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Localized Lymphomatoid Papulosis: Unilesional Lymphomatoid Papulosis, Regional Lymphomatoid Papulosis, And Persistent Agminated Lymphomatoid Papulosis

Open AccessPublished:July 27, 2022DOI:https://doi.org/10.1016/j.clindermatol.2022.07.010

      Abstract

      Lymphomatoid papulosis (LYP), the most common primary cutaneous CD30-positive lymphoproliferative disorder, is heralded by multiple papular and nodular lesions at anatomically discontiguous cutaneous sites. The histologic patterns are protean. A very uncommon form of LYP is one that is anatomically confined. Cases of unilesional lymphomatoid papulosis, regional lymphomatoid papulosis and persistent agmination of lymphomatoid papulosis were encountered in the routine and consultative practices of Weill Cornell Medicine, Division of Dermatopathology. The clinical presentation, outcomes, light microscopic findings and phenotypic profile are reviewed. There were ten cases of LYP presenting as solitary plaques or nodules primarily occurring in older patients and without a relevant past medical history in most. Most cases occurred at an acral site with many localized to the foot; the morphology of these was one of a necrotizing angiocentric type E pattern and borderline type C borderline morphology. Two of the unilesional patients in our series went on to develop mycosis fungoides, one at the initial site of unilesional type A LYP, and the other at a discontiguous site. Excluding one case, the solitary lesions underwent complete regression; after the lesions regressed, some cases had no apparent recurrence. The second anatomically confined variant of lymphomatoid papulosis in our series was regional LYP exhibiting a type E morphology in two cases and a hybrid type A and granulomatous eccrinotropic morphology in one case. There was no subsequent development of lymphoma nor was there any spread to additional anatomic sites. The final category was persistent agmination of lymphomatoid papulosis whereby the agminated papules of LYP were superimposed on a plaque of cutaneous T-cell lymphoma represented by mycosis fungoides in two and follicular helper T-cell lymphoma in one. In conclusion, anatomically confined lymphomatoid papulosis defines an uncommon form of LYP, but it is an important one to recognize as the histology can be worrisome despite an indolent clinical course. The clinical presentation, the infrequent association with lymphoma/leukemia and histology are similar to conventional LYP although there appears to be a greater tendency for complete regression without recurrence excluding cases of persistent agmination of LYP whereby the clinical course warrants categorization as a form of CTCL.
      INTRODUCTION
      The spectrum of cutaneous CD30-positive lymphoproliferative disorders encompasses lymphomatoid papulosis (LYP), primary cutaneous and secondary anaplastic large cell lymphoma (ALCL), borderline CD30-positive lymphoproliferative disorder, Hodgkin lymphoma either primarily or secondarily involving the skin, Epstein Barr Virus associated CD30 positive self-resolving T- and B- cell lymphoproliferative disease, CD30 positive variants of natural killer T-cell lymphoma and CD30-positive large B-cell lymphoma.1 Most cases are represented by anaplastic large cell lymphoma and LYP.2 An overzealous immune response can be associated with an accumulation of CD30 positive reactive T cells best exemplified by the striking immunologic responses to select viruses such as molluscum and herpes, as well as the CD30-positive angiocentric lymphomatoid drug reaction.3-7
      The striking array of cutaneous infiltrates that can be associated with CD30 expression reflects the nature of the CD30 molecule. While first described in the neoplastic lymphocyte of Hodgkin lymphoma and subsequently in other forms of T- and B-cell lymphoma, CD30 can be expressed in non-neoplastic hematopoietic cells of monocytic, T-cell, and B-cell lineage. The expression of CD30 does not always equate with a neoplastic hematopoietic process. Reactive monocytic and lymphocytic infiltrates expressing CD30 can be observed in the setting of a drug or viral trigger such as molluscum contagiosum and Epstein Barr virus and other infections including syphilis and nodular scabies. One might question a CD30 positive enriched lymphomatoid immune response as a potential precursor infiltrate to endogenous CD30 positive T-cell lymphoproliferative disease. The staining pattern within the activated benign lymphocyte mirrors those found in the neoplastic counterpart. In particular, a distinctive Golgi and cytoplasmic membrane pattern of staining typical for endogenous CD30-positive lymphoproliferative disease is also seen in the setting of reactive CD30-positive T-cell enriched lymphomatoid conditions. The CD30 cluster is an activation antigen that is part of the growth factor tumor necrosis factor family; the gene that encodes CD30 is found on chromosome 1p36.8,9 The ligand for CD30 is CD30L, which is a member of the tumor necrosis factor superfamily. The potential sequelae of a CD30 and CD30L interaction is one of apoptotic cell death in the cell expressing CD30.
      Lymphomatoid papulosis is recognized in the cutaneous lymphoma classification schemes of both the WHO and EORTC, representing the second most common form of T-cell lymphoproliferative disease after mycosis fungoides.10,11 Its first description by W. L. Macaulay in 1968 accurately summarizes this distinctive condition as one characterized by crops of papulonodular lesions at discontiguous cutaneous sites that undergo complete regression with subsequent recurrence at the same or different anatomic sites. Significant lymphoid atypia to define a histology that can mimic certain T-cell lymphomas is seen. Regardless of the extent of lymphoid atypia, including cases where the growth pattern is tumefactive and the cytology is a large cell dominant malignant appearing cell population to produce a picture that closely simulates anaplastic large cell lymphoma, the course is benign.12 In the original index paper, the self-regressing nature of the eruption was emphasized. Our conceptualization of LYP has evolved over the years. It now falls under the rubric of indolent T-cell lymphoproliferative disease given the fact that in most cases the clinical course is benign and there is no evidence of disease progression to frank lymphoma.
      The common clinical criteria currently used to diagnose LYP are:
      1. Multiple papules or nodules
      2. Lesions that undergo complete and not partial regression
      3. No evidence of progression to a diameter in excess of 3 centimeters during 3 months of observation without treatment
      4. Absence of lymphadenopathy13
      Despite a certain degree of uniformity in regards to the clinical presentation, there is significant morphologic heterogeneity in a given biopsy or between biopsies in the same patient. The most common morphologic variants have letter designations:
      • 1
        Type A is characterized by atypical angiocentric CD30 positive large, atypical cells that surround and permeate the blood vessels with variable vascular injury typically accompanied by many neutrophils and eosinophils including spongiform pustulation
      • 2
        Type B resembles mycosis fungoides and typically is characterized by an epidermotropic small cerebriform lymphocytic infiltrate that does not exress CD30
      • 3
        Type C is characterized by a tumefactive effacing infiltrate predominated by large, atypical CD30-positive T-cells with a morphology that resembles anaplastic large cell lymphoma; key in rendering this diagnosis is the natural history of the lesion which must be one of complete regression and ruling out any known history of cutaneous or nodal anaplastic large cell lymphoma14-16
      • 4
        Type D is a unique CD8-positive variant associated with epidermotropism of non-cerebriform lymphocytes and some degree of angiodestruction resembling primary cutaneous aggressive epidermotropic cytotoxic CD8-positive T cell lymphoma
      • 5
        Type E is a highly atypical angiocentric and angiodestructive infiltrate comprising a distinctive population of neoplastic T-cells that exhibit a CD8-positive, CD56-positive, or double negative phenotype. Given the baseline histology and phenotypic profile seen in type E LYP, this unusual morphologic variant can resemble an aggressive peripheral T-cell lymphoma associated with angiodestructionsuch as an NK/T-cell lymphoma or primary cutaneous gamma delta T-cell lymphoma
      There is a consensus that LYP is associated with antecedent, concurrent or subsequent development of lymphoma in a minority of cases. The incidence of the development of lymphoma is variable, but estimated to range between 4% and 20%.17-21 The most common lymphomas associated with LYP are anaplastic large cell lymphoma and mycosis fungoides (MF), although a broader spectrum of lymphomas is recognized and may include chronic lymphocytic leukemia, acute lymphoblastic lymphoma22 and Hodgkin lymphoma.16,18,23-32
      A series of 16 cases of anatomically confined LYP represented by three separate entities are presented, including unilesional LYP, regional LYP and persistently agminated LYP. The literature is also reviewed as it pertains to these three variants of lymphomatoid papulosis. The differences and similarities between unilesional LYP, regional LYP, and persistent agminated LYP are addressed.
