic or nodal disease, are critical for recognizing cases of FL involving the skin. (1,12,26) Although the pathologic features are often identical in PCFCL and secondary cutaneous FL, some features can help suggest skin involvement by FL. Strong CD10 and BCL2 expression is not frequently identified in PCFCL and suggests a cutaneous involvement by FL (Figure 3, A through E). (2) The t(14;18) is also less common in PCFCL but is identified in most FL (>75% of cases). (3,13,15,17,18) Similarly, 1p36 deletion and rearrangements of BCL6 are more common in FL but are rarely detected in PCFCL. (18,20)

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Primary cutaneous diffuse large B-cell lymphoma, leg type, is a lymphoma of large B cells, that begins in the skin. Patients are usually older women with rapidly growing nodules/tumors on the lower legs (Figure 4, A), (3,4,10,27) and PCDLBCL-LT has a worse prognosis compared with PCFCL, with a 5-year survival of 50%, (3,4,10,16) although improvements in survival have been seen with the inclusion of rituximab in polychemotherapy. (27) Patients with PCDLBCL-LT are generally treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). (26) Primary cutaneous diffuse large B-cell lymphoma, leg type, is composed of sheets of large cells with a so-called round cell morphology (Figure 4, B). These large cells include centroblasts and immunoblasts with rounded nuclear contours (Figure 4, C). Centrocytes are not identified. These lymphomas are composed of B cells that express BCL2, MUM1, IgM, and FOXP1. (4,28) BCL6 is common (68% of cases), but CD10 expression is not (<10% of cases). (4)

In some instances of PCFCL, centrocytes can be quite large and may be more than twice the size of a normal lymphocyte. (8) Primary cutaneous follicle center lymphomas with diffuse growth and/or large centrocytes can be challenging to separate from diffuse large B-cell lymphomas, particularly diffuse large B-cell lymphoma, leg type (DLBCL-LT) (Figure 5, A and B). (4,8) In some cases, these lymphomas would be classified as DLBCL at other sites. (8) However, in the skin, the presence of cells with irregular/cleaved nuclei (centrocytes) helps to exclude a diagnosis of DLBCL. In addition, the presence of follicular dendritic networks and numerous background T cells argue in favor of PCFCL. (2,4) Moreover, BCL2, MUM1, FOXP1, and IgM are not usually expressed in PCFCL. (4,28) Notably, PCDLBCL-LT shows important genetic distinctions from PCFCL. In contrast to PCFCL, PCDLBCL-LT displays an activated B-cell gene-expression profile, rearrangements of MYC and BCL6, amplification of BCL2, and MYD88 mutations. (6,29-32) A large subset of PCDLBCL-LT cases show chromosomal loss in 9p21.3 (CDKN2A gene). (29,33,34) Deletion in this region may be a poor prognostic factor. (33) In difficult cases, these genetic differences can be used to facilitate the diagnosis.

Reactive Lymphoid Hyperplasia

Reactive lymphoid hyperplasia with numerous follicles can also mimic PCFCL. Moreover, RLH often occurs on the head and may have many follicles. (15) In small skin biopsies with prominent crush artifact, these reactive follicles can be difficult to visualize and may show some features, such as irregular shape, that prompt consideration of PCFCL. However, the follicles in RLH will ideally show a customary architecture with a polarized outer mantle zone and a well-defined polarized follicle center with centrocytes and centroblasts occupying opposite halves of the follicle, a finding that can be highlighted by Ki-67 because centroblasts are more proliferative than centrocytes. In addition, [BCL6.sup.+] cells are often well-contained within CD21 and [CD23.sup.+] follicular dendritic networks, a finding that argues against PCFCL. Molecular studies are less likely to reveal a clonal B-cell population. (35) Reactive lymphoid hyperplasia also differs clinically from PCFCL. Patients with a reactive process will experience resolution spontaneously, after any initiating agent is removed or after noninvasive therapy. In addition, reactive follicles will include a mixture of B cells (polyclonality) that can be detected with molecular studies and flow cytometry.

