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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. An uncommon form of LYP is one that is anatomically confined. Cases of unilesional LYP, regional LYP, and persistent agmination of LYP 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 10 cases of LYP presenting as solitary plaques or nodules primarily occurring in older patients and without a relevant medical history in most. Most cases occurred at an acral site with many localized to the foot; the morphology was one of a necrotizing angiocentric type E pattern and borderline type C 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 LYP 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 LYP, 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 LYP defines an uncommon form of LYP, but it is an important one to recognize because 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 cutaneous T cell lymphoma cutaneous T cell lymphoma (CTCL).
The spectrum of cutaneous CD30-positive lymphoproliferative disorders encompasses lymphomatoid papulosis (LYP), primary cutaneous and secondary anaplastic large cell lymphoma, 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.
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.
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.
The striking array of cutaneous infiltrates that can be associated with CD30 expression reflects the nature of the CD30 molecule. Although 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 nonneoplastic 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. 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.
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.
LYP is recognized in the cutaneous lymphoma classification schemes of both the WHO and EORTC, representing the second most common form of primary cutaneous T-cell lymphoproliferative disease after mycosis fungoides (MF).
Its first description by Warren L. Macaulay (1915-2006) 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.
In the original index paper, the self-regressing nature of the eruption was emphasized. Our conceptualization of LYP has evolved. 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 as follows:
Multiple papules or nodules
Lesions that undergo complete and not partial regression
No evidence of progression to a diameter more than 3 cm during 3 months of observation without treatment
Despite a certain degree of uniformity in regard to the clinical presentation, there is significant morphologic heterogeneity in each biopsy or between biopsies in the same patient. The most common morphologic variants have letter designations:
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.
Type B resembles MF and typically is characterized by an epidermotropic small cerebriform lymphocytic infiltrate that does not express CD30.
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 lymphoma.
Type D is a unique CD8-positive variant associated with epidermotropism of noncerebriform lymphocytes and at times some degree of angiodestruction resembling primary cutaneous aggressive epidermotropic cytotoxic CD8-positive T-cell lymphoma.
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 angiodestruction, such 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%.
The most common lymphomas associated with LYP are anaplastic large cell lymphoma and MF, although a broader spectrum of lymphomas is recognized and may include chronic lymphocytic leukemia, acute lymphoblastic lymphoma,
A series of 16 cases of anatomically confined LYP represented by three separate entities are presented, including unilesional LYP, regional LYP, and persistent agmination of LYP. The literature is also reviewed as it pertains to these three variants of LYP. The differences and similarities between unilesional LYP, regional LYP, and persistent agminated LYP are addressed.
Materials and methods
Over a 7 year time period, one of the authors (CMM) encountered 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 10 cases of unilesional LYP, three cases of persistent agmination of LYP, and three cases of regional LYP are described from the 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 retrospective 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 LYP (10 cases)
The 10 cases of unilesional LYP predominately affected older individuals ranging in the fourth to seventh decade of life with a slight male predilection (ie, 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 cm in greatest diameter and followed a waxing and waning course over 5 years. A superimposed plaque developed, and although 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 MF 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 MF. The margins were negative, and there was no subsequent recurrence. Additional lesions did not develop elsewhere.
Four of the cases represented type E LYP based on a distinctive histology, which will be described presently. The patients ranged 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 (Fig. 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 to 3 cm in diameter. One patient received radiation, which resolved the ulcerative lesion initially; however, the patient continued to develop recurrent dermatitis, which spontaneously regressed, at the location. 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, so we were unable to gather clinical followup. Additional lesions were not reported in any of the patients.
In two of the unilesional cases, the patients presented with solitary lesions typical for a form of type C borderline LYP most reminiscent of a variant of type C LYP associated with a 6P25.3 rearrangement.
The cases included one man and one woman; their ages were 65 and 78 years, respectively. The affected sites were the chest and finger. A definitive cytogenetic abnormality could not be identified in either of these type C borderline cases 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 nonregressing plaques in the groin area diagnostic of patch stage CD8-positive MF and advanced tumor stage MF with evidence of CD30-positive transformation. 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 MF 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 LYP. Review of the previous biopsy revealed the same histologic findings. This case represents the remarkable phenomenon of unilesional LYP targeting an anatomically similar area, (ie, 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 after a second COVID-19 infection. Because he is in his early 20s, he is the age group outlier of this cohort.
