J Cutan Pathol 2015: 42: 465–470 doi: 10.1111/cup.12484 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy Perineural granulomas in cutaneous sarcoidosis have been rarely reported and their clinical significance has yet to be evaluated. Recently, a 27-year-old male presented with multiple pink papules on the flank and lower back, accompanied by a painful, burning sensation. Biopsies revealed well-defined granulomas, consistent with sarcoidosis, in the dermis and involving small cutaneous nerves. We hypothesized that perineural granulomas may be an under-recognized feature of cutaneous sarcoidosis and may be responsible for sensory disturbances. We reviewed cases from 29 consecutive patients with cutaneous sarcoidosis. Perineural granulomas were identified in 18/29 (62%) patients and in 22/40 (55%) biopsies. Perineural granulomas were identified in 7/9 biopsies from the proximal upper extremity, 1/3 from the distal upper extremity, 7/12 from the head and the neck, including 4/4 from the nose, 5/9 from the back, 1/2 from the flank and 1/1 from the proximal lower extremity and 0/4 from the distal lower extremity. The anatomical distribution is similar to sarcoidosis small-fiber neuropathy (SSFN), in which sarcoidosis patients without evident skin lesions experience sensory disturbances of unknown etiology involving the face, the proximal extremities and the trunk. Our results indicate perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated, primarily involve the head, the proximal upper extremities and the back, and may be responsible for neurological manifestations. Keywords: granuloma, perineural, sarcoid, sarcoidosis Munday WR, McNiff J, Watsky K, DiCapua D, Galan A. Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy. J Cutan Pathol 2015; 42: 465–470. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Sarcoidosis is a granulomatous disorder of unknown etiology that affects multiple organ systems. It may be present with a wide range of clinical manifestations most frequently involving the lungs, the lymph nodes and the skin. The prevalence ranges from 10–40 per 100,000 population and affects young adult males and
William R. Munday1 , Jennifer McNiff1,2 , Kalman Watsky2 , Daniel DiCapua3 and Anjela Galan1,2 1
Department of Pathology, Yale School of Medicine, New Haven, CT, USA, 2 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA, and 3 Department of Neurology, Yale School of Medicine, New Haven, CT, USA
William Robert Munday, MD Department of Pathology, Yale University School of Medicine, 310 Cedar Street LH 108, PO Box 208023, New Haven, CT 06520, USA Tel: 619961–3083 Fax: 1 203 785 7303 e-mail: [email protected] Accepted for publication March 4, 2015
females, equally.1 Although sarcoidosis most commonly affects the lungs, the frequency of cutaneous involvement has been reported to be approximately 25% in several studies.1 – 3 Furthermore, cutaneous sarcoidosis most often occurs at disease onset.4
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Munday et al. A
B
Fig. 1. Right flank pink ovoid papules (A and B). The lesions were accompanied by a painful, burning sensation. Similar lesions were also located on the back in this patient. Both initial and repeat biopsies showed granulomatous dermatitis with perineural involvement.