Primary Cutaneous Marginal Zone Lymphoma

Primary cutaneous marginal zone lymphoma, a variant of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, most commonly affects the trunk and extremities of middle-aged men (50 years and older). (4,10) Moreover, PCMZL is far more likely than PCFCL to present with multifocal disease, and most patients have dispersed lesions (60%). (4) Nevertheless, patients have an excellent prognosis, similar to PCFCL, with a 98% to 100% 5-year disease-specific survival rate and can be successfully treated with radiotherapy and/or surgery, rituximab, or careful observation. (4,8,10,26,36) Histopathologically, PCMZL may resemble PCFCL because it often includes lymphoid follicles and "centrocyte-like" cells. However, follicles in PCMZL will either be reactive in appearance or show follicular colonization, in which small- to medium-sized B cells infiltrate and destroy healthy follicles. Colonization sometimes leads to an "inside-out" appearance, in which germinal center cells appear at the periphery of a B-cell aggregate. (37) In addition, PCMZL often has a more heterogeneous appearance and may include small-to-medium-sized mature, centrocyte-like lymphocytes, monocytoid lymphocytes with more abundant cytoplasm, light-chain-restricted plasma cells, and sometimes a minor subset of larger cells resembling centroblasts and immunoblasts. Dutcher bodies may be identified, and eosinophils are seen in a few cases. (37) On low magnification, PCMZL often show a vertical distribution around the hair follicles, and plasma cells are commonly found surrounding vessels at the periphery of the lesion. (37) Primary cutaneous marginal zone lymphomas lack expression of BCL6, CD10, and CD5 but may express CD43, unlike PCFCL. In addition, PCMZL lacks the germinal center marker STMN1 (stathmin), which is expressed by PCFCL and PCDLBCL-LT. (18,20) In addition, PCMZLs often include light-chain-restricted plasma cells, which are not usually seen in PCFCL.

Other Considerations

T-cell lymphomas with a follicular helper phenotype, including follicular T-cell lymphoma and primary cutaneous follicular helper T-cell lymphoma, may mimic PCFCL. Primary cutaneous follicular helper T-cell lymphoma is a rare and relatively recently described lymphoma with only few reported cases, (38,39) and it is not included in the current World Health Organization classification system. (2) It can easily be misdiagnosed as PCFCL because it often displays a nodular architecture, includes numerous B cells, and expresses follicular markers, including CD10 and BCL6. (38,40) Similar to PCFCL, patients tend to be older (60 years) and present with multiple plaques, papules, and/or nodules, although they are more likely to be numerous, widely dispersed and involve the extremities. (38,41) However, close attention to the lymphoid infiltrate reveals that the neoplastic cells are atypical T cells that show a follicular helper T cell immunophenotype. (38,40) Primary cutaneous follicular helper T-cell lymphoma may also show syringotropism, a finding that is not seen in PCFCL. (38) These patients do not respond to rituximab. (38,40) Despite an overall indolent course, reported cases are surprisingly resistant to treatment, including multiagent chemotherapy. (40) Systemic/nodal follicular T-cell lymphoma may also mimic a follicular B-cell lymphoma and can secondarily involve the skin. (42) These patients typically have generalized lymphadenopathy and may have B symptoms. (43) Similar to primary cutaneous follicular helper T-cell lymphoma, these cases are composed of follicular helper T-cells that do not display typical centrocyte morphology; instead, they have round nuclei and relatively abundant cytoplasm. (43) Importantly, angioimmunoblastic T-cell lymphoma should be excluded in these T-cell lymphomas with follicular helper phenotype. (2,38)

Blastic plasmacytoid dendritic cell neoplasm is a rare myeloid neoplasm of immature plasmacytoid dendritic cells. (2) Patients are typically older men (60 years). This leukemia commonly involves the skin (Figure 6, A), and one series found that 9 of 33 patients (27%) had a solitary skin lesion and 20 of 33 patients (60%) presented in the skin with no evidence of systemic disease.44 Further complicating the interpretation, this leukemia may show a nodular growth pattern (Figure 6, B) and include centrocyte-like cells (Figure 6, C). (44) Immunohistochemical studies often reveal BCL2 expression (Figure 6, D), (44) and CD79a, BCL6, and MUM1 may also be positive (Figure 6, E). (2,44) These features can cause confusion with PCFCL. However, blasts can usually be identified, and hemorrhage is not uncommon; both features argue against PCFCL. The absence of expression of CD19, CD20 (Figure 6, F), and PAX5 and the expression of CD123 (Figure 6, G), CD4, and CD56 also help with correct classification. This neoplasm follows an aggressive course, even for patients with a solitary, skin-limited lesion, and patients are treated with systemic chemotherapy and bone marrow transplant.

PROGNOSIS AND TREATMENT

Primary cutaneous follicle center lymphoma has an excellent prognosis, even in cases with multifocal or recurrent disease, numerous centroblasts, or diffuse growth (5-year disease-specific survival >95%). (2-4,10,13,15-17) In fact, grading is not required in PCFCL because it provides no prognostic information. (2) The presence of BCL2 or BCL6 gene rearrangements or loss of 1p36 in PCFCL also does not affect prognosis. (13,18) Most cases do not spread beyond the skin (90%), although local recurrences are not uncommon (20%30%). (2,4,10-13,25) When it occurs, extracutaneous spread most commonly involves regional lymph nodes and the bone marrow. An important exception to the favorable prognosis in PCFCL is for PCFCL occurring on the legs. For unclear reasons, PCFCL in this location has a significantly worse prognosis, similar to that of PCDLBCL-LT, (4,12,36) although leg involvement is uncommon (5%). (4) Even weak expression of FOXP1, a marker associated with PCDLBCL-LT, is independently associated with poorer prognosis in multivariate analysis. (4) Primary cutaneous follicle center lymphoma on the leg is also more likely to express IgM. (28) Transformation to diffuse large B-cell lymphoma has been suggested in PCFCL and may be associated with MYC translocation. (8,9)