The final patient with unilesional LYP had a single, nonulcerative, 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 more recently, the patient fulfills hematologic criteria for chronic lymphocytic leukemia (Fig. 2A).
Light microscopic findings
In five of the unilesional cases, there was a highly atypical perivascular mononuclear cell infiltrate throughout the dermis (Fig. 1B). The abnormal cells were in the 20- to 30-micron size range; they exhibited asymmetrically thickened membranes with nuclear contour irregularity and large multiple basophilic nucleoli (Fig. 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 (Fig. 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 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 (Fig. 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 (Fig. 1E). The atypical cells showed extensive immunoreactivity for CD30 (Fig. 1F). The combined light microscopic and phenotypic profile was consistent with type E LYP.
In two cases, the histologic findings showed an overlapping morphology of type B and type C LYP (Fig. 2B). There was one population of small, atypical and cerebriform lymphocytes that exhibited epitheliotropism; however, the dominant cell population was one of larger and highly atypical lymphocytes, which show striking tumefactive growth within the dermis. This presentation resembled anaplastic large cell lymphoma or transformed MF given the background of a smaller and cerebriform epidermotropic T-cell infiltrate. The neoplastic cells expressed BetaF1 (Fig. 2C) and showed a marked decrement in staining for CD3, CD5 and CD7, whereas the abnormal cells expressed CD8. CD30 expression was largely confined to the larger cell population (Fig. 2D). Cytogenetic studies to assess for a chromosome 6p25.3 rearrangement were not satisfactory due to inadequate material on the slides to conduct the assays.
In two unilesional cases, the histologic findings were compatible with type C LYP. 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 MF. 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, noncerebriform nuclear contour irregularity and conspicuous nucleolation. There was extensive highlighting of the epitheliotropic and dermal infiltrate with CD3, MUM1, and CD30 (Fig. 3E). Both cases showed variable loss of CD2, CD5 (Fig. 3B), and CD7 (Fig. 3C). The atypical cells were CD8 (Fig. 3D) and granzyme positive (Fig. 3F) in one case and CD4 positive in one case (Fig. 3A). The histologic findings were suggestive of a unique form of type C LYP, namely one associated with a 6p25.3 rearrangement. The Fluorescent in situ hybridization (FISH) assay was unsuccessful because no hybridization signals were observed in the cells analyzed.
In one case, the histologic findings were consistent with type A LYP. 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; although 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, but showed a loss of CD7. This patient developed MF without any evidence of residual type A LYP.
In two cases, the histologic findings showed an overlapping morphology of type B and type C LYP (Fig. 2B). There was one population of small, atypical cerebriform lymphocytes that 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 MF given the background smaller cerebriform epidermotropic T-cell infiltrate. The neoplastic cells expressed BetaF1 (Fig. 2C) and showed a marked decrement in staining for CD3, CD5, and CD7, whereas the abnormal cells expressed CD8. CD30 expression was largely confined to the larger cell population (Fig. 2D). Cytogenetic studies to assess 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 LYP with overlapping features of MF, type B LYP, and type C LYP(See table 1)
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 3 months (Fig. 4A). The papular nodular lesions had undergone varying stages of regression, and the underlying plaque was persistent. One papular nodular lesion demonstrated ulceration (Fig. 4B). The only treatment the patient received was topical corticosteroids, which resulted in healing the ulcerative lesion and shrinking the plaque (Fig. 4C). With a combination of time and topical steroids, the plaque has improved significantly but has not regressed completely. The papular nodular lesions overlying the plaque have remained persistent.
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 passive pattern of colonization without significant epithelial destruction. The intraepidermal lymphocytes were severely atypical and defied categorization as a prelymphomatous T-cell dyscrasia. The cells were smaller, but larger atypical cells were noted. This aspect of the atypical infiltrate was most suggestive of MF; however, there was also a dermal infiltrate that was extensive. The infiltrate extended deep and infiltrated the adventitial dermis of the eccrine coil and surrounded nerves and blood vessels. There was a decrement in the extent of the infiltrate because 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.