      Materials and Methods
      Over a period of seven years, CMM has encountered a total of 16 cases that were interpreted as variants of anatomically confined LYP, primarily representing cases received in consultation, as well as those encountered in the routine diagnostic practice at Weill Cornell Medicine. A total of ten cases of unilesional LYP, three cases of persistently agminated LYP, and three cases of regional LYP are described from the time period of 2015 to 2022. The comprehensive phenotypic panel that had been conducted on the cases included antibodies to Beta F1, CD2, CD3, CD4, CD5, CD7, CD8, CD30, Granzyme and TIA-1. The study is a retrospective one based on existing material and was exempt from the Weill Cornell Medicine Institutional Review board. The immunohistochemical and molecular methods have been described previously. Cytogenetic studies to assess for the 6p25.3 translocation was conducted in certain cases.
      UNILESIONAL LYMPHOMATOID PAPULOSIS (TEN CASES)
      The ten cases of unilesional LYP predominately affected older individuals ranging in the 4th to 7th decade of life with a slight male predilection (i.e., six men versus four women). Five cases showed a hand or foot localization, two cases involved the forearm, two cases involved the chest, and the last involved the lip. A further detailed account will be given.
      A 63-year-old man presented with a solitary lesion in the chest area that was biopsied and held to be consistent with type A LYP. The lesion measured 2.5 centimeters in greatest diameter and followed a waxing and waning course over five years. A superimposed plaque developed, and while the papular lesions no longer recurred, the plaque was resistant to steroid treatment and did not undergo regression. A subsequent excisional biopsy showed classic features of patch stage mycosis fungoides without any residuum of type A LYP. The patient appeared to have progression of unilesional LYP to one of unilesional MF. The patch stage lesion demonstrated a typical small lymphocytic epidermotropic pattern characteristic for early patch stage mycosis fungoides. The margins were negative, and there was no subsequent recurrence. Additional lesions did not develop elsewhere.
      Five of the cases represented type E LYP based on a distinctive histology which will be described presently. The patients ranged in age from 56 to 71 years of age; there were two women and two men. The lesions involved the foot in all cases presenting as an expanding ulcer in three of the cases (Figure 1A). In one patient with nail bed involvement, the main clinical presentation was nail dystrophy and discoloration of the nail plate. The ulcers ranged in size from 1.5 centimeters to 3 centimeters in diameter. One patient received radiation which resolved the ulcerative lesion initially; however, the patient continued to develop recurrent dermatitis at the location which spontaneously regressed. One patient has one recurrent episode followed by complete regression per year. Another patient continues to experience an ulcerative lesion which spontaneously regresses approximately once per year. The last patient died of natural causes, and as such we were unable to gather clinical follow up. Additional lesions were not reported in any of the patients. One patient developed an ulcerative nodule on the arm a few months prior to presenting to the dermatologist. Of interest the development of the lesion was temporally associated with COVID-19 infection.
      Figure 1
      Figure 1Four of the cases of unilesional LYP presented as a solitary ulcerative lesion on the foot (A) (case 2). Histologically, these cases showed a necrotizing angiocentric infiltrate that was consistent with type E LYP (B, H&E 20x): in particular larger atypical lymphocytes surrounded and permeated blood vessels with evidence of vascular destruction (C, H&E 400x). These large, atypical lymphocytes are positive for CD8 (E, 400x) and CD30 (F, 400x), while demonstrating loss of CD7 (D, 400x) (B through F Case 6).
      In two of the unilesional cases, the patients presented with solitary lesions typical for a form of type C borderline lymphomatoid papulosis most reminiscent of a variant of type C lymphomatoid papulosis associated with a 6P25.3 rearrangement.33 The cases included one male and one female; their ages were 65 and 78 years old respectively. The affected sites were chest and finger. In neither of these type C borderline cases could a definitive cytogenetic abnormality be identified due to the material submitted being deemed unsatisfactory for cytogenetic assessment. One of the patients, the 78-year-old man, had complete regression of his solitary lesion of LYP with methotrexate therapy. A year later, he had developed multiple non-regressing plaques in the groin area diagnostic of patch stage CD8 positive mycosis fungoides and advanced tumor stage mycosis fungoides with evidence of CD30 positive transformation despite. In the other patient, the finger lesion underwent spontaneous regression; two years after her initial presentation, she is alive and well without evidence of cutaneous and/or extracutaneous disease.
      One patient presented with a small, crusty, and keratotic patch on her left ventral distal forearm. This lesion was initially irradiated after the clinician understood the diagnosis to be mycosis fungoides with large cell transformation. The lesion at this site then regressed. The patient later went on to develop a similar appearing lesion on her right ventral proximal forearm. The histology of this lesion showed overlapping features of type B and type C lymphomatoid papulosis. Review of the previous biopsy revealed the same histologic findings. This case represents the remarkable phenomenon of unilesional lymphomatoid papulosis targeting an anatomically similar area, (i.e. contralateral forearms), and still falling under the distinction of unilesional LYP but in a metachronous context.
      Another patient presented with a solitary, small, ulcerative lesion on his left ventral forearm following a second Coronavirus Disease 2019 (COVID-19) infection. As he is in his early 20s, he is the age group outlier of this cohort.
      The final patient with unilesional LYP had a single, non-ulcerative, small papule on his right lower lip that spontaneously regressed without treatment. Another small papule in the same anatomic location recurred and then regressed a year later. At the time the patient initially presented, he was diagnosed with monoclonal B cell lymphocytosis and now more recently the patient fulfills hematologic criteria for chronic lymphocytic leukemia (Figure 2A).
      Figure 2
      Figure 2Clinically, the patient had a small and unimpressive papule (A). The light microscopy (B, H&E 200x) shows a highly atypical lymphocytic infiltrate involving both the epidermis and the dermis. The epidermis contains a smaller cerebriform lymphocytic infiltrate, while the dermis exhibits a large cell tumefactive infiltrate. Immunohistochemical stains for Beta F1 (C, 200x) and CD30 (D, 200x) highlight the atypical lymphocytes (case 8).
      Light Microscopic Findings
      In five of the unilesional cases, there was a highly atypical perivascular mononuclear cell infiltrate throughout the dermis (Figure 1B). The abnormal cells were in the 20-30-micron size range; they exhibited asymmetrically thickened membranes with nuclear contour irregularity and large multiple basophilic nucleoli (Figure 1C). The severely atypical cells surrounded and permeated a few of the vessels; there was evidence of vascular injury characterized by mural and luminal fibrin deposition (Figure 1C). Accompanying ischemic alterations including epidermal necrosis with frank ulceration were observed. The biopsies showed signs of regression characterized by a reduction in the intensity of the infiltrate, a greater degree of small lymphocytic infiltration and a component of neovascularization. Inflammation around the eccrine coil was very common. There was highlighting of the abnormal cells with the pan T cell marker CD3; the lymphocytes exhibited a marked loss in the expression of CD7 (Figure 1D). A CD8 phenotype was noted in two cases, a CD4 phenotype was identified in two other cases and a double negative phenotype was observed in one case (Figure 1E). The atypical cells showed extensive immunoreactivity for CD30 (Figure 1F). The combined light microscopic and phenotypic profile was consistent with type E LYP.