Even though PCFCL is an indolent lymphoma with excellent prognosis, treatment or close follow-up is important for these patients. (26) Untreated, lesions will enlarge and may become locally aggressive. (3,6,7) Primary cutaneous follicle center lymphoma can be successfully treated with surgical excision and/or local radiation therapy. (4,11,13,26,36) Radiation therapy is often used to achieve locoregional control, especially because many of these tumors arise near the face, where complete surgical excision may be challenging because of cosmesis. Recent evidence suggests that PCFCL can be successfully eradicated using significantly lower doses of radiation than in the past (eg, 4-12 Gy in a few fractions versus the traditional 24-36 Gy for several weeks) and that these lesions can be successfully retreated/salvaged in instances of local recurrence. (45,11) Because most of these lesions are small and superficial, low-energy electrons (6 mega-electron volt [MeV]) are typically used. Systemic rituximab can be used for patients with extensive skin lesions, and most patients achieve complete remission. (12,26) Systemic multiagent chemotherapy with or without local radiation therapy may be used in PCFCL with extensive disease, extracutaneous involvement, or lesions on the legs. (2,12,26)

CONCLUSIONS

Primary cutaneous follicle center lymphoma is a cutaneous low-grade B-cell lymphoma, which tends to occur on the scalp/forehead or trunk of middle-aged men. The differential diagnosis includes not only secondary cutaneous involvement by a systemic follicular lymphoma but also reactive lymphoid hyperplasia and other types of cutaneous B-cell lymphomas. Immunoglobulin heavy-chain and k light-chain gene rearrangement studies can help to support a diagnosis of PCFCL, but it is important to consider the possibility of false-positive or false-negative results. In general, PCFCL has an excellent prognosis when treated. However, aggressive behavior has been rarely described, and transformation to DLBCL has been suggested.

We thank Charles Ross, MD, for his thorough review of this manuscript.

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Stephanie L. Skala, MD; Boris Hristov, MD; Alexandra C. Hristov, MD

Accepted for publication May 18, 2018.

From the Department of Pathology, University of Michigan Medical Center, Ann Arbor (Drs Skala and A. C. Hristov); the Department of Internal Medicine, Section of Radiation Oncology, Wright Patterson Air Force Base (Dr B. Hristov); and the Department of Dermatology, University of Michigan Medical Center (Dr A. C. Hristov).

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology meeting; October 19-21, 2017; Ann Arbor, Michigan.

Corresponding author: Alexandra C. Hristov, MD, Department of Pathology, University of Michigan Medical Center, 1301 Catherine St, 3261 Med Sci I, Ann Arbor, MI 48109-5602 (email: ahristov@ med.umich.edu).

Caption: Figure 1. Clinically, primary cutaneous follicle center lymphomas commonly present as a tumor on the head (A) or papules and plaque-like lesions on the back (B). The latter has been called reticulohistiocytoma of the dorsum or Crosti lymphoma.

Caption: Figure 2. A, Primary cutaneous follicle center lymphoma (PCFCL) displaying a dense, dermal lymphoid infiltrate with a grenz zone. Abnormal follicles appear as irregular aggregates of larger cells with prominent eosinophilic stroma (B) and include a haphazard mixture of centrocytes and centroblasts without prominent tingible body macrophages (C). The PCFCLs stain positively for CD20 (D) and BCL-6 (E) with a high Ki-67 proliferation index that is not polarized (F) (hematoxylin-eosin, original magnifications X20 [A], X100 [B] and X600 [C]; original magnification X200 [D and E]; original magnification X100 [F]).

Caption: Figure 3. A, Systemic/nodal follicular lymphoma secondarily involving the skin is found as a dense dermal infiltrate separated from the epidermis by a grenz zone. B, Lymphoid cells display a centrocytic appearance with cleaved nuclei. Unlike typical cases of primary cutaneous follicle center lymphoma, this case of systemic/nodal follicular lymphoma showed CD20+ B-cells (C) that also expressed strong CD10 (D) and BCL2 (E) (hematoxylin-eosin, original magnifications X40 [A] and X400 [B]; original magnification X100 [C]; original magnification X100 [D]; original magnification X100 [E]).