Skin lesions can be classified as being specific, when histopathologic examination shows classic sarcoidal granulomas or as being non-specific. Common specific lesions include lupus pernio, infiltrative plaques, subcutaneous nodules, scars and a maculopapular eruption.5 The most common non-specific lesion is erythema nodosum of the lower extremities, which is typically acute in presentation and is referred to as Lofgren syndrome when associated with hilar lymphadenopathy.6 Rare presentations include alopecia, ulcers, hypopigmented patches and ichthyosis. In general, skin lesions of sarcoidosis are not associated with neurological symptoms. We recently encountered a patient with multiple painful, burning, pink papules on the flank and lower back. Biopsies showed granulomas with perineural involvement, primarily involving small cutaneous nerves. These findings prompted further investigation of perineural involvement in cutaneous sarcoidosis. We hypothesized that perineural granulomas in cutaneous sarcoidosis may be more common than previously appreciated and may be responsible for sensory disturbances. Index patient A 27-year-old previously healthy male presented with right flank and lower back pink, ovoid firm papules, which were accompanied by a burning sensation (Fig. 1). Biopsy showed granulomatous dermatitis with perineural involvement, consistent with sarcoidosis (Fig. 2). A repeat biopsy 1 week later showed similar histopathology. In both biopsies, Periodic acid-Schiff (PAS) and acid-fast bacilli (AFB) stains were negative for fungal and mycobacterial organisms,
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respectively. Skin cultures failed to grow bacterial, fungal or mycobacterial organisms. Polymerase chain reaction (PCR) studies for mycobacteria were negative. The patient did not have a history of foreign travel. Imaging studies did not detect lung involvement. Laboratory investigation of angiotensin-converting enzyme (ACE) was within normal limits (37 U/l; reference range, 9–67 U/l). Methods Twenty nine consecutive cases (13 males and 16 females) of cutaneous sarcoidosis were selected and reviewed from our institutional database between 2011 and 2014. Cases were defined by biopsies diagnosed as cutaneous sarcoidosis based on routine evaluation of hematoxylin and eosin (H&E), AFB and PAS stains. A total of 40 biopsies were evaluated. In each case, H&E stains were reviewed by two pathologists for the presence or the absence of cutaneous sarcoid perineural granulomas. Perineural granulomas were defined as non-caseating epithelioid perineural granulomas involving small cutaneous nerve fibers. Results Perineural granulomas were identified in 18/29 (62%) of cases and in 22/40 (55%) biopsies. Males and females were affected equally. By site, perineural granulomas were identified in 7/9 (78%) biopsies from the proximal upper extremity, 1/3 (33%) from the distal upper extremity, 7/12 (58%) from the head and the neck, including 4/4 (100%) from the nose, 5/9 (56%) from the back, 1/2 (50%) from the
Perineural granulomas in cutaneous sarcoidosis A
B
C
D
Fig. 2. Skin biopsies from two different sarcoid patients show large epithelioid granulomas involving small cutaneous nerves. (A) Biopsy of painful flank papule (index case) showing a deep cutaneous nerve (arrow) involved by a perineural granuloma. (B) Higher power view of small cutaneous nerve flanked by large granulomas seen in (A). (C) Biopsy showing sarcoid perineural granuloma in mid portion of dermis (arrow). (D) The cutaneous nerve appears distorted by granulomatous inflammation.
flank and 1/1 (100%) from the proximal lower extremity(thigh) and 0/4 (0%) from the distal lower extremity (Table 1). PAS and AFB stains were negative in each case. In three cases, a clinical correlate of cutaneous pain was identified. Two cases presented with painful lesions and one with pain in the vicinity of cutaneous lesions. In the remaining cases, information regarding the presence or the absence of associated pain was not available. Multiple organ system involvement or multiple cutaneous site involvement was present in 15/29 cases. One patient presented with erythema nodosum. In 6/29 cases, sarcoidosis was limited to the skin. In 7/29 cases, charts were not available for review. Discussion Cutaneous sarcoidosis is considered a diagnosis of exclusion and therefore needs to be distinguished from other disorders, such as infections, foreign body reactions and neoplastic diseases.7
Histopathologically, sarcoidal granulomas are typically composed of epithelioid histiocytes surrounded by a thin peripheral rim of lymphocytes and plasma cells; hence, the canonical term naked granuloma.8 Tuberculoid granulomas, on the other hand, are less well circumscribed with a more prominent rim of mononuclear cells and plasma cells and may show central caseation necrosis.9 Unfortunately, the pathologic features of tuberculoid granulomas are non-specific, and clinical correlation is often critically important.9 Occasionally, sarcoidosis may cause a perineural granulomatous response that closely resembles that associated with Mycobacterium leprae or other Mycobacterium subtypes.8 AFB staining, cultures and PCR studies are helpful in establishing the correct diagnosis. Other infectious processes, such as fungal infections, can also cause sarcoid-like lesions and should be ruled out.10 Foreign material has been postulated to serve as a nidus for sarcoidal granulomas, and its presence should not exclude a diagnosis of
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Munday et al. Table 1. Perineural sarcoid granulomas by anatomical location Perineural granulomas by site Cases total Cases involved Biopsies total Biopsies involved Location Head/Neck Nose UE (P) UE (D) Back Flank LE (P) LE (D)
29 18 (62%) 40 22 (55%) 7/12 (58%) 4/4 (100%) 7/9 (78%) 1/3 (33%) 5/9 (56%) 1/2 (50%) 1/1 (100%) 0/4 (0%)
LE(D), distal lower extremity; LE(P), proximal lower extremity; UE(D), distal upper extremity; UE(P), proximal upper extremity.
