Journal oj Cutaneous Pathology 1975: 2: 170-178
Langerhans Cells in Actinic Reticuloid L. ScHNiTZLER, J. L. VERRET, B . SCMUBERT AND M . D . PICARD
Service de Dermatologie, Centre Hospitalo-Universitaire, Angers, France Actinic reticuloid was observed in a patient following the development of porphyria cutanea tarda. A cutaneous lymphoma-like infiltrate was found histologically and at the ultrastructural level. In the infiltrate, the main population was histioeytic, with some mast cells and mononuciear cells. Most of the histioeytic cells contained numerous typical Langerhans granules and worm-like structures. Crystalloid cytoplasmic incltisions were occasionally detected. (Received jor publicatioti January 18, 1975)
Under treatment (alcoholic diet, metabolic alcalinization, citroflavonoids and iron ehelation) improvement oecurred, but in September 1972, severe itehing followed by swelling and a weeping eruption strietly limited to light exposed areas developed. In April 1973, because of intense papular and pruritic lesions, a "dark room" maintenance was instituted whieh improved the patient status. A biopsy showed a lymphoma-like infiltrate. Irradiation with a xenon UV solar simulator resulted in very low minimal erythema dose on unexposed skin (2 seconds instead of about 60 seconds in similar conMaterial and Methods trols). A skin biopsy of an irradiated area showed a milder infiltrate morphologieally Case Report In July 1970, a fifty-four-year old male pa- similar to that found in exposed skin. The patient was capable of a delayed tient was seen in the Service of Dermatology at Angers, with a elinieal picture of PCT. hypersensitivity response to antigenic stimuUrine was fluorescent, uroporphyrins were lation. No treatment proved to be effective 1.5 mg/1, coproporphyrins 0.450 mg/1 wilh- although systemie steroids resulted in tranout porphobilinogen; seric iron was 0.210 sient improvement of itching. mg/1; liver funetion tests showed evidence A biopsy specimen from an actinie reticuof hepatic disturbanee. A skin biopsy re- loid lesion of the faee was divided lor three studies: a) Histology: seetions were stained vealed suhepidermal blister formation.
Actinic reticuloid was first described hy Ive et al. (1969) who reported 10 eases of a disease, precipitated by exposure to sunlight with a lymphoma-like histology, the treatment and pathogenesis of whieh are still unknown. Soon after, Degos et al. (1969) reported another ease. Although about 50 patients have been observed to date, few authors have published ultrastructural studies. None of them, except the patient reported here (Sehnitzler et al. 1974), was assoeiated with a history of porphyria cutanea tarda (PCT).
171
ACTINIC RETICULOID
Figs. 1 and 2. Skin biopsy specimen of a papular lesion on the face, showing the lymphonia-likc infiltrate. HES X 100 and X 160. with hematoxylin-eosin-safran, PAS, Alciati blue, KmnO4-Aleian blue, b) Itrttittittofliiorescence: tissues were immediately ftozen for diiect immtinofhioresccnce study, c) Electron microscopy: small blocks were immediately placed in cold glutaraldehyde ( 4 % in phosphate buffer (O.lM-pH 7.2) 1 1/2 h at 4°C) and then in OSO4 2 % in the same buffer, dehydrated in alcohol and embedded in Epon 812. Thick sections (O.OOi mm) were observed by light micro-
scopy after staitning with toiuiditie blue. Sections of the Epon-embedded tissues were stained with uranyl acetate and lead citrate and then examined in a Jeol lOOB electron microscope operating at 80 KV. Results
a) Hi.stotogicitl sttidy demotistrated the typical lymphoma-Iike infiltrate as described by Ive et al. (1969). A dense band-like or
172
SCHNITZLER ET AL. b) Direct immtttwfhiorescence was negative; spontaneous fluorescence was not recorded. e) Fine structure. The main finding was a dermal infiltrate eotnposed of tiionotiuclear cells. Most of these cells were histiocytes with large relatively translucent cytoplasm with well developed otganelles and an often indented nucleus with nutnerous intranuclear inclusions. The tnost striking finding in this bistiocytic infiltrate was the presence of typical Langethans granules, with tod-like profiles, zipper or tennis-raeket-like structures. A few of them were attached to the cell metnbrane but the tnajority were randotiily distributed within the cytoplastn, often in close proximity to the Golgl region (Figs. 5 and 6).
