BRIEF REPORTS
Sinus Histiocytosis With Massive Lymphadenopathy: A “Massive” Misnomer Divesh Sardana, M.D.S.,* Ashima Goyal, M.D.S., and Krishan Gauba, M.D.S.
Sinus histiocytosis with massive lymphadenopathy also known as Rosai–Dorfman disease is a rare, benign, histiocytic disorder of unknown origin characterized by lymphadenopathy. Since its original description by Rosai and Dorfman in 1969, small number of cases has been reported; hence no specific diagnostic criteria and treatment guidelines have been suggested. The purpose of this article is to present and discuss a case of Rosai Dorfman Syndrome in 4-year-old child diagnosed with the help of Fine Needle Aspiration Cytology. The swelling resolved over a period of 18 months without any recurrence in 2-year followup period. This case report highlights the role of Fine Needle Aspiration Cytology in the diagnosis of Rosai–Dorfman disease and the importance of regular follow ups using a careful wait and watch approach in its management. The report also briefly discusses the various dilemmas associated with its diagnosis and treatment. Diagn. Cytopathol. 2015;43:315–319. VC 2014 Wiley Periodicals, Inc.
accompanied by fever, leukocytosis, elevated erythrocytes sedimentation rate (ESR), and hyperglobulinemia.2 Lymph nodes other than cervical may be involved and the involvement of extra nodal sites is not uncommon.3 Since its original description, RDD has become a rare but distinct clinic-pathological entity with Fine Needle Aspiration Cytologic (FNAC) findings of presence of large histiocytes that tend to be isolated and characteristically contain mature lymphocytes in their cytoplasm (a process termed emperipolesis).4–6 These specific and unique histiocytes are sometimes called as “Rosai–Dorfman cells.” The aim of this article is to report a case of RDD diagnosed with the help of FNAC in a 4-year-old child, which resolved over a period of 18 months without any surgical or therapeutic intervention.
Key Words: sinus histiocytosis; massive; Rosai–Dorfman disease; lymphadenopathy
Case Report
Rosai–Dorfman disease (RDD), also known as Sinus Histiocytosis with Massive Lymphadenopathy (SHML), is a rare, benign histiocytic disorder that was first described by Rosai and Dorfman in 1969.1 It consists of chronic massive enlargement of cervical lymph nodes, frequently
Unit of Pedodontics and Preventive Dentistry, Oral Health Sciences Center, Post-Graduate Institute of Medical Education and Research, Chandigarh, India *Correspondence to: Divesh Sardana, M.D.S., Unit of Pedodontics and Preventive Dentistry, Oral Health Sciences Center, Post-graduate Institute of Medical Education and Research, Chandigarh, India. E-mail: [email protected] Received 11 December 2013; Revised 7 June 2014; Accepted 17 July 2014 DOI: 10.1002/dc.23198 Published online 4 August 2014 in Wiley Online Library (wileyonlinelibrary.com). C 2014 WILEY PERIODICALS, INC. V
A 4-year-old male child reported to the Department of Pedodontics, PGIMER, Chandigarh with a chief complaint of swelling in the sub-mental region since 4 months (Fig. 1a). The swelling was insidious in onset and had remained constant in size over the period of time with no other local signs and symptoms. On examination, the swelling measured 2.5 cm 3 3.0 cm approximately and; was non-tender, non-fluctuant, and soft in consistency. On general physical examination, child was found to be of normal height and weight for his age with no swelling seen elsewhere in the body; and no signs of any systemic infection, splenomegaly, or hepatomegaly. On extra-oral examination, no lymph nodes were palpable in the neck region and other areas of the body. Intra-orally the patient was in deciduous dentition stage with dental caries in relation to few teeth which were indicated for restorations. Besides dental caries, there was no tooth mobility, pus discharge, intra-oral swelling, or any other abnormality. Intra-oral periapical radiographs of carious teeth and orthopantomogram were taken. Diagnostic Cytopathology, Vol. 43, No 4
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Diagnostic Cytopathology DOI 10.1002/dc
SARDANA ET AL.