sarcoidosis.11,12 Yet, when the clinical history includes trauma and the biopsy shows abundant polarizable material, a foreign body giant cell reaction should be considered.13 Secondary syphilis, although classically considered a plasma cell predominant dermal infiltrate, can cause a sarcoid-like granulotamous reaction.14 Finally, plexiform fibrohistiocytic tumor may occasionally mimic cutaneous sarcoidosis. Close attention to the clinical history and the histopathologic pattern should be sufficient to differentiate between the two conditions. These tumors generally occur in children and young adults and are biphasic lesions, with a plexiform histiocytic component and fibroblastic cells associated with multinuclear giant cells.15 Cutanous sarcoidosis is a diagnosis of exclusion, which should be rendered only after the above-mentioned differential diagnoses have been considered. Sarcoidosis is known to commonly involve the skin, although it is not often thought to be associated with painful skin lesions. Here, we present a patient with painful pink papules, in which repeat biopsies showed numerous perineural sarcoid granulomas. Next, via investigation of 29 cases, we show that sarcoid perineural granulomas are more common than previously appreciated. Previous studies have shown between 13 and 25% of cutaneous sarcoidosis cases show perineural granulomas.8,16,17 In contrast to previous findings, our analyzes indicated that perineural granulomas were present in 62% of patients and in 55% of total biopsies. From our observations, small cutaneous nerves can be subtly identified within sarcoidal granulomas, which might be easily overlooked. This may account for the higher percentage of perineural granulomas
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found in our study. Furthermore, we identified two patients with painful skin lesions and one patient with regional pain in the vicinity of sarcoid lesions. In all three cases, perineural sarcoid granulomas were found. Unfortunately, comment on the presence or the absence of pain was not found in the remaining cases in our series. In the series of cases we investigated, the anatomical distribution of perineural involvement was most common on the nose, the proximal upper extremity and the head and neck biopsies (Fig. 3). Interestingly, the overall site distribution presented here seems to overlap with the entity known as sarcoidosis small-fiber neuropathy (SSFN). Sarcoidosis can manifest with inexplicable cutaneous sensory disturbances, referred to as SSFN. SSFN is considered a peripheral neuropathy in which injury is limited to small, thinly myelinated Adelta and unmyelinated C fibers.18 These fibers carry sensory information originating from the skin, such as thermal and nociceptive stimuli, to the spinal cord.18 Patients usually report burning pain, allodynia and hyperalgesia, in a patchy distribution that typically affects the face, the unilateral flank, the chest, the upper limbs and the thigh.19,20 Clinical signs include thermal and pinprick hypoesthesia, while others include hair loss, skin discoloration and hypohydrosis at the site of involvement.19 In one study, these signs and symptoms were present in 44% of sarcoidosis patients.21 The pain syndrome has occurred with the development of subcutaneous nodules, which on biopsy showed sarcoid granulomas, although without mention of perineural involvement.22 Routine nerve-conduction studies, which are unable to detect pathologic processes in cutaneous nerves, are invariably normal in this patient population. Newer, non-conventional tests have been developed, although each has been relatively unsuccessful, and there is currently no gold standard diagnostic test.20 Importantly, there are no studies of the skin in these patients and dermatology is not routinely consulted. Therefore, it is possible that cutaneous lesions are present in SSFN but are not detected because they are not evaluated. Indeed, the frequency of cutaneous lesion discovery in sarcoidosis is a product of how thoroughly they are sought after.23,24 Of particular note, SSFN appears to be an unusual, unconventional subtype of small-fiber neuropathy. The vast majority of patients with conventional small-fiber neuropathy are diabetic and present with lower extremity,