Fig. 5. Thick section, Epon embedded and toluidine blue stained. Dense histiocytic dermal infiltrate: histiocytcs are large and hyperchromatic with deeply indented and darkly stained nuclei (-^). X 400.
nodular infiltrate (Fig. I) invaded the entire dermis particularly in the superficial layer but sparing the epidertnis, except for mild exocytosis either of individual cells or of very small nests of cells. The infiltrate consisted tnainly of eells of the reticulohistiocyticand lytnpbocytic series associated with mast cells, plasma eells, lymphoid cells and few granulocytes; tbis reaction closely simulated a pre-tetieulotie eruption (Figs. 1 and 2). Thick serial sections showed large and hyperchromatic histioeytes with darkly stained nuclei. Some looked particularly abnortnal, but were without definite malignant cytological characteristics (Fig. 2). In Ihc upper dermis we found, in one block, foci of large mactophagie cells with round granules (Fig. 4).
Fig. 4. Thick section. In the upper dertnis a dense bistioeytic infiltrate and foci of large macrophagic cells with round granules ( t ) (mast cells?) are seen. X 400.
ACTINIC RETICULOID
173
/•'/.y. .V L l e c U o n n i i c r o g r a p h sluivviiig an a c l i v e histiocyte u i l h n u n i c r o i i s i n t r a c y l o p l a s i i i i c L a n g e r h a n s g r a n u l e s (Lg) (-=-) in t h e d e r m a l infiltrate. X 5(),t)0t).
These Langerhans cells also exhibited niultivesicular bodies, fibrillar material and a nutnber of worm-like structures (Fig. 7). Moteover, non-membrane-bounded crystalloid eytoplasmie inclusions were occasionally detected. They were about 0.5 to I u long with periodie strtictures of abotit 210-245 A with transverse thiti bridges separated by spaces of 125-145 A (Figs. 8 and 9). The eells with Langerhans granules were not the only eomponent of the lesion but accounted for a considerable mass of the total infiltrate. There was, in fact, little in the fine tnorphology to separate Langethans cells from these abnormal histioeytes. Other cells observed included sotne lytnphoid cells with indented nucleus, latge
prominent nitcleohis and endoplasmic relicuhtm as in blast transformation of lytnphocytes, or in the Sezary syndrome. These findings are similar to those reported by Piriol Aguade et al. (1975). Apart fiom the infilttate previously deseribed occasional large cells were tioted in the upper part of the dertnis and in the epidermis (Fig. 10). These cells contained latge vesicles made up of degenerated tnyelinie structutes, or rolled metnbranes as observed in mast cell granules, but their nature temains questionable. Sitice Langerhans granules were absent, they may be presutned to be macrophagic cells eontaining remnants of ititralysosotnal digested tnaterial.
Fig. (>• Langerbans granules witb raeket-shaped profiles (ra). X 80,000. Inset shows a higher magtiification of typical Langerhans grantiles. X 135,000. Fig. 7. Area of a histiocyte in tbe dermal infiltrate showing worm-like structures (w), lamellar mitochondria (m) and fibrillar matetial (f). X 70,000,
SCHNITZLER ET AL.
174
A
i ra •'.»'•'•
rn
•
.
•
'
ACTINIC RETICULOID
175
Fig. tS. Cytoplasmic crystalloid inclusion in a cell of the dermal infiltrate. X yO.OOO. Details of the inclusion are seen in the inset at a higher magnification. X l.S3,()0().
.A
., -"^si.
/•'/i'. '''. Another cylo|>las]iiic CI>.S1;IIII>KI inclusion. X 90.000.
SCHNITZLER ET AL.
176
Fifi. 10. Area within ihc epidermis of two histiocytic macrophiigic cells (H) containing remnants of digested material. Keratinocytes (K) are also seen. X 25,000. Inset shows at a higher magnification a large cytoplasmic vesicle with rolled membrane structures ( ^ ) . X 50,000.
