Posted by Jenny on August 15, 2005 at 14:21:52:
Repost
Posted by Voyajer on May 20, 2003 at 18:39:03:
J Dermatol 2000 Mar;27(3):181-94
Post-scabetic nodules: a lymphohistiocytic reaction rich in indeterminate cells.
Hashimoto K, Fujiwara K, Punwaney J, DiGregorio F, Bostrom P, el-Hoshy K, Aronson PJ, Schoenfeld RJ.
Department of Dermatology & Syphilology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
We studied six infants and two adult cases of nodular scabies with immunostains and electron microscopy. All eight cases have had either direct (KOH) or family histories of scabies and were treated with lindane 1% cream or permethrin 5% cream. Family members responded very well, but our patients developed multiple papulo-nodular lesions [bumps] which were initially very pruritic [itchy] and, in some cases, persisted from several months to over one year.
Introduction
Papulo-modular tumors of infants and young children are usually biopsied to make an accurate diagnosis. When lymphohistiocytic cell proliferation is found in the lesion, the current standard of care requires
immunophenotyping of the infiltrating cells. The routine panel of mimmunostains in cludes CD1a, S-100 and HLA-DR. If these are all positive in a large number of the infiltrating cells, it is very likely that the tumor under study represents Langerhans cell histiocytosis or indeterminate cell histiocytosis. Differentiation between these two further requires electron microscopy to identify the presence of Birbeck’s granules in the former and the absence of the same in the latter. We report six infant and two adult cases of postscabetic nnodules in which indeterminate cells
were rich in the epidermis and dermis. Even after the repeated scabicidal treatments, these patients continued to develop papulo-nodular lesions,
sometimes for over a year. Clinically, these lesions resembled mastocytosis, juvenile xanthogranuloma, nodular type histiocytosis-X, self-healing reticulohistiocytosis, or prurigo nodularis. Biopsy specimens showed a heavy lymphopistiocytic infiltration with or without eosinophils. Immunophenotypes of these cells suggested that they may be Langerhans cells because epitopes of CD1, S-100 and HLA-DR were expressed in a large number of cells. However, electron microscopy and, in one case, immunostain with Lag failed to detect Birbeck’s granules.
Case Histories
Case #1: A 10-month-old white female infant had scabies (diagnosed by scraping and KOH) and was treated with Kwell lotion (y-benzene-hexachloride) several times over a period of months because of continuous pruritus and persistent scaly papules and urticarial eruptions. The patient gradually developed urticarial and nodular eruptions on her trunk and extremities. Palms, soles, buttocks, and genitalia (common sites for scabies for this age group) were free from eruptions. A diagnosis of post-scabetic pruritus and urticaria was made, and a medium potency corticosteroid cream was prescribed. A few months later, the patient developed about 15 papulo-nodular lesions on her trunk, groin, thighs, and legs. These were pinkish brown and asymptomatic; pruritus, excoriations and urticaria had disappeared. Mastocytosis, including the papulo-nodular variety ourticaria pigmentosa, juvenile xanthogranuloma, and Langerhans cell histiocytosis were considered in the differential diagnosis. Systemic workups were all negative for lymphoma and mastocytosis. The patient continued to develop new lesions of over one year, while the one ones subsided within 1 – 2 months. Two 3 mm punch biopsy specimens were taken from her trunk and shoulder for H & E stain, various immunostains, and electron microscopy.
Histopathology: H & E stain revealed that histiocytic large cells were admixed in predominantly lymphocytic small cell infiltrations in perivascular, periappendageal, and papillary dermis. Perivascular infiltrations were seen even in the deep dermis. Mast cells were not increased by Giemsa stain. No eosinophils were present. Serial sections of the entire tissue block were negative for mites.
Immunostains: The standard immunoperoxidase stains were performed with ABC method on frozen sections except for S-100 stain, which was done on formalin fixed tissue. Although the infiltration appeared to be lymphocyte-predominant by H & E stain, a sufficient number of these cells showed the immunophenotypes of Langerhans cell histiocytosis; these were CD1a and S-100. A large number of monocytes/histiocytes were detected with Leu M5.
Electron Microscopy
Glutaraldehyde (5%) fixed, uranyl acetate-lead citrate stained thin sections were used. Extensive search for Birbeck’s granules in over 200 histiocytic cells could not detect them. The ultrastructure of these Birbeck’s granule negative histiocytes was otherwise identical to Langerhans cells; well-developed Golgi apparatus, vesicular cytoplasm, lysosomal dense bodies, numberous peripheral villi, and indented nuclear contour were present.