Perineural granulomas in cutaneous sarcoidosis
Fig. 3. Pattern of neuropathy in sarcoidosis small-fiber neuropathy (SSFN), sarcoidosis perineural granulomas and small fiber neuropathy (SFN). (A) The typical pattern of neuropathy in SFN (blue) is length dependent, in a stocking and glove distribution predominantly affecting the lower extremities. (B)The anatomical sites affected in SSFN (yellow) and (C) sarcoidosis perineural granulomas (red) have a similar pattern of distribution. Both SSFN and sarcoidosis perineural granulomas are quite distinct from the typical pattern of neuropathy in SFN (blue).
length-dependent, neuropathic symptoms.18 Nerve injury in diabetic patients is considered the result of metabolic injury of peripheral nerves. The diagnosis of small-fiber neuropathy is made when routine nerve-conduction studies fail to detect large fiber involvement in patients with length-dependent symptoms and abnormalities to small-fiber modalities. In any case, diabetic patients present with a classic stocking and glove pattern of conventional small-fiber neuropathy. In SSFN patients, however, the stocking and glove pattern of neuropathy is distinctly absent (Fig. 3).19 This is an important point because such a large majority of patients with conventional small-fiber neuropathy have length-dependent symptoms that it is considered a requirement for the diagnosis.18 Therefore, the distinctive, non length-dependent, clinical presentation of SSFN raises the possibility that it may be caused by pathology quite different than that of conventional small-fiber neuropathy. Furthermore, the pattern of skin involvement in SSFN is similar to the pattern of cutaneous sarcoid perineural granulomas identified in our study (Fig. 3). We suggest that the pathology of SSFN may be because of localized granulomas of small cutaneous nerves. Although sarcoidosis commonly affects the skin, the disease rarely affects the nervous system. Indeed, less than 5% of sarcoidosis patients have nervous system involvement, and among these rare cases, less than 20% are affected by a peripheral neuropathy.25 – 27 Thus, peripheral neuropathies in sarcoidosis are exceedingly rare. On the occasion that sarcoidosis does affect peripheral nerves, the pathologic process involves perineural granulomas, which cause destruction of peripheral
nerve axons and the myelin sheath.28,29 The clinical presentation includes distal sensory-motor polyneuropathy, acute inflammatory demyelinating polyneuropathy, mononeuritis multiplex, radiculopathy and mononeuropathy.25,26,30 In the majority of these clinical situations, the presenting complaint involves a motor component, and nerve-conduction studies are consistently abnormal.31,32 This is distinct from SSFN, in which there are no motor symptoms, and nerve-conduction studies are invariably normal. Additionally, “asymptomatic” sarcoidosis patients have been found to have abnormal
Fig. 4. Sarcoid neuropathy by nerve distribution. When sarcoid granulomas involve peripheral nerves (red), the pattern of neuropathy is both sensory and motor (SM). When granulomas are localized to small cutaneous nerve branches (green), the neuropathy is strictly sensory (S). When granulomas involve skeletal muscle nerve branches, the neuropathy is strictly motor (M).