Fig. 1. Photograph of the child patient showing (a) swelling in the sub-mental region, (b) complete resolution of swelling at 18-month follow-up visit. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
However, radiographs did not reveal any abnormality relevant to the swelling. Complete blood analysis of the child was performed which showed a normal blood picture of a healthy child. FNAC of the swelling was performed under local anesthesia using 24 gauge needle which is suitable for children. Skin over swelling was cleansed and immobilized with fingers while the needle was inserted into it. Single puncture multi-directional technique was used for aspiration. Aspirated material was recovered and expressed onto slide. Few smears were wet fixed with ethyl alcohol and few were air dried and heat fixed to perform acid-fast staining. FNAC findings of Giemsa stained cytosmears showed presence of extensive emperipolesis in the background of mixed inflammatory cells (Figs. 2a and b). Detailed examination of Giemsa and Hematoxylin and Eosin stained cytosmears revealed numerous histiocytes showing anisocytosis, with vesicular, small round to oval nuclei with distinct contours (Figs. 2c and d). Emperipolesis of variable numbers of lymphocytes and occasional plasma cells was also noted (Figs. 2c and d). Ingested cells showed no signs of mitosis. The background cells were composed of lymphocytes which included larger and immature forms along with plasma cells, few neutrophils, and rare eosinophils (Figs. 2c and d). Acid fast staining of air dried and heat fixed smears was found to be negative for Acid Fast Bacilli. With the classical features of lymphadenopathy and histiocytosis with emperipolesis on cytopathology, a diagnosis of SHML or RDD was made. Considering the age of the patient and small size of swelling, the patient was kept on regular follow up of every 3 months without any active treatment. Parents of the child were counseled and reassured and medical or surgical interventions were kept as next line of treatment if the size of the swelling had increased. At each follow up, the 316
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patient was checked thoroughly for any changes in swelling. However, no change in the size of swelling was observed over a period of 15 months and hence no treatment was rendered except for restoration of carious teeth. At 18-month follow-up visit, the swelling had disappeared completely (Fig. 1b); the reason for which could not be identified. There was no recurrence of the swelling at 24 months of follow-up visit. Currently, the patient is still under regular follow up every 6 months.
Discussion In 1969, Rosai and Dorfman described four cases of a disease which they called SHML. Later in 1972, they analyzed 30 additional cases, establishing SHML as a clinic-pathologic entity.7 Although the definite etiology of RDD is unknown, various factors have been postulated to cause RDD like immunodeficiency,8 defect in immune mechanisms,9 infectious agents (like Herpes virus, Varicella zoster virus, Epstein–Barr Virus, Cytomegalovirus, Brucella, or Klebsiella),10–12 hematopoetic malignancies,13–15 and even genetic predisposition due to its reported occurrence in pairs of siblings.16,17 The disease most commonly affects younger age group; children being most commonly affected. Males are more commonly affected and there is reported higher predilection for occurrence in individuals of African descent.18 The disease clinically present as painless, bilateral massive cervical lymphadenopathy frequently accompanied by plethora of symptoms ranging from fever, malaise, weight loss, night sweats, tonsillitis, rhinorrhea, and so forth to hepatosplenomegaly1,7,10,11,19 which may add to the confusion regarding diagnosis and treatment. This case is also observed in a 4-year-old child with small swelling in submental region without any other clinical
Diagnostic Cytopathology DOI 10.1002/dc
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
Fig. 2. Photomicrograph of FNAC smear showed presence of extensive emperipolesis in the background of mixed inflammatory cells (a) (Giemsa, 310), (b) (Giemsa, 320); and presence of lymphocytes, plasma cells and histiocytes showing emperipolesis (c) (Giemsa, 340), (d) (Hematoxylin and Eosin, 340). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
features. Documented sites of extranodal involvement include skin, respiratory tract, bone, genitourinary system, oral cavity, central nervous system, eyes/orbit/ocular adnexa, salivary gland, tonsil, breast, soft tissue, and heart. The bone marrow is rarely involved.20 In this case, no extranodal involvement of disease is seen. Laboratory investigations may reveal anemia, leukocytosis with neutrophilia, and raised ESR with hypergammaglobulinemia [7]. Complete blood analysis of child in this case did not reveal any above mentioned laboratory findings. As the lymphadenopathy was not massive and no association with any of the systemic manifestations was seen with a normal blood picture, it was difficult to establish diagnosis based solely on these findings. FNAC is a simple, accurate, and economic tool, which has been widely used for the diagnosis of superficial and deep-seated lesions. Also, biopsy being an invasive procedure requires patient’s cooperation and probable administration of general anesthesia with subsequent hospital stay; thereby increasing the treatment cost and inconvenience to the patient. Review of the literature has revealed 49 reported cases of RDD diagnosed by FNAC.21 FNAC was used in this case considering the young age of the patient and because of its usefulness and reliability in diagnosis of RDD. Typically, FNA specimens show non-cohesive, diffusely distributed, enlarged histiocytes. These cells have