No increase of mast cells was noted.
Case # 2
An 8-week-old black male infant developed non-pruritic eruptions from about day 26 afer birth. The parents also had pruritic eruptions. He was treated with Eurax (crotamiton) cream under the diagnosis of scabies by a primary care physician. Examination of the skin revealed multiple, pink-brown to dark brown, papulo-nodular lesions on the trunk, extremities, and scalp. The face was not involved. Large nodules were deeply indurated, and their surface was often studded with vesicles. Apparently these eruptions were not pruritic and did not bother the patient. Scratching did not elicit Darier’s sign. Intergluteal fold, buttocks, groin, palms, and feet were free from scabetic eruptions. Scraping and KOH were negative. The patient was nevertheless treated twice with Elimite (permethrin) cream and the parents twice with Kwell. Temovate (clobetasol propionate) ointment was applied twice daily to a few large nodular lesions after two biopsies were taken from nodular lesions on the thigh. Continuous treatment with Temovate and Tridesilon (desonide) was prescribed. Five months later, the patient still developed a few new lesions occasionally on the chest and axillae despite the Temovate/Tridesilon regimen.
Histopathology: H & E stain showed a similar but heavier lymphocytic infiltration than that seen in Case #1. Clusters of eosinophils was seen in many foci as well as in the epidermal vesicle. Mast cells were absent by Giemsa stain. No mites were detected in serial sections.
Immunostains:
Sufficient numbers of infiltrating cells were reactive for CD1, S-100, and HLD-DR to make a diagnosis of Langerhans cell histiocytosis or indeterminate cell histiocytosis. Histicytic cells in the epidermal vesicle were also positive for these. Lympho cytes were predominantly helper T cells with CD4 reactivity. The monocyte/histiocyte population was significant in the mixed infiltration as detected by Leu M5 stain.
Electron Microscopy:
Over 200 histiocytic cells were surveyed for
Birbeck’s granules, but none were found. These cells satisfied the ultrastructural criteria of Langerhans cells except for Birbeck’s granules.
Case #3
A 4-week-old black female baby developed multiple, dark brown, papulo-nodular lesions on the trunk and extremities. These eruptions seemed to be pruritic according to her mother. Her brother and sister were treated for scabies on the groin and genitalia and responded very well to scabicide. Some large nodular lesions were superficially eroded, while others were slightly erythematous.
Small vesicular components were also present surrounding or within the groups of papulo-nodular eruptions. Eruptions on her upper arms resembled papular urticaria. Darier’s sign was negative. Predilection sites of scabies such as hands, feet, buttocks, and genitalia were free from scabetic eruptions. Scraping and KOH were not done because of the previous treatment. A large nodular lesion was biopsied, and the rest were treated with Aclovate (aclometasone dipropionate) ointment and then with Temovate ointment. The latter worked to accelerate the resolution of the large nodular lesions. New lesions continued to develop while old ones healed. This process gradually subsided six months later with only occasional new lesions.
Histopathology
H & E stain showed a similar pattern of histology to those of cases #1 and #2. Infiltration of the lower epidermis was also noticed.
No eosinophils were present. No mites were found in the horny layer in the serial sections of the entire tissue block.
Immunostains:
Only moderate numbers of CD1a, S-100 and HLA-DR reactive cells were detected. The epidermal Langerhans cells were poorly stained with anti-S-100 antibody, and it was believed that the tissue fixation was not properly done.
Electron Microscopy:
Large histiocytic cells contained vesicular
cytoplasm, well developed Golgi apparatus and indented nuclei, satisfying all ultrastructural characteristics of Langerhans cells. However, no Birbeck’s granules were found in any cell out of over 200 histiocytic cells surveyed. Some cells had tubuloreticular inclusion bodies.
Case #4:
A three-month-old Hispanic male infant and his family members had pruritic eruptions for one month. KOH examination of scraping from this patient was positive for scabies. The patient and his family were treated with Elimite.
Family members responded well to this treatment. However, in this patient, some eruptions disappeared, but new ones developed. Physical examination of the skin showed multiple hyperpigmented papulo-nodular and vesicular eruptions on his trunk and extremities. Palms and soles were free from eruptions. Two biopsy specimens were taken from the anterior trunk and left inner arm near the axilla.