      In two unilesional cases, the histologic findings were compatible with type C lymphomatoid papulosis. The biopsies showed a highly atypical lymphocytic infiltrate involving both the epidermis and dermis. Within the epidermis, there were discrete aggregates of atypical cells; several lymphocytes demonstrated markedly hyper-convoluted cerebriform outlines typical for those encountered in mycosis fungoides. Within the dermis, there was a tumefactive proliferation of atypical lymphocytes. Many of the cells were in the 15- to 20-micron size range and exhibited an open chromatin, non-cerebriform nuclear contour irregularity and conspicuous nucleolation. There was extensive highlighting of the epitheliotropic and dermal infiltrate with CD3, MUM1 and CD30 (Figure 3E). Both cases showed variable loss of CD2, CD5 (Figure 3B), and CD7 (Figure 3C). The atypical cells were CD8 (Figure 3D) and granzyme positive (Figure 3F) in one case and CD4 positive in one case (Figure 3A). The histologic findings were suggestive of a unique form of type C lymphomatoid papulosis, namely one associated with a 6p25.3 rearrangement. The FISH assay was unsuccessful as no hybridization signals were observed in the cells analyzed.
      Figure 3
      Figure 3The forearm lesion demonstrates a tumefactive and very atypical neoplastic lymphocytic infiltrate of T-cell lineage within the dermis. High power magnification reveals large atypical mitotically active immunoblastic cells (D, H&E 400x). Extensive immunohistochemical workup showed a significant decrement in staining for CD5 (D, 200x) and CD7 (E, 200x), while demonstrating extensive positivity for CD8 (F, 200x) and CD30 (G, 200x). Despite, the degree of atypia and predominance of CD30-positive large cells, this lesion spontaneously regressed without any therapeutic intervention (case 9).
      In one case, the histologic findings were consistent with type A lymphomatoid papulosis. In particular, there was a nodular infiltrate composed of large immunoblastic appearing lymphocytes admixed with smaller lymphocytes and histiocytes, neutrophils and eosinophils surrounding and permeating sampled blood vessels; while some degree of vascular injury was identified it was not to a degree that resulted in ischemic undermining of the skin sample. The immunoblastic cells exhibited prominent nucleoli and abundant grayish cytoplasm. The atypical lymphocytes were highlighted by CD30 and CD2 although showed a loss of CD7. This patient developed mycosis fungoides with without any evidence of residual type A LYP.
      In two casesthe histologic findings showed an overlapping morphology of type B and type C lymphomatoid papulosis (Figure 2B). There was one population of small, atypical cerebriform lymphocytes which exhibited epitheliotropism. The dominant cell population was, however, one of larger and highly atypical lymphocytes which show striking tumefactive growth within the dermis, hence resembling anaplastic large cell lymphoma or transformed mycosis fungoides given the background smaller cerebriform epidermotropic T-cell infiltrate. The neoplastic cells expressed BetaF1 (Figure 2C) and showed a marked decrement in staining for CD3, CD5, and CD7, while the abnormal cells expressed CD8. CD30 expression was largely confined to the larger cell population (Figure 2D). Cytogenetic studies to asses for a chromosome 6p25.3 rearrangement were not satisfactory due to inadequate material let on the slides to conduct the assays.
      Case 11 PERSISTENT AGMINATION OF LYMPHOMATOID PAPULOSIS WITH OVERLAPPING FEATURES OF MYCOSIS FUNGOIDES, TYPE B AND TYPE C LYMPHOMATOID PAPULOSIS
      Case History
      The patient was an otherwise healthy 32-year-old man who presented with a regionally confined area that was several centimeters in diameter characterized by coalescing papules and nodules superimposed on a somewhat infiltrative, hyperpigmented base on the leg that had been present for three months (Figure 4a). The papular nodular lesions had undergone varying stages of regression, while the underlying plaque was persistent. One papular nodular lesion demonstrated ulceration (Figure 4b). The only treatment the patient received was topical corticosteroids which resulted in healing the ulcerative lesion and shrinking the plaque (Figure 4c). With a combination of time and topical steroids, the plaque has improved significantly, although has not regressed completely. The papular nodular lesions overlying the plaque have remained persistent.
      Figure 4
      Figure 4The initial clinical presentation of persistent agminated LYP showed crops of papules and nodules superimposed on a hyperpigmented base (A), and there was no evidence of regression over a five-month period. However, one of the papules evolved into an ulcerative lesion (B). While the ulcerative component healed following treatment with topical steroids, residual disease was still present and characterized by the remaining hypopigmented plaque along with the persistent papules and nodules (C) (case 11).
      Light Microscopic findings: The biopsy was remarkable for a very atypical epidermotropic and pan-dermal lymphocytic infiltrate. The intraepidermal lymphoid populace extensively colonized the lower half of the epidermis; there was a fairly passive pattern of colonization without significant epithelial destruction. The intraepidermal lymphocytes were severely atypical and defied categorization as a pre-lymphomatous T-cell dyscrasia. The cells were smaller but as well larger atypical cells were noted. This aspect of the atypical infiltrate was most suggestive of mycosis fungoides; however, there was also a dermal infiltrate that was very extensive. The infiltrate extended deep and infiltrated the adventitial dermis of the eccrine coil but also surrounded nerves and blood vessels. There was a decrement in the extent of the infiltrate, as the base of the infiltrate was approached with ensuing fibrosis and a component of neovascularization compatible with regression. The dermal inflammatory cell infiltrate exhibited overlapping features of eccrinotropic LYP and type A LYP.
      Phenotypic Profile
      There was extensive highlighting of the infiltrate for the pan T cell markers CD2 and CD3 although there was a significant decrement in staining for CD5 and CD7. The larger atypical cells surrounding blood vessels and found within the adventitial dermis of the eccrine coil were positive for CD30 and CD8. The Ki-67 proliferation index was in the 30 to 40% realm within the dermal zones of large cell infiltration.
      Case 12 PERSISTENT AGMINATION OF LYMPHOMATOID PAPULOSIS WITH FEATURES OF THE SMALL LYMPHOCYTIC ECCRINOTROPIC GRANULOMATOUS VARIANT
      Case History:
      The patient was a 77-year-old woman presented with a persistent infiltrative plaque comprising agminated violaceous papules in a background of hyperpigmentation and focal hypopigmentation that began in in the latter part of 2019. While the individual papules may have undergone regression, there has always been some evidence of a regionally confined plaques with superimposed fluctuating papules. The plaque has been treated intermittently with intralesional corticosteroids. After 4 injections of 5 milligrams of trimancinolone acetate per injection, the plaque is inactive without any recurrent papular lesions and the plaque. Although still visible, it appears significantly less infiltrative. If the plaque was worsening, the lesion would have been treated with radiation, however, given the quiescent nature of the lesion the patient has not undergone any further treatment; at this point in the patient's clinical course she is being followed clinically without any treatment intervention (Figure 7A-C).
      Light Microscopic Findings:
      There were multiple biopsies taken over a period of time. They appeared similar. They both demonstrated a superficial and deep nodular vasocentric, peri-neural and peri-eccrine lymphocytic infiltrate with scattered eosinophils (Figure 7D). As with the subsequent biopsy, it was an infiltrate that was predominated by smaller lymphocytes with some degree of atypia characterized by cells manifesting irregularly contoured and focally angulated nuclear outlines with nuclear hyperchromasia; there were a few larger atypical lymphoid elements. Injurious vascular changes were observed as evidenced by mural and luminal fibrin deposition with concomitant red cell extravasation. A subtle interstitial granulomatous component along with interstitial mucin and focal fibrosis were observed.