Discussion
Aetinie reticuloid may be considered another benign condition whieh shows eells with abnormal eytologieal features. However, it is impossible to make any definite statements at present about the prognosis of aetinie retieuloid from the haematological point of view since most cases have been followed for too short a time (Ive et al. 1969, Degos et al. 1969, Gtiix Melcior et al. 1969, Jensen & Sneddon 1970, Mitehell 1970, Heid et al. 1970). In our patient, electron microscopie observations revealed a histiocytie infiltrate witb numerous intraeytoplasmic Langerhans granules and wortn-like structures, features which have not previously been reported in this condition. The Langerbans granule may be considered a specific marker, so cells exhibiting this cytoplasmic marker are called Langer-
hans eells. Langerhans eells are well known in epidermis, skin appendages and mueous membranes (Zeliekson 196.5, Breathnach & Wyllie 1967). Their extra-epidermal loealization has been reported by several authors in lungs, lymph-nodes (Clawson et al. 1970), eutaneous tumors, Ehlets Danlos syndrotne, pityriasis rosea, etc. with the granules sotnetitnes seattered into the cytoplastn (Wolff 1973). In histioeytosis (Letlerer Siwe, HandSchiiller-Christian, eosinophilie granulotna) and in other fatal granulomatous diseases (retieulum eell sarcoma, malignant histioeytosis, monoeytie leuketnia) the Langerhans granule appears to he a consistent eotnponent of the eellular histioeytie infilttate (Basset & Nezelof 1969, Gianotti & Caputo 1969, Intvtnura et al. 1971, Nezelof et al. 1973). However, actinic retictiloid is a elinical entity different from these pathologic eonditions.
ACTINIC RETICULOID Worm-like structures have been observed by Gianotti et al. (1971) in non-tnalignant child histiocytosis and by Hashimoto & Pritzker (1973) and Laugier et al. (1975) in congenital self-healing teticulo-histiocytosis but they ate not uncommoti in histiocytosis (Basset & Nezelof 1969, Gianotti & Caputo 1969) and in mycosis fungoides. This case report further emphasizes that it is becotning inctcasingly appatent that histioeytes witb Langerhans gtanules and worm-like structures tnay reptesent a reaetional stage in various diseases and tnay be an utiexplained featute of the histioeytic futiction. The intracyloplastnic crystalloid bodies discoveted in eells of the dertnal itililtrate have sotne morphological sitnilarities with the crystalline inchtsions described in hepatocytcs (Scotto et al. 1969. Butns et al. 1974). Intetestingly. Norutn et al. (1972) reported obscrvafiotis in the livers of two patients that were similar to our own findings.
177
Notuy, D. F., Lartegue, M. & Audebeit, G. (1969) Photosensibilisation et reticulose lyniphohistiocytaire histologiquc. (Poussees erythrodermiques et papuleuses.) Bulletin de la Societe Fran^aise de Derniatologie et Syphiligraphie 76, 269. Gianotti, F. & Caputo. R. (1969) Skin ultrastructure in Hanol-Scbiiller-Christian disease. Archives of Dermatology 100. .?42-349. Gianotti, F.. Caputo, R. & Ermacora. E. (1971) Singuliere "histiocytose infantile a cellules avec particules vermiformes intracytoplasmiques". Bulletin de la Societe Fran^aise de Derniatologie et Sypliiligraphie 78. 232-233. Guix Melcior, R., Gimenez, C. J. M. & PinolAguade, J. (1969) Existe la fotoalergia? Medicina cutanea 111. 489-493. Hashimoto, K. & Pritzket, M. S. (1973) An unusual case of congenital, self healing reticulo-bistiocytosis. Archives of Dermatolotiv 107, 263-270. Heid, E., Grosshans, E., Scbubett, B., Betgoend. H. & Maleville. J. (1970) Les dermites photoallergiqucs chroniques: aspects cliniques et anatoniopathologiques. (Pseudo lymphotnes actiniques.) Bulletin de la Societe Fran^n'se de Derniatologie et Syphiligraphie 77, 16-24. lnamura, M., Sakamato, S. & Hanazono. H. (1971) Malignant histiocytosis: a case of generalized histiocytosis with infiltration of Langerhans granule containing bistiocytes. Acknowledgments Cancer 2S, 467-475. We are grateful to 1. P. Ciislard and R. FilIve, F. A., Magnus. I. A.. Warin. R. P. & Wilmoti for their techtiical assistance. son-lones, E. (1969) "Actinic teticuloid" a cbronic dermatosis associated witb severe photosensitivity and the histological resReferences semblance to lytiiphotna. British Journal of Dermatology