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Munday et al. nerve-conduction studies.32 Often this is because of negative sensory deficits to which they are unaware. Therefore, when nerve-conduction studies are normal, as they are in SSFN, we can confidently assume peripheral nerves, aside from cutaneous nerves, are not involved in the pathologic process. Evidently, SSFN does not seem to have the typical pattern seen in peripheral neuropathy caused by sarcoidosis. However, the discrepancies cease to exist when we conceptualize the pathology of SSFN as localized to small, cutaneous nerves, which are simply the distal most cutaneous branches of the peripheral nerves from which they originate. If the pathology of SSFN is localized to these small cutaneous nerve branches, nerve-conduction studies would be
expected to be normal, and motor symptoms would also be absent (Fig. 4). The sensory abnormalities notable in SSFN are additionally explained by cutaneous granulomas, as in our index case. Thus, if sarcoid granulomas are located in a mixed peripheral nerve, the clinical manifestation is a sensory-motor disturbance; if the granulomas are confined to cutaneous nerves, the pathology is strictly sensory. In summary, perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated and may be responsible for sensory disturbances. Furthermore, sarcoid perineural granulomas may provide the pathologic basis for the entity known as sarcoidosis small-fiber neuropathy.
References 1. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 1224. 2. English JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol 2001; 44: 725. 3. Wilson NJ, King CM. Cutaneous sarcoidosis. Postgrad Med J 1998; 74: 649. 4. Hanno R, Needelman A, Eiferman RA, Callen JP. Cutaneous sarcoidal granulomas and the development of systemic sarcoidosis. Arch Dermatol 1981; 117: 203. 5. Mañá J, Marcoval J, Graells J, Salazar A, Peyrí J, Pujol R. Cutaneous involvement in sarcoidosis: relationship to systemic disease. Arch Dermatol 1997; 133: 882. 6. Lofgren S, Lundback H. The bilateral hilar lymphoma syndrome; a study of the relation to age and sex in 212 cases. Acta Med Scand 1952; 142: 259. 7. Hirsh BC, Johnson WC. Pathology of granulomatous diseases. Foreign body granulomas. Int J Dermatol 1984; 23: 531. 8. Ball NJ, Kho GT, Martinka M. The histologic spectrum of cutaneous sarcoidosis: a study of twenty-eight cases. J Cutan Pathol 2004; 31: 160. 9. Santa Cruz DJ, Strayer DS. The histologic spectrumof the cutaneous mycobacterioses. Hum Pathol 1982; 13: 485. 10. Tchernev G, Cardoso JC, Chokoeva AA, et al. The “mystery” of cutaneous sarcoidosis: facts and controversies. Int J Immunopathol Pharmacol 2013; 27: 321. 11. Marcoval J, Mañá J, Moreno A, Gallego I, Fortuño Y, Peyrí J. Foreign bodies in granulomatous cutaneous lesions of patients with systemic sarcoidosis. Arch Dermatol 2001; 137: 427. 12. Walsh NM, Hanly JG, Tremaine R, Murray S. Cutaneous sarcoidosis and foreign bodies. Am J Dermatopathol 1993 Jun; 15: 203.
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13. Coleman DL, King RN, Andrade JD. The foreign body reaction: A chronic inflammatory response. J Biomed Mater Res 1974; 8: 199. 14. Kahn LB, Gordon W. Sarcoid-like granulomas in secondary syphilis. A clinical and histopathologic study of five cases. Arch Pathol 1971; 92: 334. 15. Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol 1988; 12: 818. 16. Ishak R, Kurban M, Kibbi A-G, Abbas O. Cutaneous sarcoidosis: clinicopathologic study of 76 patients from Lebanon. Int J Dermatol 2015; 54: 33. 17. Cardoso J, Cravo M, Reis J, Tellechea O. Cutaneous sarcoidosis: a histopathological study. J Eur Acad Dermatol Venereol 2009; 23: 678. 18. Lauria G, Merkies ISJ, Waxman SG, Faber CG. Approach to small fiber neuropathy. In Katirji B, Kaminski HJ, Ruff RL, eds. Neuromuscular disorders in clinical practice. New York: Springer, 2014; 507. 19. Tavee J, Culver D. Sarcoidosis and small-fiber neuropathy. Curr Pain Headache Rep 2011; 15: 201. 20. Heij L, Dahan A, Hoitsma E. Sarcoidosis and pain caused by small-fiber neuropathy. Pain Res Treat 2012; 2012: 256024. 21. Hoitsma E, Marziniak M, Faber C, et al. Small fibre neuropathy in sarcoidosis. Lancet 2002; 359: 2085. 22. Hoitsma E, Faber CG, van Santen-Hoeufft M, De Vries J, Reulen JPH, Drent M. Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab. Sarcoidosis Vasc Diffuse Lung Dis 2006; 23: 73.