      Phenotypic Studies:
      Phenotypically the infiltrate represented a mixture of CD4 and CD8 T-cells; the ratio was within normal limits. There were a few CD30-positive larger atypical lymphocytes.
      Case 13 PERSISTENT AGMINATION OF LYMPHOMATOID PAPULOSIS IN A BACKGROUND OF PRIMARY CUTANEOUS SYRINGOTROPIC T-CELL DYSCRASIA OF PROBABLE FOLLICULAR HELPER T-CELL ORIGIN
      Case History:
      The patient is a 69-year-old man with persistent dermatitis on the left arch for three years. There are superimposed lesions which periodically ulcerate and regress. He has received no treatment. The ulcerative papular lesions undergo a course of spontaneous regression and recurrence while the baseline plaque remains unchanged (Figure 5a1).
      Figure 5
      Figure 5The patient has a persistent rash on the arch of their foot, with a superimposed ulcerative lesion that undergoes partial, but never complete regression. The biopsy of the ulcerative lesion shows a deep-seated eccrinotropic lymphocytic infiltrate (A, H&E 20x). The lymphocytic infiltrate permeative of the ducts and glands is one comprising small to intermediate sized lymphocytes with nuclear contour irregularities (B, H&E 400x), but without a cerebriform morphology. This infiltrate is primarily one of a CD4 (C, 400x) subset, with preservation of CD5 (D, 400x) and CD7 (E, 400x). Reactive CD8 (F, 400x) positive cells are present. There are very occasional CD30 (G, 400x) positive staining cells (case 12).
      Light Microscopic Findings:
      The background dermatitis demonstrated a very striking superficial band-like lymphocytic infiltrate with a component of neovascularization along with a deeper-seated eccrinotropic lymphocytic infiltrate, whereby lymphocytes surrounded and permeated the ducts and glands of the eccrine coil (Figure 5a2). The epidermis was infiltrated by small, degenerated leukocytes. In examining the lymphocytic infiltrate including that permeative of the ducts and glands, the infiltrate was one comprising small to intermediate sized lymphocytes manifesting nuclear contour irregularity(Figure 5b), although without a frankly cerebriform cytology. The other specimen, which was of the ulcer, showed a completely regressed process, whereby there was an ulcer and a minimal lymphocytic infiltrate. There was an admixture of neutrophils and plasma cells. The lymphocytes were similar to those noted on the first specimen but the reduction in the extent of lymphocytic infiltration was around 90%; the ducts and glands showed some patulous ectasia.
      Phenotypic Studies:
      The CD3 stain highlighted the lymphocytes in the epidermis, the superficial dermis, and the ducts and glands of the eccrine coil. The lymphocytic infiltrate is also highlighted by CD7. Compared to CD3, there was some decrement in staining, likely in the 20% to 30% realm. The CD20 preparation showed a minimal infiltrate with only rare positive staining B cells. The CD4 to CD8 ratio was in excess of 10 (Figure 5c; Figure 5f); there was preservation of CD5 (Figure 5d) and CD7 (Figure 5e). The atypical small lymphocytes were extensively PD1-positive including the syringotropic atypical lymphocytes. As one would expect with this small cell-dominant infiltrate, the Ki-67 proliferation index was very low, around 1%. A CD30 stain demonstrated rare positive staining cells (Figure 5g).
      Case 14 REGIONAL LYMPHOMATOID PAPULOSIS EXHIBTING OVERLAPPING FEATURES OF GRANULOMATOUS ECCRINOTROPIC, FOLLICULOTROPIC AND TYPE E VARIANTS
      Case History:
      The patient was a 43-year-old man with recurrent plaques on his forehead over the last three years, some appearing to ulcerate. He has had at least three prior episodes whereby each episode resolved, leaving a significant depression. With each episode, a biopsy was performed. The biopsies had been interpreted as a primary inflammatory process including one of facial cellulitis.
      Light Microscopic Findings:
      The most recent biopsy showed a very striking inflammatory cell rich process associated with significant necrosis including full thickness epidermal necrosis (Figure 6a). The dermis was remarkable for a dense lymphocytic and histiocytic infiltrate intimately apposed to the hair follicle, eccrine coil and blood vessels whereby the infiltrate surrounded and permeated vessels with injurious vascular alterations as revealed by the degree of mural and luminal fibrin deposition. The lymphocytes exhibited a heterogeneous mixture comprising small and intermediate sized lymphocytes and a number of transformed elements. The larger immunoblastic forms exhibited conspicuous nucleolation (Figure 6b).
      Figure 6
      Figure 6In case 13 a biopsy of the forehead ulcer showed full thickness epidermal necrosis with a dense and deep lymphohistiocytic infiltrate containing numerous eosinophils (B, H&E 20x). Higher power magnification demonstrates that the inflammatory infiltrate permeates the eccrine coil (C, H&E 200x) as well as nerves and blood vessels (D, H&E 200x) with notable injurious vascular changes. Immunohistochemistry shows that the lymphocytic component of the infiltrate is largely represented by CD4 (E, 200x) positive T-cells, with some loss of CD5 (F, 200x) staining and significant decrement in CD7 (G, 200x) staining. The CD8 (H, 200x) stain highlights a prominent population of larger lymphocytes, while the CD30 (I, 200x) preparation stains the atypical cells throughout the infiltrate (case 14).
      Figure 7
      Figure 7This case of persistent agminated LYP presented as crops of papules on the left inner thigh (A), which was initially thought to be nummular dermatitis. Some of the lesions spontaneously regressed, with new papules presenting a few months later (B). These lesions did improve on topical therapy, and an itchy rash developed underlying the persistent papules (C). After multiple Kenalog injections, the papules regressed and the rash diminished with only a quiescent area of discoloration remaining (D). The biopsy showed a striking superficial and deep perivascular and eccrinotropic lymphocytic infiltrate comprising a heterogeneous mixture of small relatively bland appearing lymphocytes intimately admixed with larger atypical lymphocytes that were phenotypically shown to be CD30 positive (E).
      Phenotypic Studies:
      Phenotypic studies demonstrated positivity of the infiltrate for CD2, CD3, and CD5. There was a 50% significant decrement in staining for CD7. A CD30 preparation showed positivity of the larger atypical cells that were dispersed throughout the infiltrate (Figure 6c); as well the cells showed very focal TIA and granzyme staining. The CD4 to CD8 ratio was within normal limits, although the larger atypical cells were primarily of the CD8 subset.
      Case 15 REGIONAL TYPE E LYMPHOMATOID PAPULOSIS
      Case History:
      The patient was a 70-year-old man who had a regional eruption confined to his ankle and foot. The ankle eruption appeared similar to the dermatitis that is currently on the bottom of the foot. The ankle process had since resolved. The lesions on the foot undergo ulceration and appeared to be responding to steroid cream. The clinical images show discrete ulcerative erythematous plaques and papules on the plantar surface of the foot. They appeared to be focally agminated in the center of the foot. The main medial heel lesion has remained persistent, while the surrounding lesions have regressed.
      Microscopic Findings:
      The biopsy showed very striking epidermal and superficial dermal necrosis in association with a dense lymphohistiocytic infiltrate that was found in intimate apposition to blood vessels, nerves, and the eccrine coil. Frank vasculitic changes with ensuing ischemic alterations were observed. The lymphocytes were heterogeneous comprising a mixture of small, intermediate, and a number of larger atypical lymphoid forms. Comprehensive phenotypic studies were performed.
      Phenotypic Studies:
      There was extensive highlighting of the infiltrate for the pan T-cell markers CD3 and CD5. There was, however, a decrement in staining for CD7. The reduction is in the 50% realm. The atypical larger lymphocytes stained positively for CD8 and CD30.