variable nuclei, abundant cyanophilic cytoplasm, and demonstrate emperipolesis of lymphocytes, plasma cells, and occasionally erythrocytes.22,23 Emperipolesis (also known as or lymphophagocytosis) is the engulfment of different cells (viz. intact lymphocytes, plasma cells, other leukocytes, or red blood cells) by cytoplasm of histiocytes; this is of great diagnostic significance. The internalized lymphocytes are usually located within cytoplasmic vacuoles.24 This process whereby cells enter and transit through a cell evading cellular degradation, known as emperipolesis was first described by Humble et al.25 Although the definitive cause of this phenomenon is not known, it may be due to unusual response of sinus histiocytes to local inflammatory factors. Although the nuclear shapes of histiocytes vary from round to extremely bizarre configurations, the chromatin is fine and evenly distributed and the nucleoli are usually not prominent. Occasionally, atypical morphology may be seen and, when present, it can lead to a misdiagnosis of malignancy [22]. Lymphocytes, plasma cells, neutrophils, and follicular center cells are often found in the background of the smear [23, 26]. FNAC findings in this case also showed presence of numerous multinucleated giant cells with extensive emperipolesis in the background of mixed inflammatory cells composed of lymphocytes, neutrophils, a few plasma cells, and rare eosinophils. Diagnostic Cytopathology, Vol. 43, No 4
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Numerous characteristic histiocytes showing anisocytosis, with vesicular, small round to oval nuclei with distinct contours were observed. Emperipolesis of numerous neutrophils, variable numbers of lymphocytes, and occasional plasma cells was noted. Ingested cells showed no signs of mitosis or necrosis. Familiarity with the cytomorphologic features of RDD is important as prognosis and treatment are quite different from other benign or malignant diseases for which it may clinically masquerade [21]. Misdiagnosis of RDD can be rendered in both FNA and surgical biopsy specimens. When compared to surgical core or excisional biopsy, FNA can at times be misinterpreted due to limited or non-representative sampling and, as FNA does not permit examination of the tissue architecture, diagnosis can be further confounded. Despite these potential limitations, FNA is still a very useful tool for the diagnosis of RDD. In fact, emperipolesis, the hallmark for RDD, tends to be more prominent in FNA material than on tissue sections. This is believed to be due, in part, to the fact that in FNA smears, an entire cell may be observed by focusing through the different planes of the slide, whereas in surgical pathology sections, generally a single plane of tissue is available for review. Furthermore, the physical action of spreading the sample into a smear of single cells renders the cellular borders of histiocytes more clearly defined and, thereby, emperipolesis may be more readily and definitively identified [21]. It is important to note, however, that the occurrence of emperipolesis per se should not be considered diagnostic of RDD. Instead, diagnosis requires correlation of the appropriate clinical presentation with an adequately preserved and properly prepared FNA sample of consistent cytomorphologic features [21]. Thus, the final diagnosis of RDD based on correlation of clinical findings and cytologic analysis of the smears obtained from FNAC of the swelling was made. When extranodal sites are involved, similar morphologic features to the nodal counterpart are seen although with more fibrosis, fewer typical RDD histiocytes, and less prominent emperipolesis.26 Immunohistochemical stains are useful when diagnosing RDD as the RDD cells have been found to express pan-macrophage antigens (CD68, HAM56, CD14, etc.), antigens associated with phagocytosis (CD64, Fc receptor for immunoglobulin G), lysosomal activity (lysozyme alpha 1-antitrypsin, alpha1-antichymotrypsin), and immune activation and adhesion molecules (transferring receptor, interleukin 2 receptor) [21]. The most consistent and reliable phenotypes for RDD are S100(1), CD68(1), and CD1a(2). Ultrastructurally, histiocytes lack Birbeck granules and viral particles.27 Because of the rarity of the lesion, no consensus has been reached regarding the definitive treatment of RDD; although nearly 50% of the patients may not require any treatment.28 Various treatment modalities have been dis318
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cussed in literature ranging from antibiotics or chemotherapeutic agents to radiation therapy or even surgical debulking of the lesions in case of compression symptoms to vital organs. For patients with vital organ compression, surgery and high-dose corticosteroids should be tried first, but radiotherapy may be needed in resistant cases or whenever surgery is not feasible [28]. Considering the young age of patient and small size of swelling in this case, no active treatment was rendered and the patient was kept on regular follow-up every 3 months. Medical or surgical interventions were kept as reserve treatment modalities in case the swelling would have increased in size or if it would have shown any sign of worsening. The clinical course of RDD may be characterized by spontaneous resolution of swelling in most of the cases to varied and unpredictable periods of exacerbation and regression in some cases. However, the prognosis of the disease is generally good. There was complete regression of the swelling at 18 months follow-up with no sign of recurrence at 24-month follow-up in this case.