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 LYP with features of the small lymphocytic eccrinotropic granulomatous variant
The patient was a 77-year-old woman who presented with a persistent infiltrative plaque comprising agminated violaceous papules in a background of hyperpigmentation and focal hypopigmentation that began in the latter part of 2019. Although the individual papules may have undergone regression, there is evidence of a regionally confined plaque with superimposed fluctuating papules. The plaque had been treated intermittently with intralesional corticosteroids. After four injections of 5 mg of triamcinolone acetate per injection, the plaque is inactive without any recurrent papular lesions. Although still visible, it appears significantly less infiltrative. If the plaque worsened, 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 (Fig. 5A-C).
Light microscopic findings
There were multiple biopsies taken over a period. They appeared similar. They both demonstrated a superficial and deep nodular vasocentric, perineural and perieccrine lymphocytic infiltrate with scattered eosinophils (Fig. 5D). 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 was observed.
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 LYP in a background of primary cutaneous syringotropic T-cell dyscrasia of probable follicular helper T-cell origin
The patient is a 69-year-old man with persistent dermatitis on the left arch for 3 years. There are superimposed lesions that periodically ulcerate and regress. He has received no treatment. The ulcerative papular lesions undergo a course of spontaneous regression and recurrence, whereas the baseline plaque remains unchanged
Light microscopic findings
The background dermatitis demonstrated a 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 (Fig. 6A). 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 (Fig. 6B), 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.
The CD3 stain highlighted the lymphocytes in the epidermis, the superficial dermis, and the ducts and glands of the eccrine coil. The lymphocytic infiltrate was also highlighted by CD7. Compared with 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 more than 10 (Fig. 6C and 6F); there was preservation of CD5 (Fig. 6D) and CD7 (Fig. 6E) (Fig. 5E). The atypical small lymphocytes were extensively PD1-positive, including the syringotropic atypical lymphocytes. As expected with this small cell-dominant infiltrate, the Ki-67 proliferation index was low, at around 1%. A CD30 stain demonstrated rare positive staining cells (Fig. 5) (Fig. 6G).
Case 14: Regional LYP exhibiting overlapping features of granulomatous eccrinotropic, folliculotropic, and type E variants(See table 1)
The patient was a 43-year-old man with recurrent plaques on his forehead over the last 3 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 ) (Fig. 7A). The dermis was remarkable for a dense lymphocytic and histiocytic infiltrate intimately apposed to the hair follicle, eccrine coil (Fig. 7B), nerves (Fig. 7C) 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 several transformed elements. The larger immunoblastic forms exhibited conspicuous nucleolation .
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 ; also, the cells showed 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 (Fig. 7D-H).
Case 15: Regional type E LYP(See table 1)
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, whereas the surrounding lesions have regressed.
The biopsy showed 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 larger atypical lymphoid forms. Comprehensive phenotypic studies were performed.
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 was in the 50% realm. The atypical larger lymphocytes stained positively for CD8 and CD30.
Case 16: Regional type E LYP(See table 1)
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 6 years after her initial diagnosis (Fig. 8A-D).
The biopsy showed a 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 the infiltrate was permeative of the epidermis. The dominant infiltrate was a larger atypical cell in the 20- to 30-micron size range that surrounded and permeated the vessel wall. The cells had conspicuous eosinophilic nucleoli and exhibited a finely dispersed chromatin; cytoplasm was moderately abundant and eosinophilic in quality. There was an admixture of smaller lymphocytes and histiocytes.
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.
A monoclonal T-cell rearrangement was detected.
We have presented 16 cases of anatomically confined LYP. In 10 patients, the lesions were in the context of solitary plaques and/or nodules. Three patients had regional LYP and three cases were represented by persistent agmination of LYP. The current literature devoted to the topic of an anatomically limited form of LYP is in the context of regional LYP, where the cases are characterized by discrete separate nodules and/or papules confined to one anatomic region. Most 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 50s, 60s, and 70s, but one patient was in his 30s; 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, whereas additional other sites were 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.
Two of the unilesional patients in our series went on to develop MF, 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 LYP. 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 cytogenetic abnormality could not be confirmed. One patient had the type A morphology.