      Case 16 REGIONAL TYPE E LYMPHOMATOID PAPULOSIS
      Case History:
      The patient was a 32-year-old woman who presented with an ulcer in the upper inner aspect of the left calf; the clinical impression encompassed ecthyma gangrenosum vasculitis and calciphylaxis. The patient subsequently developed additional similar ulcerative lesions that flowed a course of complete regression in the same vicinity. Intralesional steroids facilitated regression of the lesions. After this initial outbreak of lesions, they underwent full regression with the help of intralesional steroids; she has had no additional recurrent episodes six years after her initial diagnosis (Figure 8A-D).
      Figure 8
      Figure 8The cases of regional LYP involved multiple lesions spanning an anatomically confined site. The ulcerative inner thigh lesions (A) responded to intralesional Kenalog injections (B) without further recurrence (case 16). The erythematous and erosive foot lesions (C) have a variable response to topical steroids, and the ankle lesion (D) has remained persistent despite topical treatment (case 15).
      Microscope Findings:
      The biopsy showed a very striking angiocentric pan dermal atypical mononuclear cell infiltrate that was both superficial and deep accompanied by frank vasculitic changes. In addition, there was accentuation of the infiltrate around the eccrine coil and as well the infiltrate was permeative of the epidermis. The dominant vascocentric infiltrate was a larger atypical cell in the 20-30-micron size range that surrounded and permeated the vessel wall. The cells had conspicuous eosinophilic nucleoli and exhibited a finely dispersed chromatin; cytoplasms were moderately abundant and eosinophilic in quality. There was an admixture of smaller lymphocytes and histiocytes.
      Phenotypic Studies:
      The infiltrate was highlighted by the pan T-cell markers CD2, CD3, and CD5; there was a significant reduction in staining for CD7. The larger atypical cells stained for CD4, TIA-1, granzyme and CD30. CD20 highlights a few reactive B cells in the background.
      Molecular Studies:
      A monoclonal T-cell rearrangement was detected.
      Discussion
      We have presented 16 cases of anatomically confined LYP. In ten patients, the lesions were in the context of solitary plaques and or nodules. We also presented three patients with regional LYP and 3 cases of persistently agminated LYP. The current literature devoted to the topic of an anatomically limited form of LYP are in the context of regional LYP, where the cases are characterized by discrete separate nodules and or papules confined to one anatomic region. The vast majority of cases of LYP present as recurrent crops of papulonodular lesions at discontiguous anatomic sites on the skin with each regressing crop involving different anatomic sites.
      Our cases of unilesional LYP presented primarily in older individuals in their fifties, sixties and seventies but one patient was in his thirties; there was a slight male sex predilection. Most patients were previously healthy; one patient reported a potential temporal association with COVID-19. In addition, there was an unusual predilection for acral sites. Most cases occurred at an acral site, largely involving the foot and including the toes, while additional other sites included the face, chest and forearms. All four acral cases located on the foot and one case involving the forearm showed a necrotizing lymphomatoid vasculitis with resultant ischemic injury of the skin consistent with type E LYP. In none of our cases did additional lesions of LYP develop at other anatomic cutaneous sites. This distinction is important to specify; in the original series reporting type E angiodestructive LYP, patients presented with one or two ulcers per episode, but it was not clear if the recurrent lesions were specifically at this same site.34 Two of the unilesional patients in our series went on to develop mycosis fungoides, one at the initial site of unilesional type A LYP and the other at the groin, discontiguous from the initial site of the type C LYP diagnosis. The disease progression in both cases was heralded by the progressive expansion of a plaque with persistence. One patient in this series was discovered to have clonal B-cell lymphocytosis. There was no antecedent history of a hematologic dyscrasia or subsequent development of a hematologic malignancy in the remaining five cases. Apart from the one patient who developed MF at a site of waxing and waning LYP, the solitary lesions in the other cases underwent complete regression, some after treatment. After the lesions regressed, some cases had no apparent recurrence, which defines a clinical course that differs from classic LYP where the recurrent nature of the eruption can be protracted over many years.
      In the unilesional presentations, over half of the cases exhibited classic features of type E lymphomatoid papulosis. The hallmark is one of a necrotizing lymphomatoid vasculitis. Atypical larger neoplastic cellular elements surround and infiltrate the vessel wall and there is ensuing significant vascular injury heralded by luminal and mural fibrin deposition. Two additional patients, showing a tumefactive effacing growth pattern of large atypical accompanied by a small cerebriform epidermotropic pattern were encountered; the morphology was most reminiscent of a variant of type C LYP associated with a deletion in chromosome 6p25.3, although this particular cytogenetic abnormality could not be confirmed. One patient had the classic type A morphology.33 It is reasonable to state that cases exhibiting a unilesional presentation manifest a more aggressive and atypical histology; paradoxically, the clinical course is one of regression without multiple recurrent episodes.
      As for the destructive angiocentric lymphomatoid reaction encountered in almost half of the patients, one might consider a type of aggressive peripheral T-cell lymphoma that can exhibit angiocentricity such as a gamma delta T-cell lymphoma and NK/T-cell lymphoma. A phenotypic scenario could emerge where those diagnostic considerations seem plausible if there is a null phenotype and as well, if the atypical cells express CD56. In most instances, the atypical T-cells are CD4 positive and as well the extensive CD30 positivity is supportive of a diagnosis of endogenous CD30 positive lymphoproliferative disease but there is a caveat which is that NK T cell lymphomas can in fact express CD30.35,36 Often a significant background inflammatory cell infiltrate can be an important clue, specifically in regards to spongiform pustulation and significant tissue eosinophilia, findings that support a diagnosis of lymphomatoid papulosis.
      Due to the general unfamiliarity of most physicians with unilesional lymphomatoid papulosis, a diagnosis could escape detection. In fact, in one of our cases, the patient had multiple skin biopsies, and none were diagnosed as a neoplastic process. All specimens were held to represent a reactive process reflective of a traumatic ulcer. The severity of vascular involvement resulted in ischemic undermining in a number of the cases. Any recurrent ulcer in one location showing a mixed perivascular and deeper seated eccrinotropic inflammatory cell should be considered suspicious for lymphomatoid papulosis. While the histomorphologic differential diagnosis would encompass an arthropod bite reaction, the unique clinical circumstances of a lesion that is recurrent in an anatomically restricted area would be considered most unusual.
      Reported cases in the literature under the designation of unilesional LYP is limited to one anecdotal case report. A 2018 report included a patient with unilesional locally recurrent lymphomatoid papulosis and a variable histologic presentation.37 A 72-year old woman was referred in 2004 with a single lesion that was roughly 5 millimeters in diameter situated under the right knee without other skin lesions. The biopsy showed a very atypical angiocentric infiltrate comprising T cells that expressed CD30, CD43, and perforin expression but without immunoreactivity for CD3. Given the extent of the infiltrate and degree of large cell transformation, the findings were held to be consistent with type C borderline lymphomatoid papulosis. The first episode in fact occurred in 2001. Over time the morphology evolved whereby the original biopsy showed a type C morphology while the two subsequent recurrences in 2009 and 2013 demonstrated a type B morphology, hence resembling mycosis fungoides. The lesions lasted a total of 4 to 6 weeks before recurring. The individual lesions did not exceed 1 centimeter in diameter. Of interest was the fact that each recurrent episode was treated with an excision. Apart from this one case report, to our knowledge there are no additional papers on unilesional LYP.
      Another anatomically confined variant of lymphomatoid papulosis in our series was regional LYP characterized by typical lesions of lymphomatoid papulosis confined to one region of the skin. In the original index series the authors described four patients ranging in age from 12 to 47 years of age who developed LYP in a segmental unilateral distribution; two of the patients had type A LYP and two patients had the type B variant.38 In the two patients who received radiotherapy to the area there was no further lesional recurrence. One patient developed conventional multifocal LYP 24 years after his initial episode of regional LYP.