Caption: Figure 4. A, Diffuse large B-cell lymphoma, leg type, characteristically presents with rapidly enlarging tumors on the legs. B, Biopsy shows sheets of lymphoid cells that replaced much of the dermis and are separated from the epidermis by a grenz zone. C, On closer inspection, lymphoid cells include centroblasts and immunoblasts (hematoxylineosin, original magnifications X40 [B] and X600 [C]).

Caption: Figure 5. Primary cutaneous follicle center lymphoma, with a diffuse growth pattern, may resemble diffuse large B-cell lymphoma, leg type, at low magnification (A), but it includes centrocytic cells on closer inspection (B). Differences in immunophenotype are also critical in separating these entities (see the Table) (hematoxylin-eosin, original magnifications X100 [A] and X600 [B]).

Caption: Figure 6. A, Blastic plasmacytoid dendritic cell neoplasm may resemble primary cutaneous follicle center lymphoma with hematolymphoid cells that replace much of the dermis and are separated by the epidermis by a grenz zone. These cells may form aggregates (B) and may resemble centrocytes (C). In addition, they may express BCL6 (D) and BCL2 (E). However, they lack CD20 (F) and are positive for CD123 (G), CD4 and CD56 (hematoxylin-eosin, original magnifications X40 [A], X100 [B], X600 [C]; original magnification X600 [D through G].
Considerations in the Differential Diagnosis of Primary Cutaneous
Follicle Center Lymphoma (PCFCL)

Lymphoma   Key Clinical          Cytology              Follicular
           Features                                    Architecture

PCFCL      Slow growing,         Intermixed              [+ or -]
             solitary or           centrocytes and
             localized lesions     centroblasts;
             on forehead or        prominent stromal
             trunk of middle-      component
             aged man

FL         B symptoms,           Centrocytes and         [+ or -]
             lymphadenopathy,      centroblasts,
             or other evidence     intermixed
             of systemic
             disease

DLBCL-LT   Rapidly growing,      Centroblasts and           -
           leg of older woman    immunoblasts

RLH        Usually head and      Centrocytes and        Intermixed
             neck or trunk in      centroblasts,          reactive

             setting of            polarized             secondary
             acneiform lesions                           follicles
             or bite

PCMZL      More likely to be     Centrocyte-like B     Follicular
             multiple, widely      cells, monocytoid   colonization;
             dispersed, lesions    B cells;plasma      intermixed,
             than in PCFCL         cells, Dutcher      reactive,
                                   bodies;             secondary
                                   eosinophils         follicles

Lymphoma   [CD3.sup.+] T Cells   Ki-67 Proliferation
                                        Index

PCFCL           Numerous         Often low in
                                   abnormal
                                   follicles, but may
                                   be high; not
                                   polarized

FL              Variable         Often low in
                                   abnormal
                                   follicles; not
                                   polarized

DLBCL-LT           Few           High in a diffuse
                                   pattern

RLH             Numerous

                                 High and polarized
                                   in follicles

PCMZL      Numerous              High and polarized
                                   in follicles

                 Extended

Lymphoma   Key Immunophenotypic    Other Helpful
           Features                Features

PCFCL      [BCL6.sup.+],           [BCL-6.sup.+] cells
             [CD10.sup.-/+],         extend beyond
             [BCL2.sup.-],           [CD21.sup.+/]
             [MUM-1.sup.-],          [CD23.sup.+]
             [IgM.sup.-],            follicular
             [FOXP1.sup.-]           dendritic network

FL         Strong CD10 and         t(14;18), 1p36
             BCL2 expression         deletion

DLBCL-LT   [BCL2.sup.+],           Few [CD3.sup.+] T
             [MUM-1.sup.+],          cells; rearrangements
             [FOXP1.sup.+],          of MYC and BCL6;
RLH          [IgM.sup.+],            amplification of BCL2;
             [BCL6.sup.+/-],         MYD88 mutations, and
             [C-MYC.sup.+/-]         loss of 9p21.3
             [CD10.sup.-/+]          (CDKN2A gene)

           Ideally, no             Superficial,
             immunophenotypic        wedge-shaped
             aberrancy

PCMZL      [CD43.sup.+/-];         Vertical orientation
             light chain-            of the lymphoid
             restricted              infiltrate around
             plasma cells;           follicles; peripheral
             [BCL2.sup.+],           plasma cells
             [CD10.sup.-],           surrounding aggregates
             [BCL6.sup.-],           of B cells; light
             and [CD5.sup.-]         chain restriction

Abbreviations: DLBCL-LT, diffuse large B-cell lymphoma, leg-type; FL,
follicular lymphoma; RLH, reactive lymphoid hyperplasia/
pseudolymphoma; PCMZL, primary cutaneous marginal zone lymphoma.
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Title Annotation:Special Section--2017 New Frontiers in Pathology, Part II
Author:Skala, Stephanie L.; Hristov, Boris; Hristov, Alexandra C.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Nov 1, 2018
Words:5210
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