23. Rizzato G, Palmieri G, Agrati AM, Zanussi C. The organ-specific extrapulmonary presentation of sarcoidosis: a frequent occurrence but a challenge to an early diagnosis. A 3-year-long prospective observational study. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 119. 24. Yanarda˘g H, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients. Respir Med 2003; 97: 978. 25. Hobson-Webb LD, Donofrio PD. Inflammatory neuropathies: an update on evaluation and treatment. Curr Rheumatol Rep 2005; 7: 348. 26. Gullapalli D, Phillips LH. Neurologic manifestations of sarcoidosis. Neurol Clin 2002; 20: 59. 27. Garg S, Wright A, Reichwein R, Boyer P, Towfighi J, Kothari MJ. Mononeuritis multiplex secondary to sarcoidosis. Clin Neurol Neurosurg 2005; 107: 140. 28. Said G, Lacroix C, Planté-Bordeneuve V, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11 patients. Brain J Neurol 2002; 125(Pt 2): 264. 29. Said G, Hontebeyrie-Joskowicz M. Nerve lesions induced by macrophage activation. Res Immunol 1992; 143: 589. 30. Delaney P. Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases. Ann Intern Med 1977; 87: 336. 31. Zivkovi´c SA, Lacomis D. Sarcoid Neuropathy: Case Report and Review of the Literature. J Clin Neuromuscul Dis 2004 Jun; 5: 184. 32. Challenor YB, Felton CP, Brust JC. Peripheral nerve involvement in sarcoidosis: an electrodiagnostic study. J Neurol Neurosurg Psychiatry 1984; 47: 1219.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy Perineural granulomas in cutaneous sarcoidosis have been rarely reported and their clinical significance has yet to be evaluated. Recently, a 27-year-old male presented with multiple pink papules on the flank and lower back, accompanied by a painful, burning sensation. Biopsies revealed well-defined granulomas, consistent with sarcoidosis, in the dermis and involving small cutaneous nerves. We hypothesized that perineural granulomas may be an under-recognized feature of cutaneous sarcoidosis and may be responsible for sensory disturbances. We reviewed cases from 29 consecutive patients with cutaneous sarcoidosis. Perineural granulomas were identified in 18/29 (62%) patients and in 22/40 (55%) biopsies. Perineural granulomas were identified in 7/9 biopsies from the proximal upper extremity, 1/3 from the distal upper extremity, 7/12 from the head and the neck, including 4/4 from the nose, 5/9 from the back, 1/2 from the flank and 1/1 from the proximal lower extremity and 0/4 from the distal lower extremity. The anatomical distribution is similar to sarcoidosis small-fiber neuropathy (SSFN), in which sarcoidosis patients without evident skin lesions experience sensory disturbances of unknown etiology involving the face, the proximal extremities and the trunk. Our results indicate perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated, primarily involve the head, the proximal upper extremities and the back, and may be responsible for neurological manifestations. Keywords: granuloma, perineural, sarcoid, sarcoidosis Munday WR, McNiff J, Watsky K, DiCapua D, Galan A. Perineural granulomas in cutaneous sarcoidosis may be associated with sarcoidosis small-fiber neuropathy. J Cutan Pathol 2015; 42: 465–470. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Sarcoidosis is a granulomatous disorder of unknown etiology that affects multiple organ systems. It may be present with a wide range of clinical manifestations most frequently involving the lungs, the lymph nodes and the skin. The prevalence ranges from 10–40 per 100,000 population and affects young adult males and
William R. Munday1 , Jennifer McNiff1,2 , Kalman Watsky2 , Daniel DiCapua3 and Anjela Galan1,2 1
Department of Pathology, Yale School of Medicine, New Haven, CT, USA, 2 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA, and 3 Department of Neurology, Yale School of Medicine, New Haven, CT, USA
William Robert Munday, MD Department of Pathology, Yale University School of Medicine, 310 Cedar Street LH 108, PO Box 208023, New Haven, CT 06520, USA Tel: 619961–3083 Fax: 1 203 785 7303 e-mail: [email protected] Accepted for publication March 4, 2015