      In accordance with the definition of regional LYP, lesions are confined to a single anatomic site most commonly in the buttock and trunk areas. Regional LYP patients are younger than in conventional LYP with a mean and median age of 31 and 33 years respectively along with a male predominance. There is one documented case of a secondary malignancy.39 We encountered three cases of regional LYP ranging in age from 32 years to 70 years of age; in two of the cases the morphology captured was one of type E lymphomatoid papulosis while the last case demonstrated a hybrid type A and granulomatous eccrinotropic morphology. The cases followed a course typical for conventional lymphomatoid papulosis being one of regression followed by a recurrence. In two cases the lesions, although initially recurrent, ultimately regressed completely without subsequent recurrence. One case still shows recurrent papules.
      A unique variant of localized lymphomatoid papulosis falls under the designation of persistent agmination of lymphomatoid papulosis.40 There are roughly 13 cases of this entity described in the literature. As suggested by the designation of agmination, it refers to the presence of a localized area of papular nodular lesions whereby each of the papular nodular foci are typical for LYP represented by any of the histologic variants. The distinct crops of papulonodular lesions occur in an erythematous background, the latter suggestive of mycosis fungoides. The area of involvement is characteristically several centimeters. It has been suggested that this variant of LYP is really a form of lymphoma since the lesions are persistent and if left untreated, transformation into mycosis fungoides may occur.40 Recently, one group reported that seven of their nine cases exhibited persistent disease and had to undergo further treatment primarily with radiation to induce lesional regression. Of these nine total cases, two progressed to more conventional disseminated LYP; neither of these showed features of persistent disease.41
      In our three cases of persistent agmination of lymphomatoid papulosis, the patients were 32, 69 and 77 years. The histologic findings combined type C lymphomatoid papulosis and type B lymphomatoid papulosis in one case. The extent of large cell infiltration exhibited an almost tumefactive growth pattern within the dermis; the infiltrate demonstrated features reminiscent of type C borderline LYP. The extensive epidermotropic pattern also encompassed smaller atypical epidermotropic lymphocytes. As to whether or not one would designate the process as so called type D LYP because of the prevalence of CD8 T cells in the epidermis and dermis it would be reasonable to use that designation if the histology resembled primary cutaneous epidermotropic cytotoxic CD8 positive T cell lymphoma. The cells would be smaller, non-cerebriform without this degree of large cell transformation and as well would show a proclivity to surround and permeate blood vessels leading to a destructive lymphomatoid vasculitis. Regarding the other two cases, a type A lymphomatoid papulosis pattern was seen in one patient and a small cell dominant granulomatous eccrinotropic morphology in the other. In two of the three cases there were background features of mycosis fungoides representing the persistent non-regressing component of the lesion while in one patient the background non-regressing plaque of the foot arch was an acral syringotropic T cell lymphoma of follicular helper T cell origin. The designation of syringotropic mycosis fungoides was not use due to the atypical non-cerebriform cytology of the cells and the overall phenotypic profile which showed extensive immunoreactivity for PD1 and BCL6 with preservation of CD7. One case partially responded to topical steroids. The individual LYP like papular and nodular lesions partially improved while the hyperpigmented plaque became less infiltrative. Complete regressionof the plaque was not achieved. The other case showed an excellent response to four sessions of intralesional steroid injections. The final patient is currently being evaluated and has not received any treatment.
      LYP presenting in an anatomically confined fashion is an uncommon expression of this form of indolent T-cell lymphoproliferative disorder. In cases where there is a tumefactive growth of highly atypical, transformed lymphocytes as we encountered in a few of our cases, the differential diagnosis is one of a peripheral T-cell lymphoma, specifically in regards to anaplastic large cell lymphoma. There are two practical points that allows relatively easy distinction of LYP from anaplastic large cell lymphoma. The first concerns the size of the lesion. Typically, in anaplastic large cell lymphoma the tumor is largely than three centimeters in size. The second aspect relates to the regressive tendency of lymphomatoid papulosis. Only 25% of cases of anaplastic large cell lymphoma are associated with spontaneous regression. Therefore, the clinical history is of paramount importance in the separation of LYP from anaplastic large cell lymphoma. In fact one case that had been incorporated into the original study was eliminated eventually when we discovered that the patient had an established history of nodal anaplastic large cell lymphoma. At the time the patient presented to the dermatologist both the dermatologist and the pathologist were under the impression that the patient's past medical history was unremarkable. Likely rendering a diagnosis of borderline type C LYP should be made with caution and with a caveat which is that anaplastic large cell lymphoma either primary or secondary can never be excluded without a thorough history and examination.
      Due to the degree of inflammation around nerves, the hair follicle and eccrine coil that was seen in several of the cases in this series there is a significant morphologic overlap with reactive conditions such molluscum contagiosum and folliculocentric herpes.42 Like LYP, molluscum contagiosum and folliculocentric herpes can be recurrent and of course in any persistent immunologic response transformed cells expressing CD30 can be observed and there can be lymphoid atypia and additional phenotypic abnormalities. The concept of a lymphomatoid reactive response triggered by a virus is an established one and can be a source of diagnostic confusion from LYP.
      Conclusion
      Anatomically confined lymphomatoid papulosis is defined by unilesional lymphomatoid papulosis, regional lymphomatoid papulosis and persistently agminated lymphomatoid papulosis. The entity of persistent agminated variant remains indeterminate in regard to categorization but it is likely safe to state that cases that do not undergo full regression are better categorized as a form of cutaneous T-cell lymphoma with superimposed LYP. Cases that represent unilesional lymphomatoid papulosis have a tendency to occur in older patients with a peculiar proclivity for acral involvement; the histology is disproportionately represented by a necrotizing lymphomatoid vasculitic variant, namely type E lymphomatoid papulosis or a borderline type C morphology. When presenting in this unilesional context, the course is usually benign but just like conventional LYP, patients may develop lymphoma; in our own series two patients developed MF while one patient was discovered to have monoclonal B-cell lymphocytosis and was later diagnosed with chronic lymphocytic leukemia. The basis for recurrent lymphoproliferative disease at one anatomic site is unclear. One could hypothesize a role of circulating neoplastic memory T-cells to repopulate the same anatomic site involves unique homing mechanisms that may recapitulate those involved in other recurrent localized forms of cutaneous T-cell infiltration.
      Table 1SUMMARY OF ANATOMICALLY CONFINED LYP
      Case #AgeSexLocationHistoryDiagnosisOutcome
      UNILESIONAL171MToe

      lesion
      Initially diagnosed with an infection for which he received antibiotics and wound care without improvement.  After a diagnosis was made of type E lymphomatoid papulosis, he was placed on methotrexate and the lesion underwent complete regressionTYPE E LYMPHOMATOID PAPULOSISresolved with methotrexate
      261MFootThe patient presented with a solitary ulcer on the foot. After a diagnosis was made of type E lymphomatoid papulosis, the patient received corticosteroids.TYPE E LYMPHOMATOID PAPULOSISresolved with corticosteroids
      371FRight second great toe/ pigmented lesionThe patient presents with a pigmented lesion on the nail bed of her right second great toe whereby the tip of the toe appeared hypertrophic and there was conconitant nail dystrophyTYPE E LYMPHOMATOID PAPULOSISlost to F/U
      478MRight chestThe patient presents with a neoplasm of uncertain behavior versus irritated

      seborrheic keratosis versus squamous cell carcinoma whereby the morphology of the lesion clinically is described as

      “pink and crusted.” The past medical history was otherwise unremarkable
      BORDERLINE TYPE C LYMPHOMATOID PAPULOSIS WITH FEATURES REMINISCENT OF A VARIANT ASSOCIATED WITH THE 6P25.3 REARRANGEMENTresolved with methotrexate but the patient developed advanced intertriginous MF
      563MRight upper chestThe patient is presented with a 2.5-centimeter x 0.5-centimeter erythematous plaque on the chest that had followed a recrudescent course over a period of 5 years with periods of complete regression. While the application of topical corticosteroids was of some help, the subsequent clinical course was one characterized by disease progression to MF localized to the original site of LYPType A LYMPHOMATOID PAPULOSISThe lesions of LYP resolved however in the same region classic unilesional patch stage mycosis fungoides developed; the area was excised without recurrence
      656FPlantar surface of the footThe patient presents with a solitary 2.5 centimeter ulcer on the plantar surface of the foot of a few weeks duration. History of Diabetes mellitusTYPE E LYMPHOMATOID PAPULOSIS WITH OVERLAPPING FEATURES OF BORDERLINE TYPE C LYMPHOMATOID PAPULOSISThe lesion resolved with a short course of corticosteroid treatment and methotrexate.