The patient and all family members were re-treated with Elimite, and the patient’s large indurated lesions on trunk and extremities were treated with Temovate cream. The eruptions subsided within two months.
Histopathology
H & E stain showed a diffuse heavy infiltration of
lymphophistiocytic cells in the papillary dermis, pervascular spaces and surrounding hair follicles and eccrine glands. Eosinophils were only
occasionally seen among infiltrating cells. No mite was encountered in serial sections.
Immunostains:
Moderate to large number of CD1a, S-100 and HLA-DR reactive cells were detected among these infiltrating cells. Markers of histiocyte/moncyte were positive in these cells.
Electron Microscopy:
Histiocytic cells demonstrated all characteristics of Langerhans cells except for Birbeck’s granule.
Case #5
The patient was a 2-year-old black female who had a one-month history of a pruritic erythematous eruption involving her right arm and axilla and eventually spreading to her left arm, legs, hands, axillae, chest, abdomen, and buttocks. She had been treated with anti-scabetics, oral antibiotics, oral anti-histamines, and topical hydrocortisone, all to no avail. Her mother and two brothers had similar pruritic eruptions.
Cutaneous examination revealed multiple 2 – 5 mm erythematous papules and larger nodular eruptions on her trunk, buttocks, legs, arms, and hands. There were several 5 – 10 mm indurated hyperpigmented nodules involving her right arm, right chest, and both axillae. A scraping of the nodular lesions was negative.
The patient and her entire family were re-treated with Elimite cream. Her mother and brothers all noted improvement; however, the patient continued to develop new papulo-nodular lesions on her hands, forearms, axillae and chest for several months. Punch biopsies were done on two fresh lesions of her right axilla.
Histopathology
Histological features were similar to those of
previous cases. There were no eosinophils. Large histiocytic cells were particularly noticeable around hair follicles and eccrine secretory coils. These
cells also infiltrated the lesional epidermis and hair follicles. No mites were detected in serial sections.
Immunostains
CD1a was strongly positive among these infiltrating cells including those in the hair follicles. S-100 and HLA-DR were likewise strongly positive in the infiltrations. It is noted that Lag, a specific monoclonal antibody for Birbeck’s granules, was only sparsely positive in the dermal infiltrating cells, although many epiderman cells were reactive. Lag dermal cell numbers did not compare to those other CD1a and HLA-DR cell populations.
Electron Microscopy
Large histiocytic cells exhibited all the
ccharacteristics of Langerhans cells except for the total absense of Birbeck’s granules.
Case #6
A 40-year-old white male had pruritic eruptions for one week prior to his first visit to our clinic. He had already been treated with Kwell twice.
Physical examination revealed numerous papulo-nodules in scabetic distribution under the
axillae, on the chest, areolae, popliteal fossae and thigh and small papulo-vesicular lesions on the toes and between fingers. KOH for mites was negative, probably due to previous treatments. Elimite application overnight was prescribed with a diagnosis of partially treated scabies. Two days later, the patient returned because of no improvement, further development of nodular lesions, and enhanced pruritus. Biopsy was done on one nodular lesion of popliteal fossa. Temovate ointment twice a day was prescribed. Two weeks later, the patient returned with significant improvement of eruptions and pruritus.
Histopathology
Histological features similar to those of previous cases were confirmed. Endothelial cells were swollen, and large histiocytes were admixed with lymphocytes in the perivascular space. No eosinophils were present in thes infiltrations.
Immunostains
CD1a positive cells were numerous and they were also positive for S-100 and HLA-DR particularly in the upper dermis, epidermis, and vesicles in the upper epidermis.
Electron Microscopy
No Birbeck’s granule positive cells were found. Large histiocytes were otherwise similar to Langerhans cells.
Next part will start with Case #7
Case #7
A one-year-old white boy developed a red pruritic (itchy) eruption over all areas of his body. Both of the parents were employed, and the infant was placed in a day care center during working hours. The parents stated that they had been itching for several weeks.
Physical examination revealed a well developed, well nourished white male having erythematous (red) papules and nodules (bumps) (3-5 mm) scattered over the trunk and extremities. The face was spared, the diaper area was involved, and moderately erythematous (red). Some were excoriated (scratched). A scraping of several from the arms was negative for scabies mites. Three treatments with pyrethrum cream (Elimite) were ineffective in relieving the pruritus (itching) or resolving the lesions. Temovate ointment (synthetic
corticosteroid) and intralesional injection of triamcinolone acetonnide suspension (10 mg/cc) were effective in reducing the nodules. A punch biopsy of a nodule on the left shoulder was performed.