Langerhans Cells in Actinic Reticuloid L. ScHNiTZLER, J. L. VERRET, B . SCMUBERT AND M . D . PICARD
Service de Dermatologie, Centre Hospitalo-Universitaire, Angers, France Actinic reticuloid was observed in a patient following the development of porphyria cutanea tarda. A cutaneous lymphoma-like infiltrate was found histologically and at the ultrastructural level. In the infiltrate, the main population was histioeytic, with some mast cells and mononuciear cells. Most of the histioeytic cells contained numerous typical Langerhans granules and worm-like structures. Crystalloid cytoplasmic incltisions were occasionally detected. (Received jor publicatioti January 18, 1975)
Under treatment (alcoholic diet, metabolic alcalinization, citroflavonoids and iron ehelation) improvement oecurred, but in September 1972, severe itehing followed by swelling and a weeping eruption strietly limited to light exposed areas developed. In April 1973, because of intense papular and pruritic lesions, a "dark room" maintenance was instituted whieh improved the patient status. A biopsy showed a lymphoma-like infiltrate. Irradiation with a xenon UV solar simulator resulted in very low minimal erythema dose on unexposed skin (2 seconds instead of about 60 seconds in similar conMaterial and Methods trols). A skin biopsy of an irradiated area showed a milder infiltrate morphologieally Case Report In July 1970, a fifty-four-year old male pa- similar to that found in exposed skin. The patient was capable of a delayed tient was seen in the Service of Dermatology at Angers, with a elinieal picture of PCT. hypersensitivity response to antigenic stimuUrine was fluorescent, uroporphyrins were lation. No treatment proved to be effective 1.5 mg/1, coproporphyrins 0.450 mg/1 wilh- although systemie steroids resulted in tranout porphobilinogen; seric iron was 0.210 sient improvement of itching. mg/1; liver funetion tests showed evidence A biopsy specimen from an actinie reticuof hepatic disturbanee. A skin biopsy re- loid lesion of the faee was divided lor three studies: a) Histology: seetions were stained vealed suhepidermal blister formation.
Actinic reticuloid was first described hy Ive et al. (1969) who reported 10 eases of a disease, precipitated by exposure to sunlight with a lymphoma-like histology, the treatment and pathogenesis of whieh are still unknown. Soon after, Degos et al. (1969) reported another ease. Although about 50 patients have been observed to date, few authors have published ultrastructural studies. None of them, except the patient reported here (Sehnitzler et al. 1974), was assoeiated with a history of porphyria cutanea tarda (PCT).
171
ACTINIC RETICULOID
Figs. 1 and 2. Skin biopsy specimen of a papular lesion on the face, showing the lymphonia-likc infiltrate. HES X 100 and X 160. with hematoxylin-eosin-safran, PAS, Alciati blue, KmnO4-Aleian blue, b) Itrttittittofliiorescence: tissues were immediately ftozen for diiect immtinofhioresccnce study, c) Electron microscopy: small blocks were immediately placed in cold glutaraldehyde ( 4 % in phosphate buffer (O.lM-pH 7.2) 1 1/2 h at 4°C) and then in OSO4 2 % in the same buffer, dehydrated in alcohol and embedded in Epon 812. Thick sections (O.OOi mm) were observed by light micro-
scopy after staitning with toiuiditie blue. Sections of the Epon-embedded tissues were stained with uranyl acetate and lead citrate and then examined in a Jeol lOOB electron microscope operating at 80 KV. Results
a) Hi.stotogicitl sttidy demotistrated the typical lymphoma-Iike infiltrate as described by Ive et al. (1969). A dense band-like or
172
SCHNITZLER ET AL. b) Direct immtttwfhiorescence was negative; spontaneous fluorescence was not recorded. e) Fine structure. The main finding was a dermal infiltrate eotnposed of tiionotiuclear cells. Most of these cells were histiocytes with large relatively translucent cytoplasm with well developed otganelles and an often indented nucleus with nutnerous intranuclear inclusions. The tnost striking finding in this bistiocytic infiltrate was the presence of typical Langethans granules, with tod-like profiles, zipper or tennis-raeket-like structures. A few of them were attached to the cell metnbrane but the tnajority were randotiily distributed within the cytoplastn, often in close proximity to the Golgl region (Figs. 5 and 6).