Conclusion SHML is a rare benign self-limiting disorder primarily affecting children with unknown etiology. It is important for clinicians managing head and neck problem to be aware of this entity and its variable presentation. Its diagnosis is imperative to differentiate it from other conditions which may present with similar features. Diagnosis of SHML can be made from fine needle aspiration cytology and other clinical clues that help to avoid unnecessary investigative procedures and surgical intervention. A long-term follow-up in these cases is important to assess for extrinsic compression and extranodal manifestations that may require surgical or medical treatment.
Acknowledgments The authors are thankful to the Department of Histopathology, PGIMER, Chandigarh (India) for providing the necessary facilities in diagnosis of this case and Dr. Kanu Jain, Senior Lecturer, Department of Oral Pathology, SRDC, Faridabad (India) for helping with this work.
References 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathological entity. Arch Pathol 1969;87:63–70. 2. Kismet E, Koseoglu V, Atay AA, Deveci S, Demirkaya E, Tuncer K. Sinus histiocytosis with massive lymphadenopathy in three brothers. Paediatr Int 2005;47:473–476. 3. Gupta L, Batra K, Motwani G. A rare case of Rosai Dorfman disease of the paranasal sinuses. Indian J Otolaryngol Head Neck Surg 2005;57:352–354. 4. Pentinatto G, Manivel JC, d’Amore ES, Petrella G. Fine needle aspiration cytology and immunocytochemical characterization of the histiocytes in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Syndrome). Acta Cytol 1990;34:771–777.
Diagnostic Cytopathology DOI 10.1002/dc
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY 5. Layfield LJ. Fine needle aspiration cytologic findings in a case of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Syndrome). Acta Cytol 1990;34:767–770.
lings with retropharyngeal involvement in both. Ann Otol Rhinol Laryngol 1978;87:327–331.
7. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 1972;30:1174–1188. 8. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive. Arch Otolaryngol 1978;104:687–693.
18. Lauwers GY, Perez-Atayde A, Dorfman RF, Rosai J. The digestive system manifestations of Rosai-Dorfman disease (Sinus histiocytosis with massive lymphadenopathy): Review of 11 cases. Hum Pathol 2000;31:380–385. 19. Baden E, Caverivie`re P, Carbonnel S. Sinus histiocytosis with massive lymphadenopathy (Destombes-Rosai-Dorfman syndrome) occurring as a single enlarged submandibular lymph node: A light and immunohistochemical study with review of the literature. Oral Surg Oral Med Oral Pathol 1987;64:320–326.
9. Foucar E, Rosai J, Dorfman RF, Eyman JM. Immunological abnormalities and their significance in sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol 1984;82:515–525.
20. Huang Q, Chang KL, Weiss LM. Extranodal Rosai-Dorfman disease involving the bone marrow: A case report. Am J Surg Pathol 2006;30:1189–1192.
10. Thomson ER, Newman P, Dunstan S et al. The Rosai Dorfman syndrome in a 50-year old male. Br J Oral Maxillofac Surg 1989; 27:39–45.
21. Shi Y, Griffin AC, Zhang PJ, Palmer JN, Gupta P. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease): A case report and review of 49 cases with fine needle aspiration cytology. Cytojournal 2011;8:3.