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, 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 in which those diagnostic considerations seem plausible if there is a null phenotype and if the atypical cells express CD56. In most instances, the atypical T-cells are CD4 positive, and the extensive CD30 positivity is supportive of a diagnosis of endogenous CD30-positive lymphoproliferative disease; however, there is a caveat that NK T-cell lymphomas can express CD30.
Often a significant background inflammatory cell infiltrate can be an important clue, specifically in regard to spongiform pustulation and significant tissue eosinophilia, findings that support a diagnosis of LYP.
Due to the general unfamiliarity of most physicians with unilesional LYP, a diagnosis could escape detection. 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 some cases. Any recurrent ulcer in one location showing a mixed perivascular and deeper seated eccrinotropic inflammatory cell should be considered suspicious for LYP. Although 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 unusual.
Reported cases in the literature under the designation of unilesional LYP are limited to one anecdotal case report. A 2018 report included a patient with unilesional locally recurrent LYP and a variable histologic presentation.
A 72-year-old woman was referred in 2004 with a single lesion that was roughly 5 mm 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 LYP. The first episode occurred in 2001. Over time, the morphology evolved, whereby the original biopsy showed a type C morphology, whereas the two subsequent recurrences in 2009 and 2013 demonstrated a type B morphology resembling MF. The lesions lasted a total of 4 to 6 weeks before recurring. The individual lesions did not exceed 1 cm in diameter. Each recurrent episode was treated with an excision. Apart from this case report, to our knowledge there are no additional papers on unilesional LYP.
Another anatomically confined variant of LYP in our series was regional LYP characterized by typical lesions of LYP confined to one region of the skin. In the original index series, the authors described four patients ranging 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.
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.
We encountered three cases of regional LYP ranging from 32 to 70 years of age; in two of the cases, the morphology captured was one of type E LYP, whereas the last case demonstrated a hybrid type A and granulomatous eccrinotropic morphology. The cases followed a course typical for conventional LYP, meaning 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 LYP falls under the designation of persistent agmination of LYP.
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 MF. The area of involvement is characteristically several centimeters. It has been suggested that this variant of LYP is a form of lymphoma because the lesions are persistent and if left untreated, transformation into MF may occur.
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 cases, two progressed to more conventional disseminated LYP; neither of them showed features of persistent disease.
In our three cases of persistent agmination of LYP, the patients were 32, 69, and 77 years. The histologic findings combined type C LYP and type B LYP 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 one would designate the process as 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, noncerebriform, without this degree of large cell transformation, and would show a proclivity to surround and permeate blood vessels leading to a destructive lymphomatoid vasculitis. Regarding the other two cases, a type A LYP pattern was seen in one patient, and a small cell dominant granulomatous eccrinotropic morphology was seen in the other. In two of the three cases, there were background features of MF representing the persistent nonregressing component of the lesion, whereas in one patient, the background nonregressing plaque of the foot arch was an acral syringotropic T-cell lymphoma of follicular helper T-cell origin. The designation of syringotropic MF was not used due to the atypical noncerebriform 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, whereas the hyperpigmented plaque became less infiltrative. Complete regression of 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 regard to anaplastic large cell lymphoma. There are two practical points that allow relatively easy distinction of LYP from anaplastic large cell lymphoma. The first point concerns the size of the lesion. Typically, in anaplastic large cell lymphoma, the tumor is largely than 3 cm in size. The second aspect relates to the regressive tendency of LYP. 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. One case that had been incorporated into the original study was eliminated when we discovered that the patient had an established history of nodal anaplastic large cell lymphoma. When 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. Rendering a diagnosis of borderline type C LYP should be made with caution and with the caveat 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 is a significant morphologic overlap with reactive conditions such molluscum contagiosum and folliculocentric herpes.
Like LYP, molluscum contagiosum and folliculocentric herpes can be recurrent, and 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.
Anatomically confined LYP is defined by unilesional LYP, regional LYP, and persistently agminated LYP. The entity of persistent agminated variant remains indeterminate regarding categorization, but cases that do not undergo full regression are probably better categorized as a form of cutaneous T-cell lymphoma with superimposed LYP. Cases that represent unilesional LYP tend 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 LYP or a borderline type C morphology. When presenting in this unilesional context, the course is usually benign, but like conventional LYP, patients may develop lymphoma; in our series, two patients developed MF, and 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. It is possible that 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 1.