Fig. 5. Thick section, Epon embedded and toluidine blue stained. Dense histiocytic dermal infiltrate: histiocytcs are large and hyperchromatic with deeply indented and darkly stained nuclei (-^). X 400.
nodular infiltrate (Fig. I) invaded the entire dermis particularly in the superficial layer but sparing the epidertnis, except for mild exocytosis either of individual cells or of very small nests of cells. The infiltrate consisted tnainly of eells of the reticulohistiocyticand lytnpbocytic series associated with mast cells, plasma eells, lymphoid cells and few granulocytes; tbis reaction closely simulated a pre-tetieulotie eruption (Figs. 1 and 2). Thick serial sections showed large and hyperchromatic histioeytes with darkly stained nuclei. Some looked particularly abnortnal, but were without definite malignant cytological characteristics (Fig. 2). In Ihc upper dermis we found, in one block, foci of large mactophagie cells with round granules (Fig. 4).
Fig. 4. Thick section. In the upper dertnis a dense bistioeytic infiltrate and foci of large macrophagic cells with round granules ( t ) (mast cells?) are seen. X 400.
ACTINIC RETICULOID
173
/•'/.y. .V L l e c U o n n i i c r o g r a p h sluivviiig an a c l i v e histiocyte u i l h n u n i c r o i i s i n t r a c y l o p l a s i i i i c L a n g e r h a n s g r a n u l e s (Lg) (-=-) in t h e d e r m a l infiltrate. X 5(),t)0t).
These Langerhans cells also exhibited niultivesicular bodies, fibrillar material and a nutnber of worm-like structures (Fig. 7). Moteover, non-membrane-bounded crystalloid eytoplasmie inclusions were occasionally detected. They were about 0.5 to I u long with periodie strtictures of abotit 210-245 A with transverse thiti bridges separated by spaces of 125-145 A (Figs. 8 and 9). The eells with Langerhans granules were not the only eomponent of the lesion but accounted for a considerable mass of the total infiltrate. There was, in fact, little in the fine tnorphology to separate Langethans cells from these abnormal histioeytes. Other cells observed included sotne lytnphoid cells with indented nucleus, latge
prominent nitcleohis and endoplasmic relicuhtm as in blast transformation of lytnphocytes, or in the Sezary syndrome. These findings are similar to those reported by Piriol Aguade et al. (1975). Apart fiom the infilttate previously deseribed occasional large cells were tioted in the upper part of the dertnis and in the epidermis (Fig. 10). These cells contained latge vesicles made up of degenerated tnyelinie structutes, or rolled metnbranes as observed in mast cell granules, but their nature temains questionable. Sitice Langerhans granules were absent, they may be presutned to be macrophagic cells eontaining remnants of ititralysosotnal digested tnaterial.
Fig. (>• Langerbans granules witb raeket-shaped profiles (ra). X 80,000. Inset shows a higher magtiification of typical Langerhans grantiles. X 135,000. Fig. 7. Area of a histiocyte in tbe dermal infiltrate showing worm-like structures (w), lamellar mitochondria (m) and fibrillar matetial (f). X 70,000,
SCHNITZLER ET AL.
174
A
i ra •'.»'•'•
rn
•
.
•
'
ACTINIC RETICULOID
175
Fig. tS. Cytoplasmic crystalloid inclusion in a cell of the dermal infiltrate. X yO.OOO. Details of the inclusion are seen in the inset at a higher magnification. X l.S3,()0().
.A
., -"^si.
/•'/i'. '''. Another cylo|>las]iiic CI>.S1;IIII>KI inclusion. X 90.000.
SCHNITZLER ET AL.
176
Fifi. 10. Area within ihc epidermis of two histiocytic macrophiigic cells (H) containing remnants of digested material. Keratinocytes (K) are also seen. X 25,000. Inset shows at a higher magnification a large cytoplasmic vesicle with rolled membrane structures ( ^ ) . X 50,000.