6. Trautman BC, Stanley MW, Goding GS, Rosai J. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Diagnosis by fine-needle aspiration. Diagn Cytopathol 1991;7:513–516.
11. Lampert F, Lennert K. Sinus histiocytosis with massive lymphadenopathy: Fifteen new cases. Cancer 1976;37:783–789. 12. Nawroz IM, Wilson-Storey D. Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman disease). Histopathology 1989; 14:91–99. 13. Maia DM, Dorfman RF. Focal changes of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) associated with nodular lymphocyte predominant Hodgkin’s disease. Hum Pathol 1995;26:1378–1382. 14. Lu D, Estalilla OC, Manning JT, Jr, Medeiros LJ. Sinus histiocytosis with massive lymphadenopathy and malignant lymphoma involving the same lymph node: A report of four cases and review of the literature. Mod Pathol 2000;13:414–419. 15. Garel L, Lucaya J, Piqueras J. Clinical quiz. Large anaplastic lymphoma coexisting with Rosai-Dorfman disease. Pediatr Radiol 2004;34:509–510. 16. Buchanan GR, Weinberg AG, Sawyer MK. Autoimmune pancytopenia in identical twins with sinus histiocytosis. Pediatr Res 1978; 12:461. 17. Bankaci M, Morris RF, Stool SE, Paradise JL. Sinus histiocytosis with massive lymphadenopathy. Report of its occurrence in two sib-
22. Deshpande V, Verma K. Fine needle aspiration (FNA) cytology of Rosai Dorfman disease. Cytopathol 1998;9:329–335. 23. Kumar B, Karki S, Paudyal P. Diagnosis of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Diseases) by fine needle aspiration cytology. Diag Cytopathol 2008;36:691–695. 24. Foucar E, Rosai J, Dorfman RE. Sinus Histiocytosis with massive lymphadenopathy. An analysis of 14 deaths occurring in a patient registry. Cancer 1984;54:1834–1840. 25. Humble JG, Jayne WH, Pulvertaft RJ. Biological interaction between lymphocytes and other cells. Br J Haematol 1956;2: 283–294. 26. Gaitonade S. Multifocal, extranodal sinus histiocytosis with massive lymphadenopathy. Arch Pathol Lab Med 2007;131:1117–1121. 27. Jani PA, Banjan D. A case of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Syndrome) from Western India. Mcgill J Med 2008;11:156–159. 28. Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Report of a case and literature review. Am J Hematol 2002;69: 67–71.
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Sinus Histiocytosis With Massive Lymphadenopathy: A “Massive” Misnomer Divesh Sardana, M.D.S.,* Ashima Goyal, M.D.S., and Krishan Gauba, M.D.S.
Sinus histiocytosis with massive lymphadenopathy also known as Rosai–Dorfman disease is a rare, benign, histiocytic disorder of unknown origin characterized by lymphadenopathy. Since its original description by Rosai and Dorfman in 1969, small number of cases has been reported; hence no specific diagnostic criteria and treatment guidelines have been suggested. The purpose of this article is to present and discuss a case of Rosai Dorfman Syndrome in 4-year-old child diagnosed with the help of Fine Needle Aspiration Cytology. The swelling resolved over a period of 18 months without any recurrence in 2-year followup period. This case report highlights the role of Fine Needle Aspiration Cytology in the diagnosis of Rosai–Dorfman disease and the importance of regular follow ups using a careful wait and watch approach in its management. The report also briefly discusses the various dilemmas associated with its diagnosis and treatment. Diagn. Cytopathol. 2015;43:315–319. VC 2014 Wiley Periodicals, Inc.
accompanied by fever, leukocytosis, elevated erythrocytes sedimentation rate (ESR), and hyperglobulinemia.2 Lymph nodes other than cervical may be involved and the involvement of extra nodal sites is not uncommon.3 Since its original description, RDD has become a rare but distinct clinic-pathological entity with Fine Needle Aspiration Cytologic (FNAC) findings of presence of large histiocytes that tend to be isolated and characteristically contain mature lymphocytes in their cytoplasm (a process termed emperipolesis).4–6 These specific and unique histiocytes are sometimes called as “Rosai–Dorfman cells.” The aim of this article is to report a case of RDD diagnosed with the help of FNAC in a 4-year-old child, which resolved over a period of 18 months without any surgical or therapeutic intervention.