Histopathology
A very heavy lymphohistiocytic infiltration occupied the upper 2/3 of the lesional dermis. Some eosinophils were admixed.
Immunostains
CS1a and HLA-DR were weakly positive, and S-100 wa not done.
Lag was positive in the epidermal Langerhans cells but in only a small fraction of the infiltrating cells.
Electron Microscopy
Langerhans cell-like cells were abundant but did not contain Birbeck’s granules.
Case #8
A 30-year-old HIV positive white male had pruritic (itchy)
papulovesicular (bumps with whiteheads or pus) lesions on the groin, penis, and trunk. Confluent and scattered nodular lesions were seen over the lower abdomen.
These were intensely pruritic (itchy). One biopsy was interpreted as lymphoma (cancer). The patient was treated with multiple topical antiscabetic preparations without improvement. Ivermectin (stromectol) (single oral dosage of 18 mg) was not effective. Prednisone 40 mg/day combined with Temovate ointment improved the condition significantly.
Histopathology
Histological features were similar to those of previous cases. Occasional eosinophils were observed.
Immunostains
CS1a was positive in 25 – 50% of infiltrating cells which were only occasionally Lag positive. Lymphocyte infiltration was mainly helper T cells.
Electron Microscopy
Langerhans cell-like cells without Birbeck’s
granules were admixed with lymphocytes.
Discussion
Clinical features of post-scabetic nodules or nodular scabies can be summarized as follows:
1. There is a history of definitive or presumptive
scabies which had been treated
2. Papulonodular lesions may occur in non-scabetic distribution, although in early stages papules (bumps), vesicles (pus or sacs), scales, and papular urticaria (redness, itching, hives, bumps) may still be in scabetic distributions.
3. Pruritus (itching) may be severe in the early stage but mild to absent in the late stage. Anti-scabetic regimens are ineffective, and the disease can persist over one year, although a good response to high potency corticosteroid ointments (medications that stop itching) or intralesional injection is expected.
4. It is more common in infants, but as in cases 6 and 8, adults may also be affected. Cases 5, 7 and 8 illustrate the evolution of nodules from acute scabies and case 3 suggests an over-lap with popular urticaria secondary to scabies. Thus, this entity seems to be a late stage immune reaction to Sarcoptes scabiei in which typical distribution, signs and symptoms of scabies have subsided and papulo-nodular lesions predominate in trunk, arms and legs. Without knowledge of preceding scabies, these lesions elecit suspicion of mastocytosis, urticaria pigmentosa, juvenile santhogranuloma, Langerhans cell histiocytosis including self-healing
reticulohistiocytosis, and lymphomas.
Histological features are essentially those of insect bite; perivascular and perappendageal infiltration of lymphohistiocytic cells is so heavy in some lesions that the upper dermis is diffusely occupied by a dense infiltration.
However, unlike insect bites, eosinophils are scarce or absent in most infiltrations, particularly in late stage nodular lesions. The absence of mites in the nodular lesions may explain this. Histiocytes (indeterminate cells) are significant components, although the predominant lymphocytes often mask them.
Histiocyte-monocyte markers such as Leu M5 and HLA-DR appear in these large histiocytic cells, and many of them possess more specific Langerhans cell epitopes for CD1a and S-100. The absence of Birbeck’s granules in these cells by electron microscopy and the monoclonal antibody against these granules, Lag, enabled us to classify them with indeterminate cells.
Thus, post-scabetic nodules are essentially composed of helper T cells and indeterminate cells. Interdigitate cell sarcoma may show the S-100/CD1a phenotype and develop skin lesions, but it is primarily a lymph node tumor.
Similarly, follicular dendritic sarcoma may express the S-100 phenotype but it is exclusively a lymph node or soft tissue tumor, and the tumor cells are connected with desmosomes; such ultra-structural features were absent in histiocytic cells infiltrating the lesions in our cases. Clinical resemblance of post scabetic nodules to mastocytosis and prurigo nodularis prompted us to do Giemsa stain in most specimens, because mast cells are prominent in both conditions. Giemsa stain was negative in all specimens. Electron microscopy did not detect any significant increase in mast cells in the lesion.