Discussion
Aetinie reticuloid may be considered another benign condition whieh shows eells with abnormal eytologieal features. However, it is impossible to make any definite statements at present about the prognosis of aetinie retieuloid from the haematological point of view since most cases have been followed for too short a time (Ive et al. 1969, Degos et al. 1969, Gtiix Melcior et al. 1969, Jensen & Sneddon 1970, Mitehell 1970, Heid et al. 1970). In our patient, electron microscopie observations revealed a histiocytie infiltrate witb numerous intraeytoplasmic Langerhans granules and wortn-like structures, features which have not previously been reported in this condition. The Langerbans granule may be considered a specific marker, so cells exhibiting this cytoplasmic marker are called Langer-
hans eells. Langerhans eells are well known in epidermis, skin appendages and mueous membranes (Zeliekson 196.5, Breathnach & Wyllie 1967). Their extra-epidermal loealization has been reported by several authors in lungs, lymph-nodes (Clawson et al. 1970), eutaneous tumors, Ehlets Danlos syndrotne, pityriasis rosea, etc. with the granules sotnetitnes seattered into the cytoplastn (Wolff 1973). In histioeytosis (Letlerer Siwe, HandSchiiller-Christian, eosinophilie granulotna) and in other fatal granulomatous diseases (retieulum eell sarcoma, malignant histioeytosis, monoeytie leuketnia) the Langerhans granule appears to he a consistent eotnponent of the eellular histioeytie infilttate (Basset & Nezelof 1969, Gianotti & Caputo 1969, Intvtnura et al. 1971, Nezelof et al. 1973). However, actinic retictiloid is a elinical entity different from these pathologic eonditions.
ACTINIC RETICULOID Worm-like structures have been observed by Gianotti et al. (1971) in non-tnalignant child histiocytosis and by Hashimoto & Pritzker (1973) and Laugier et al. (1975) in congenital self-healing teticulo-histiocytosis but they ate not uncommoti in histiocytosis (Basset & Nezelof 1969, Gianotti & Caputo 1969) and in mycosis fungoides. This case report further emphasizes that it is becotning inctcasingly appatent that histioeytes witb Langerhans gtanules and worm-like structures tnay reptesent a reaetional stage in various diseases and tnay be an utiexplained featute of the histioeytic futiction. The intracyloplastnic crystalloid bodies discoveted in eells of the dertnal itililtrate have sotne morphological sitnilarities with the crystalline inchtsions described in hepatocytcs (Scotto et al. 1969. Butns et al. 1974). Intetestingly. Norutn et al. (1972) reported obscrvafiotis in the livers of two patients that were similar to our own findings.
177
Notuy, D. F., Lartegue, M. & Audebeit, G. (1969) Photosensibilisation et reticulose lyniphohistiocytaire histologiquc. (Poussees erythrodermiques et papuleuses.) Bulletin de la Societe Fran^aise de Derniatologie et Syphiligraphie 76, 269. Gianotti, F. & Caputo. R. (1969) Skin ultrastructure in Hanol-Scbiiller-Christian disease. Archives of Dermatology 100. .?42-349. Gianotti, F.. Caputo, R. & Ermacora. E. (1971) Singuliere "histiocytose infantile a cellules avec particules vermiformes intracytoplasmiques". Bulletin de la Societe Fran^aise de Derniatologie et Sypliiligraphie 78. 232-233. Guix Melcior, R., Gimenez, C. J. M. & PinolAguade, J. (1969) Existe la fotoalergia? Medicina cutanea 111. 489-493. Hashimoto, K. & Pritzket, M. S. (1973) An unusual case of congenital, self healing reticulo-bistiocytosis. Archives of Dermatolotiv 107, 263-270. Heid, E., Grosshans, E., Scbubett, B., Betgoend. H. & Maleville. J. (1970) Les dermites photoallergiqucs chroniques: aspects cliniques et anatoniopathologiques. (Pseudo lymphotnes actiniques.) Bulletin de la Societe Fran^n'se de Derniatologie et Syphiligraphie 77, 16-24. lnamura, M., Sakamato, S. & Hanazono. H. (1971) Malignant histiocytosis: a case of generalized histiocytosis with infiltration of Langerhans granule containing bistiocytes. Acknowledgments Cancer 2S, 467-475. We are grateful to 1. P. Ciislard and R. FilIve, F. A., Magnus. I. A.. Warin. R. P. & Wilmoti for their techtiical assistance. son-lones, E. (1969) "Actinic teticuloid" a cbronic dermatosis associated witb severe photosensitivity and the histological resReferences semblance to lytiiphotna. British Journal of Dermatology