Key Words: sinus histiocytosis; massive; Rosai–Dorfman disease; lymphadenopathy
Case Report
Rosai–Dorfman disease (RDD), also known as Sinus Histiocytosis with Massive Lymphadenopathy (SHML), is a rare, benign histiocytic disorder that was first described by Rosai and Dorfman in 1969.1 It consists of chronic massive enlargement of cervical lymph nodes, frequently
Unit of Pedodontics and Preventive Dentistry, Oral Health Sciences Center, Post-Graduate Institute of Medical Education and Research, Chandigarh, India *Correspondence to: Divesh Sardana, M.D.S., Unit of Pedodontics and Preventive Dentistry, Oral Health Sciences Center, Post-graduate Institute of Medical Education and Research, Chandigarh, India. E-mail: [email protected] Received 11 December 2013; Revised 7 June 2014; Accepted 17 July 2014 DOI: 10.1002/dc.23198 Published online 4 August 2014 in Wiley Online Library (wileyonlinelibrary.com). C 2014 WILEY PERIODICALS, INC. V
A 4-year-old male child reported to the Department of Pedodontics, PGIMER, Chandigarh with a chief complaint of swelling in the sub-mental region since 4 months (Fig. 1a). The swelling was insidious in onset and had remained constant in size over the period of time with no other local signs and symptoms. On examination, the swelling measured 2.5 cm 3 3.0 cm approximately and; was non-tender, non-fluctuant, and soft in consistency. On general physical examination, child was found to be of normal height and weight for his age with no swelling seen elsewhere in the body; and no signs of any systemic infection, splenomegaly, or hepatomegaly. On extra-oral examination, no lymph nodes were palpable in the neck region and other areas of the body. Intra-orally the patient was in deciduous dentition stage with dental caries in relation to few teeth which were indicated for restorations. Besides dental caries, there was no tooth mobility, pus discharge, intra-oral swelling, or any other abnormality. Intra-oral periapical radiographs of carious teeth and orthopantomogram were taken. Diagnostic Cytopathology, Vol. 43, No 4
315
Diagnostic Cytopathology DOI 10.1002/dc
SARDANA ET AL.
Fig. 1. Photograph of the child patient showing (a) swelling in the sub-mental region, (b) complete resolution of swelling at 18-month follow-up visit. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
However, radiographs did not reveal any abnormality relevant to the swelling. Complete blood analysis of the child was performed which showed a normal blood picture of a healthy child. FNAC of the swelling was performed under local anesthesia using 24 gauge needle which is suitable for children. Skin over swelling was cleansed and immobilized with fingers while the needle was inserted into it. Single puncture multi-directional technique was used for aspiration. Aspirated material was recovered and expressed onto slide. Few smears were wet fixed with ethyl alcohol and few were air dried and heat fixed to perform acid-fast staining. FNAC findings of Giemsa stained cytosmears showed presence of extensive emperipolesis in the background of mixed inflammatory cells (Figs. 2a and b). Detailed examination of Giemsa and Hematoxylin and Eosin stained cytosmears revealed numerous histiocytes showing anisocytosis, with vesicular, small round to oval nuclei with distinct contours (Figs. 2c and d). Emperipolesis of variable numbers of lymphocytes and occasional plasma cells was also noted (Figs. 2c and d). Ingested cells showed no signs of mitosis. The background cells were composed of lymphocytes which included larger and immature forms along with plasma cells, few neutrophils, and rare eosinophils (Figs. 2c and d). Acid fast staining of air dried and heat fixed smears was found to be negative for Acid Fast Bacilli. With the classical features of lymphadenopathy and histiocytosis with emperipolesis on cytopathology, a diagnosis of SHML or RDD was made. Considering the age of the patient and small size of swelling, the patient was kept on regular follow up of every 3 months without any active treatment. Parents of the child were counseled and reassured and medical or surgical interventions were kept as next line of treatment if the size of the swelling had increased. At each follow up, the 316
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patient was checked thoroughly for any changes in swelling. However, no change in the size of swelling was observed over a period of 15 months and hence no treatment was rendered except for restoration of carious teeth. At 18-month follow-up visit, the swelling had disappeared completely (Fig. 1b); the reason for which could not be identified. There was no recurrence of the swelling at 24 months of follow-up visit. Currently, the patient is still under regular follow up every 6 months.