Table 1Summary of anatomically confined LYP.
Initially diagnosed with an infection, for which he received antibiotics and wound care without improvement. After a diagnosis was made of type E LYP, he was placed on methotrexate and the lesion underwent complete regression.
Type E LYP
Resolved with methotrexate.
The patient presented with a solitary ulcer on the foot. After a diagnosis was made of type E LYP, the patient received corticosteroids.
Type E LYP
Resolved with corticosteroids.
Right second great toe/ pigmented lesion
The 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 concomitant nail dystrophy.
Type E LYP
Lost to F/U.
The patient presents with a neoplasm of uncertain behavior vs irritated seborrheic keratosis vs 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 LYP with features reminiscent of a variant associated with the 6p25.3 rearrangement
Resolved with methotrexate, but the patient developed advanced intertriginous MF.
Right upper chest
The patient presented with a 2.5 × 0.5-cm erythematous plaque on the chest that had followed a recrudescent course over a period of 5 years with periods of complete regression. Although 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 LYP.
Type A LYP
The lesions of LYP resolved; however, in the same region, classic unilesional patch stage mycosis fungoides developed; the area was excised without recurrence.
Plantar surface of the foot
The patient presents with a solitary 2.5-cm ulcer on the plantar surface of the foot of a few weeks’ duration. History of diabetes mellitus.
Type E LYP with overlapping features of borderline type C LYP
The lesion resolved with a short course of corticosteroid treatment and methotrexate.
The patient presents with a finger lesion. It is a nodule. It is of 1 months’ duration. The patient has a history of asthma. The patient otherwise does not have a 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 LYP possibly representing the unique variant of LYP associated with a chromosome 6p25.3 rearrangement
The lesion underwent spontaneous regression without recurrence as of December 2020.
The patient presents with a spontaneously regressing papule above the lip in the setting of chronic lymphocytic leukemia.
Unilesional LYP with hybrid type B and type C features
The lesion underwent regression in March 2022 and has not recurred.
The patient has no significant past medical history and presents with a nodule <3 cm in diameter that has undergone regression. The patient had a virtually identical lesion on the opposite arm 7 months previously.
Unilesional LYP with borderline type C and overlapping type B features
The lesion has undergone regression.
The patient has no significant past medical history but had two prior episodes of COVID-19 before developing unilesional LYP.
Type E LYP
It is undergoing regression.
Lower medial leg/ multiple papules and nodules
The patient is an otherwise healthy 32-year-old man who presents with a regionally confined area that is several centimeters in diameter, characterized by multiple papules and nodules superimposed on a somewhat infiltrative hyperpigmented base that has been present for 3 months without evidence of regression.
Persistent agmination of LYP showing a background of mycosis fungoides with supervening features of LYP.
The papular nodular component eventually regressed. The plaque became less infiltrative with the application of topical steroids, although it is still present.
The patient presents with a persistent infiltrative plaque comprising agminated violaceous papules in a background of hyperpigmentation and focal hypopigmentation. Although the individual papules may have undergone regression, there has always been some evidence of this regionally confined agminated papular process.
Persistent agmination of LYP with features of the small lymphocytic eccrinotropic granulomatous variant
The plaque became less infiltrative without any supervening recurrent papules after four courses of intralesional steroids (5 mg per session).
Arch of the foot
The patient has had a persistent dermatitis on the arch of the foot for 3 years but does undergo some regression characterized by superimposed lesions that ulcerate and then regress.
The patient presents with a recurrent plaque on the forehead over the last 3 years. He has had at least three prior episodes, whereby each episode resolved, leaving a significant depression.
LYP manifesting overlapping features of the eccrinotropic granulomatous, follicular and type E variants
He continues to have waxing and waning lesions.
Foot/ulcerative erythematous plaques and papules
The patient has a regional eruption that commenced in April involving the ankle and foot. The ankle eruption appears similar to the eruption 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 LYP
The lesions have regressed with topical corticosteroid application.
Upper left inner calf
The 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 healthy.
Type E LYP
The lesions resolved with intralesional steroids and have not recurred.
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.