In 1968, Zelickson and Mottaz described a cell type in the normal human epidermis that resembles a Langerhans cell in all aspects but lacks Birbeck’s granules; they named this cell “indeterminate cell” and seemed to believe that this type represents an undifferentiated stage of either the melanocyte or the Langerhans cell. They calculated the indeterminate cell population in the epidermis at about 1% by counting them in three different locations. More recently, Harrist et al demonstrated epidermal indeterminate cells with CD1 monoclonal antibody, and Murphy et al reported the presence of dermal indeterminate cells with immunoelectron microscopy. While the exact nature of the indetermintate cell is not clear, its relationship to the Langerhans cell is suggested in the study of typical congenital self-healing reticulohistiocytosis by Schaumberg-Lever et al. They did not find any Birbeck’s granules in a heavy infiltration of histiocytic cells that were CD1a positive and contained numerous dense laminated bodies. They believed that Birbeck’s granules were converted into laminated bodies because such transitional pictures were found in the epidermal Langerhans cells in the lesion. Levisohn et al reported a case of solitary congenital indeterminate cell histiocytoma. This case could represent solitary congential self-healing reticulohistiocytosis in which Birbeck’s granules were degenerated; if so, this is another example of conversion of Langerhans cells to indeterminate cells. In post-scabetic indeterminate cell histiocytosis (PSIH), as reported in this communication, histiocytic cells were
phenotypically andultrastructurally Langerhans cells except for the lack of Birbeck’s granules. Monoclonal antibody Lag, which decorates Birbeck’s granules, was largely negative in thes infiltrating histiocytes. There were no dense laminated bodies suggestive of degeneration of pre-existing Birbeck’s granules.
The indeterminate cells of PSIH may be immature Langerhans cells derived from bone marrow in resonse to scabetic antigen stimulation; mitotic marker antigen as detectable with Ki67 was mostly negative in the lesions. These indeterminate cells constitute variable proportions of infiltrating cells in PSIH and are admixed with predominantly helper % cells. Factor XIIIa epitope was absent in these cells, suggesting that no dermal dendritic cells are involved.
Some of the early cases reported as non-X histiocytosis or indeterminate cell histiocytosis are not adequately analyzed with immunostains. In the case of Fowler et al, the presence of Touton type giant cells suggested a xanthogranulomatous process. In the case of Sigal-Nahum, S-100 was negative. It seems necessary that more strict criteria of indeterminate cell be applied before the case is called indeterminate ccell histiocytosis. The clinical picture has varied in the previously reported cases from multiple papules and small nodules to plaques. Face and extremities are predilections sites.
Spontaneous regression can occur in some cases, but systemic involvement can be serious and fatal. No connection with scabies was mentioned.
Our cases probably constitute a new definition of so-call “persistent nodules in scabies” or “persistent, recurring itchy papules after scabies”. In these reports, cases similar to ours have been documented, namely persistent pruritic nodules after scabetic treatment, absence of mite, lymphohistiocytic infiltration resembling lymphoma, mastocytosis or granuloma and rsistance to repeated scabicidal treatments. In one series, patients were mostly infants or young children and in another, all were adults. Lesions similar to PSIH may be induced by other arthropod bites.
Immunophotypes of the infiltrating cells in PSIH are suggestive of Langerhans cell histiocytosis, and the formation of epidermal microabscesses is similar to that of more severe Letterer-Siwe disease. Because clinical presentation and H & E histology in infant patients of PSIH can very closely resemble Langerhans cell histiocytosis or lymphomas, the current standard of care requires comprehensive analysis by phenotyping in such situations. When Langerhans cell phnotypes are confirmed in a large number of infiltrating cells, further examination for Birbeck’s granules should be done by electron microscopy, but the current trend to skip it with the assumption that these immunophenotypes adequately identify Langerhans cells. The recognition of this entity reemphasizes the necessity of electron microscopy in the diagnosis of Langerhans cell histiocytosis until reliable monoclonal antibodies against Birbeck’s granule become universally available. Lag is probably the best monoclonal antibody for recognizing Birbeck’s granules, but it also labels membranes and vacuoles unrelated to Birbeck’s granules.
Scabies is no longer the cyclic disease it used to be; it is one of the common conditions we encounter in daily practice. Awareness of the existene of this entity would avoid an unnecessary crisis situation for the patient’s family and perhaps the physician. Costly systemic workups could also be avoided.