Discussion In 1969, Rosai and Dorfman described four cases of a disease which they called SHML. Later in 1972, they analyzed 30 additional cases, establishing SHML as a clinic-pathologic entity.7 Although the definite etiology of RDD is unknown, various factors have been postulated to cause RDD like immunodeficiency,8 defect in immune mechanisms,9 infectious agents (like Herpes virus, Varicella zoster virus, Epstein–Barr Virus, Cytomegalovirus, Brucella, or Klebsiella),10–12 hematopoetic malignancies,13–15 and even genetic predisposition due to its reported occurrence in pairs of siblings.16,17 The disease most commonly affects younger age group; children being most commonly affected. Males are more commonly affected and there is reported higher predilection for occurrence in individuals of African descent.18 The disease clinically present as painless, bilateral massive cervical lymphadenopathy frequently accompanied by plethora of symptoms ranging from fever, malaise, weight loss, night sweats, tonsillitis, rhinorrhea, and so forth to hepatosplenomegaly1,7,10,11,19 which may add to the confusion regarding diagnosis and treatment. This case is also observed in a 4-year-old child with small swelling in submental region without any other clinical
Diagnostic Cytopathology DOI 10.1002/dc
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
Fig. 2. Photomicrograph of FNAC smear showed presence of extensive emperipolesis in the background of mixed inflammatory cells (a) (Giemsa, 310), (b) (Giemsa, 320); and presence of lymphocytes, plasma cells and histiocytes showing emperipolesis (c) (Giemsa, 340), (d) (Hematoxylin and Eosin, 340). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
features. Documented sites of extranodal involvement include skin, respiratory tract, bone, genitourinary system, oral cavity, central nervous system, eyes/orbit/ocular adnexa, salivary gland, tonsil, breast, soft tissue, and heart. The bone marrow is rarely involved.20 In this case, no extranodal involvement of disease is seen. Laboratory investigations may reveal anemia, leukocytosis with neutrophilia, and raised ESR with hypergammaglobulinemia [7]. Complete blood analysis of child in this case did not reveal any above mentioned laboratory findings. As the lymphadenopathy was not massive and no association with any of the systemic manifestations was seen with a normal blood picture, it was difficult to establish diagnosis based solely on these findings. FNAC is a simple, accurate, and economic tool, which has been widely used for the diagnosis of superficial and deep-seated lesions. Also, biopsy being an invasive procedure requires patient’s cooperation and probable administration of general anesthesia with subsequent hospital stay; thereby increasing the treatment cost and inconvenience to the patient. Review of the literature has revealed 49 reported cases of RDD diagnosed by FNAC.21 FNAC was used in this case considering the young age of the patient and because of its usefulness and reliability in diagnosis of RDD. Typically, FNA specimens show non-cohesive, diffusely distributed, enlarged histiocytes. These cells have
variable nuclei, abundant cyanophilic cytoplasm, and demonstrate emperipolesis of lymphocytes, plasma cells, and occasionally erythrocytes.22,23 Emperipolesis (also known as or lymphophagocytosis) is the engulfment of different cells (viz. intact lymphocytes, plasma cells, other leukocytes, or red blood cells) by cytoplasm of histiocytes; this is of great diagnostic significance. The internalized lymphocytes are usually located within cytoplasmic vacuoles.24 This process whereby cells enter and transit through a cell evading cellular degradation, known as emperipolesis was first described by Humble et al.25 Although the definitive cause of this phenomenon is not known, it may be due to unusual response of sinus histiocytes to local inflammatory factors. Although the nuclear shapes of histiocytes vary from round to extremely bizarre configurations, the chromatin is fine and evenly distributed and the nucleoli are usually not prominent. Occasionally, atypical morphology may be seen and, when present, it can lead to a misdiagnosis of malignancy [22]. Lymphocytes, plasma cells, neutrophils, and follicular center cells are often found in the background of the smear [23, 26]. FNAC findings in this case also showed presence of numerous multinucleated giant cells with extensive emperipolesis in the background of mixed inflammatory cells composed of lymphocytes, neutrophils, a few plasma cells, and rare eosinophils. Diagnostic Cytopathology, Vol. 43, No 4
317
Diagnostic Cytopathology DOI 10.1002/dc
SARDANA ET AL.