      765FFingerThe patient presents with a finger lesion. It is a nodule. It is of one months duration. The patient has a history of asthma. The patient otherwise does not have a very remarkable history. Of interest is the fact that the lesions originally presented as grouped erythematous vesicles and erosions on the dorsal right finger compatible with herpetic whitlow.UNILESIONAL LYMPHOMATOID PAPULOSIS POSSIBLY REPRESENTING THE UNIQUE VARIANT OF LYMPHOMATOID PAPULOSIS ASSOCIATED WITH A CHROMOSOME 6P25.3 REARRANGEMENTThe lesion underwent spontaneous regression without recurrence as of December 2020.
      868MAbove lipThe patient presents with a spontaneously regressing papule above the lip in the setting of chronic lymphocytic leukemiaUNILESIONAL LYMPHOMATOID PAPULOSIS WITH HYBRID TYPE B AND TYPE C FEATURESThe lesion underwent regression in March of 2022 and has not recurred.
      965FRight forearmThe patient has no significant past medical history and presents with a nodule less than 3 centimeters in diameter that has undergone regression. Interestingly the patient had a virtually identical lesion on the opposite arm 7 months previously.UNILESIONAL LYMPHOMATOID PAPULOSIS WITH BORDERLINE TYPE C AND OVERLAPPING TYPE B FEATURESThe lesion has undergone regression.
      1018MRight armThe patient has no significant past medical history but had two prior episodes of covid-19 before developing unilesional LYPType E LYMPHOMATOID PAPULOSISIt is undergoing regression
      PERSISTENT1132MLower medial leg/ multiple papules and nodulesThe patient is an otherwise healthy 32 year-old man who presents with a regionally confined area that is several

      centimers in diameter characterized by multiple papules an dnodules superimposed on a somewhat infiltrative

      hyperpigmented base that has been present for 3 months without evidence of regression.
      PERSISTENT AGMINATION OF LYMPHOMATOID PAPULOSIS SHOWING A BACKGROUND OF MYCOSIS FUNGOIDES WITH SUPERVENING FEATURES OF LYPThe papular nodular component eventually regressed. The plaque became less infiltrative with the application of topical steroids although is still present.
      1277FthighThe patient presents with a persistent infiltrative plaque comprising agminated violaceous papules in a background of hyperpigmentation and focal hypopigmentation. While the individual papules may have undergone regression there has always been some evidence of this regionally confined agminated papular processPERSISTENT AGMINATION OF LYMPHOMATOID PAPULOSIS WITH FEATURES OF THE SMALL LYMPHOCYTIC ECCRINOTROPIC GRANULOMATOUS VARIANTThe plaque became less infiltrative without any supervening recurrent papules following four courses of intralesional steroids (5 milligrams per session)
      1369March of the footThe patient has had a persistent rash on the arch of the foot for three years but does undergo some regression characterized by superimposed lesions that ulcerate and then regress.
      REGIONAL1443MForehead/ lesionsThe patient presents with a recurrent plaque on the forehead over the last three years. He has had at least three prior episodes whereby each episode resolved, leaving a significant depression.LYMPHOMATOID PAPULOSIS MANIFESTING

      OVERLAPPING FEATURES OF THE ECCRINOTROPIC GRANULOMATOUS, FOLLICULAR

      AND TYPE E VARIANTS.
      He continues to have waxing and waning lesions.
      1570MFoot/ ulcerative erythematous plaques and papulesThe patient has a regional eruption that commenced in April involving the ankle and foot. The ankle eruption appears similar to the rash that is currently on the bottom of the foot. The ankle process has since resolved. The lesions on the foot undergo ulceration and appear to be responding to topical steroid cream.REGIONAL TYPE E LYMPHOMATOID PAPULOSISThe lesios have regressed with topical corticosteroid application.
      51632FUpper left inner calfThe patient presents with an ulcer in the upper left inner calf area; the clinical impression encompassed ecthyma gangrenosum vasculitis and calciphylaxis. The patient was otherwise healthyTYPE E LYMPHOMATOID PAPULOSISThe lesions resolved with intralesional steroids and have not recurred.
      Acknowledgements
      Case 1
      Kyle C. Mills, MD
      Bako Intergrated Physicians
      Alpharetta, GA 30005
      Case 2
      Ralph F. Winkler, MD (
      Bako Pathology Services
      Alpharetta, GA 30005
      Case 3
      Dr. Randy Leff, DPM
      Michfoot Surgeons PC
      Southfield, MI 48034
      Ralph F. Winkler, MD
      Bako Pathology Services
      Alpharetta, GA 30005
      Case 4
      Jonathan E Blume, MD
      Martin Reichel, MD
      Westwood Dermatology
      Westwood, NJ 07675
      Case 5
      Scott Sanders, M.D.
      301 North Main Street
      New City, NY 10956
      Case 6
      Lara Kozin, DPM
      Foot & Ankle Specialists of New Jersey
      Union, NJ 07083
      KIMARA WHISENANT, M.D.
      Bako Pathology Services
      Alpharetta, GA 30005
      Case 7
      W. Raymond Zhu, M.D.
      HCT Dermatopathology Services
      Baltimore, MD 21229
      Case 8
      Scott Bangert, MD
      Associated Dermatologists PC
      Tucson, AZ 85712
      Case 9
      RYANNE WAAGE, PAC
      Aberdeen Dermatology Associate
      ABERDEEN, SD 87401
      Case 10
      Garron Solomon, M.D.
      Tripoint Diagnostics
      Morrisville, NC 27560
      Case 11
      Gladys Telang, M.D.
      Brown Dermatology
      Warwick, RI 02886
      Case 12
      Jennifer E Bernstein, DPM
      Weil Foot & Ankle Institute
      Kenosha, WI 53142
      SCOTT M. ACKER, M.D.
      Bako Pathology Services
      Alpharetta, GA 30005
      Case 13
      JACOB LEVITT, MD
      Mount Sinai Hospital
      New York, NY 10029
      Case 14
      Stoedter Kathryn, DPM
      Comprehensive Foot and Ankle Center of South Jersey
      Voorhees, NJ 08043
      Scott M. Acker, M.D.
      Bako Pathology Services
      Alpharetta, GA 30005
      Case 15
      Jalong Gaan, M.D.
      Weill Cornell Medicine
      New York, NY 10021
      REFERENCES:
      Louvet S, Dompmartin A, Troussard X, Galateau F, Moreau A, Reman O, Leporrier M, Leroy D. Spectrum of CD30 lymphoproliferative diseases from lymphomatoid papulosis to anaplastic large cell lymphoma. Int J Dermatol. 1996;35:842-848.
      Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin–clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol. 1995;13:1343-1354.
      Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD-30 positive cells. J Am Acad Dermatol. 1998;38:806-809.
      Hwong H, Jones D, Prieto VG, Schulz C, Duvic M. Persistent atypical lymphocytic hyperplasia following tick bite in a child: report of a case and review of the literature. Pediatr Dermatol. 2001;18:481-484.
      Servitje O, Gallardo F, Estrach T, et al . Primary cutaneous marginal zone B-cell lymphoma: a clinical, histopathological, immunophenotypic and molecular genetic study of 22 cases. Br J Dermatol. 2002;147:1147-1158.
      Bauer J, Leinweber B, Metzler G,et al. Correlation with digital dermoscopic images can help dermatopathologists to diagnose equivocal skin tumours. Br J Dermatol. 2006;155:546-551.
      Magro CM, Olson LC, Fulmer CG. CD30+ T cell enriched primary cutaneous CD4+ small/medium sized pleomorphic T cell lymphoma: A distinct variant of indolent CD4+ T cell lymphoproliferative disease. Ann Diagn Pathol. 2017;30:52-58.
      Fonatsch C, Latza U, Dürkop H, Rieder H, Stein H. Assignment of the human CD30 (Ki-1) gene to 1p36. Genomics. 1992;14:825-826.
      Gruss, H.J., Duyster, J. and Herrmann, F., 1996. Structural and biological features of the TNF receptor and TNF ligand superfamilies: interactive signals in the pathobiology of Hodgkin's disease. Annals of oncology7, pp.S19-S26.
      Willemze R, Cerroni L, Kempf W, et al.The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019 18;133:1703-1714.
      Slater DN. The new World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005;153:874-880.
      Macaulay WL. Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign–histologically malignant. Arch Dermatol. 1968;97:23-30.
      Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol. 1994;30:379-395.
      Willemze R, Scheffer E, Van Vloten WA, Meijer CJ. Lymphomatoid papulosis and Hodgkin's disease: are they related? Arch Dermatol Res. 1983;275:159-167.
      Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol. 1993;28:973-980.
      El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol. 2004;140:441-447.
      Varga FJ, Vonderheid EC, Olbricht SM, Kadin ME. Immunohistochemicaldistinction of lymphomatoid papulosis and pityriasis lichenoides et varioliformis acuta. Am J Pathol. 1990;136:979-987.
      Beljaards RC, Willemze R. The prognosis of patients with lymphomatoidpapulosis associated with malignant lymphomas. Br J Dermatol. 1992;126:596-602.
      Kadin ME, Drews R, Samel A, Gilchrist A, Kocher O. Hodgkin's lymphoma of T-cell type: clonal association with a CD30+ cutaneous lymphoma. Hum Pathol. 2001;32:1269-1272.
      Kempf W, Haeffner AC, Zepter K, et al. Angiolymphoid hyperplasia with eosinophilia: evidence for a T-cell lymphoproliferative origin. Hum Pathol. 2002;33:1023-1029.
      Steinhoff M, Hummel M, Anagnostopoulos I, et al.. Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin. Blood. 2002 15;100:578-584.
      Oura K, Sato T, Iguchi A, Toriumi N, Sarashina T. Lymphomatoid Papulosis
      Development in Acute Lymphoblastic Leukemia. J Med Cases. 2021;12:306-309.
      Terao H, Kiryu H, Ohshima K, Kikuchi M, Furue M. Cutaneous CD30 (Ki-1)-positive anaplastic large cell lymphoma preceded by Hodgkin's disease. J Dermatol. 2000;27:170-173.
      Willemze R, Scheffer E, Ruiter DJ, van Vloten WA, Meijer CJ. Immunological, cytochemical and ultrastructural studies in lymphomatoid papulosis. Br J Dermatol. 1983;108:381-394.
      Harrington DS, Braddock SW, Blocher KS, Weisenburger DD, Sanger W, Armitage JO. Lymphomatoid papulosis and progression to T cell lymphoma: an immunophenotypic and genotypic analysis. J Am Acad Dermatol. 1989; 21; 951-957.
      Kaudewitz P, Stein H, Plewig G, et al.. Hodgkin's disease followed by lymphomatoid papulosis. Immunophenotypic evidence for a close relationship between lymphomatoid papulosis and Hodgkin's disease. J Am Acad Dermatol. 1990;22:999-1006.
      Chott A, Vonderheid EC, Olbricht S, Miao NN, Balk SP, Kadin ME. The dominant T cell clone is present in multiple regressing skin lesions and associated T cell lymphomas of patients with lymphomatoid papulosis. J Invest Dermatol. 1996;106:696-700.
      Basarab T, Fraser-Andrews EA, Orchard G, Whittaker S, Russel-Jones R. Lymphomatoid papulosis in association with mycosis fungoides: a study of 15 cases. Br J Dermatol. 1998;139:630-638.
      Silva MM, Morais JC, Spector N, Maceira J, Sousa MA, Filgueira AL. Lymphomatoid papulosis followed by Hodgkin's disease. Int J Dermatol. 1998;37:541-543.
      Wang HH, Myers T, Lach LJ, Hsieh CC, Kadin ME. Increased risk of lymphoid and nonlymphoid malignancies in patients with lymphomatoid papulosis. Cancer. 1999;86:1240-1245.
      Aoki M, Niimi Y, Takezaki S, Azuma A, Seike M, Kawana S. CD30+ lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma followed by lymphomatoid papulosis. Br J Dermatol. 2001;145:123-126.
      Gallardo F, Costa C, Bellosillo B, et al.. Lymphomatoid papulosis associated with mycosis fungoides: clinicopathological and molecular studies of 12 cases. Acta Derm Venereol. 2004;84:463-468.
      Karai LJ, Kadin ME, Hsi ED, et al.. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol. 2013;37:1173-1181.
      Kempf W, Kazakov DV, Schärer L, et al.. Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas. Am J Surg Pathol. 2013;37:1-13.
      Ferenczi K, Summers P, Aubert P, et al.. A case of CD30+ nasal natural killer/T-cell lymphoma. Am J Dermatopathol. 2008
      Dec;30:567-571.
      Chen Z, Guan P, Shan T, Ye Y, et al.. CD30 expression and survival in extranodal NK/T-cell lymphoma: a systematic review and meta-analysis. Oncotarget. 2018 8;9:16547-16556.
      Wehkamp U, Weichenthal M, Klapper W, Schwarz T, Oschlies I. Unilesional locally recurrent lymphomatoid papulosis with variable histological presentation. Leuk Lymphoma. 2018;59:262-264.
      Scarisbrick JJ, Evans AV, Woolford AJ, Black MM, Russell-Jones R. Regional lymphomatoid papulosis: a report of four cases. Br J Dermatol. 1999
      ;141:1125-1128.
      Sharma V, Xu G, Petronic-Rosic V, Gerami P. Clinicopathologic challenge. Regional lymphomatoid papulosis, type A. Int J Dermatol. 2007;46:905-909.
      Heald P, Subtil A, Breneman D, Wilson LD. Persistent agmination of lymphomatoid papulosis: an equivalent of limited plaque mycosis fungoides type of cutaneous T-cell lymphoma. J Am Acad Dermatol. 2007;57:1005-1011.
      Chan DV, Staidle J, Tamburro J, Mostow E. Rapid cutaneous dissemination of persistently agminated lymphomatoid papulosis in a 9-year-old boy. Arch Dermatol.2011;147:1340-1342.
      Crowson AN, Saab J, Magro CM. Folliculocentric Herpes: A Clinicopathological Study of 28 Patients. Am J Dermatopathol. 2017;39:89-94.