females, equally.1 Although sarcoidosis most commonly affects the lungs, the frequency of cutaneous involvement has been reported to be approximately 25% in several studies.1 – 3 Furthermore, cutaneous sarcoidosis most often occurs at disease onset.4
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Munday et al. A
B
Fig. 1. Right flank pink ovoid papules (A and B). The lesions were accompanied by a painful, burning sensation. Similar lesions were also located on the back in this patient. Both initial and repeat biopsies showed granulomatous dermatitis with perineural involvement.
Skin lesions can be classified as being specific, when histopathologic examination shows classic sarcoidal granulomas or as being non-specific. Common specific lesions include lupus pernio, infiltrative plaques, subcutaneous nodules, scars and a maculopapular eruption.5 The most common non-specific lesion is erythema nodosum of the lower extremities, which is typically acute in presentation and is referred to as Lofgren syndrome when associated with hilar lymphadenopathy.6 Rare presentations include alopecia, ulcers, hypopigmented patches and ichthyosis. In general, skin lesions of sarcoidosis are not associated with neurological symptoms. We recently encountered a patient with multiple painful, burning, pink papules on the flank and lower back. Biopsies showed granulomas with perineural involvement, primarily involving small cutaneous nerves. These findings prompted further investigation of perineural involvement in cutaneous sarcoidosis. We hypothesized that perineural granulomas in cutaneous sarcoidosis may be more common than previously appreciated and may be responsible for sensory disturbances. Index patient A 27-year-old previously healthy male presented with right flank and lower back pink, ovoid firm papules, which were accompanied by a burning sensation (Fig. 1). Biopsy showed granulomatous dermatitis with perineural involvement, consistent with sarcoidosis (Fig. 2). A repeat biopsy 1 week later showed similar histopathology. In both biopsies, Periodic acid-Schiff (PAS) and acid-fast bacilli (AFB) stains were negative for fungal and mycobacterial organisms,
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respectively. Skin cultures failed to grow bacterial, fungal or mycobacterial organisms. Polymerase chain reaction (PCR) studies for mycobacteria were negative. The patient did not have a history of foreign travel. Imaging studies did not detect lung involvement. Laboratory investigation of angiotensin-converting enzyme (ACE) was within normal limits (37 U/l; reference range, 9–67 U/l). Methods Twenty nine consecutive cases (13 males and 16 females) of cutaneous sarcoidosis were selected and reviewed from our institutional database between 2011 and 2014. Cases were defined by biopsies diagnosed as cutaneous sarcoidosis based on routine evaluation of hematoxylin and eosin (H&E), AFB and PAS stains. A total of 40 biopsies were evaluated. In each case, H&E stains were reviewed by two pathologists for the presence or the absence of cutaneous sarcoid perineural granulomas. Perineural granulomas were defined as non-caseating epithelioid perineural granulomas involving small cutaneous nerve fibers. Results Perineural granulomas were identified in 18/29 (62%) of cases and in 22/40 (55%) biopsies. Males and females were affected equally. By site, perineural granulomas were identified in 7/9 (78%) biopsies from the proximal upper extremity, 1/3 (33%) from the distal upper extremity, 7/12 (58%) from the head and the neck, including 4/4 (100%) from the nose, 5/9 (56%) from the back, 1/2 (50%) from the
Perineural granulomas in cutaneous sarcoidosis A
B
C
D
Fig. 2. Skin biopsies from two different sarcoid patients show large epithelioid granulomas involving small cutaneous nerves. (A) Biopsy of painful flank papule (index case) showing a deep cutaneous nerve (arrow) involved by a perineural granuloma. (B) Higher power view of small cutaneous nerve flanked by large granulomas seen in (A). (C) Biopsy showing sarcoid perineural granuloma in mid portion of dermis (arrow). (D) The cutaneous nerve appears distorted by granulomatous inflammation.