Numerous characteristic histiocytes showing anisocytosis, with vesicular, small round to oval nuclei with distinct contours were observed. Emperipolesis of numerous neutrophils, variable numbers of lymphocytes, and occasional plasma cells was noted. Ingested cells showed no signs of mitosis or necrosis. Familiarity with the cytomorphologic features of RDD is important as prognosis and treatment are quite different from other benign or malignant diseases for which it may clinically masquerade [21]. Misdiagnosis of RDD can be rendered in both FNA and surgical biopsy specimens. When compared to surgical core or excisional biopsy, FNA can at times be misinterpreted due to limited or non-representative sampling and, as FNA does not permit examination of the tissue architecture, diagnosis can be further confounded. Despite these potential limitations, FNA is still a very useful tool for the diagnosis of RDD. In fact, emperipolesis, the hallmark for RDD, tends to be more prominent in FNA material than on tissue sections. This is believed to be due, in part, to the fact that in FNA smears, an entire cell may be observed by focusing through the different planes of the slide, whereas in surgical pathology sections, generally a single plane of tissue is available for review. Furthermore, the physical action of spreading the sample into a smear of single cells renders the cellular borders of histiocytes more clearly defined and, thereby, emperipolesis may be more readily and definitively identified [21]. It is important to note, however, that the occurrence of emperipolesis per se should not be considered diagnostic of RDD. Instead, diagnosis requires correlation of the appropriate clinical presentation with an adequately preserved and properly prepared FNA sample of consistent cytomorphologic features [21]. Thus, the final diagnosis of RDD based on correlation of clinical findings and cytologic analysis of the smears obtained from FNAC of the swelling was made. When extranodal sites are involved, similar morphologic features to the nodal counterpart are seen although with more fibrosis, fewer typical RDD histiocytes, and less prominent emperipolesis.26 Immunohistochemical stains are useful when diagnosing RDD as the RDD cells have been found to express pan-macrophage antigens (CD68, HAM56, CD14, etc.), antigens associated with phagocytosis (CD64, Fc receptor for immunoglobulin G), lysosomal activity (lysozyme alpha 1-antitrypsin, alpha1-antichymotrypsin), and immune activation and adhesion molecules (transferring receptor, interleukin 2 receptor) [21]. The most consistent and reliable phenotypes for RDD are S100(1), CD68(1), and CD1a(2). Ultrastructurally, histiocytes lack Birbeck granules and viral particles.27 Because of the rarity of the lesion, no consensus has been reached regarding the definitive treatment of RDD; although nearly 50% of the patients may not require any treatment.28 Various treatment modalities have been dis318
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cussed in literature ranging from antibiotics or chemotherapeutic agents to radiation therapy or even surgical debulking of the lesions in case of compression symptoms to vital organs. For patients with vital organ compression, surgery and high-dose corticosteroids should be tried first, but radiotherapy may be needed in resistant cases or whenever surgery is not feasible [28]. Considering the young age of patient and small size of swelling in this case, no active treatment was rendered and the patient was kept on regular follow-up every 3 months. Medical or surgical interventions were kept as reserve treatment modalities in case the swelling would have increased in size or if it would have shown any sign of worsening. The clinical course of RDD may be characterized by spontaneous resolution of swelling in most of the cases to varied and unpredictable periods of exacerbation and regression in some cases. However, the prognosis of the disease is generally good. There was complete regression of the swelling at 18 months follow-up with no sign of recurrence at 24-month follow-up in this case.
Conclusion SHML is a rare benign self-limiting disorder primarily affecting children with unknown etiology. It is important for clinicians managing head and neck problem to be aware of this entity and its variable presentation. Its diagnosis is imperative to differentiate it from other conditions which may present with similar features. Diagnosis of SHML can be made from fine needle aspiration cytology and other clinical clues that help to avoid unnecessary investigative procedures and surgical intervention. A long-term follow-up in these cases is important to assess for extrinsic compression and extranodal manifestations that may require surgical or medical treatment.
Acknowledgments The authors are thankful to the Department of Histopathology, PGIMER, Chandigarh (India) for providing the necessary facilities in diagnosis of this case and Dr. Kanu Jain, Senior Lecturer, Department of Oral Pathology, SRDC, Faridabad (India) for helping with this work.
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