flank and 1/1 (100%) from the proximal lower extremity(thigh) and 0/4 (0%) from the distal lower extremity (Table 1). PAS and AFB stains were negative in each case. In three cases, a clinical correlate of cutaneous pain was identified. Two cases presented with painful lesions and one with pain in the vicinity of cutaneous lesions. In the remaining cases, information regarding the presence or the absence of associated pain was not available. Multiple organ system involvement or multiple cutaneous site involvement was present in 15/29 cases. One patient presented with erythema nodosum. In 6/29 cases, sarcoidosis was limited to the skin. In 7/29 cases, charts were not available for review. Discussion Cutaneous sarcoidosis is considered a diagnosis of exclusion and therefore needs to be distinguished from other disorders, such as infections, foreign body reactions and neoplastic diseases.7
Histopathologically, sarcoidal granulomas are typically composed of epithelioid histiocytes surrounded by a thin peripheral rim of lymphocytes and plasma cells; hence, the canonical term naked granuloma.8 Tuberculoid granulomas, on the other hand, are less well circumscribed with a more prominent rim of mononuclear cells and plasma cells and may show central caseation necrosis.9 Unfortunately, the pathologic features of tuberculoid granulomas are non-specific, and clinical correlation is often critically important.9 Occasionally, sarcoidosis may cause a perineural granulomatous response that closely resembles that associated with Mycobacterium leprae or other Mycobacterium subtypes.8 AFB staining, cultures and PCR studies are helpful in establishing the correct diagnosis. Other infectious processes, such as fungal infections, can also cause sarcoid-like lesions and should be ruled out.10 Foreign material has been postulated to serve as a nidus for sarcoidal granulomas, and its presence should not exclude a diagnosis of
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Munday et al. Table 1. Perineural sarcoid granulomas by anatomical location Perineural granulomas by site Cases total Cases involved Biopsies total Biopsies involved Location Head/Neck Nose UE (P) UE (D) Back Flank LE (P) LE (D)
29 18 (62%) 40 22 (55%) 7/12 (58%) 4/4 (100%) 7/9 (78%) 1/3 (33%) 5/9 (56%) 1/2 (50%) 1/1 (100%) 0/4 (0%)
LE(D), distal lower extremity; LE(P), proximal lower extremity; UE(D), distal upper extremity; UE(P), proximal upper extremity.
sarcoidosis.11,12 Yet, when the clinical history includes trauma and the biopsy shows abundant polarizable material, a foreign body giant cell reaction should be considered.13 Secondary syphilis, although classically considered a plasma cell predominant dermal infiltrate, can cause a sarcoid-like granulotamous reaction.14 Finally, plexiform fibrohistiocytic tumor may occasionally mimic cutaneous sarcoidosis. Close attention to the clinical history and the histopathologic pattern should be sufficient to differentiate between the two conditions. These tumors generally occur in children and young adults and are biphasic lesions, with a plexiform histiocytic component and fibroblastic cells associated with multinuclear giant cells.15 Cutanous sarcoidosis is a diagnosis of exclusion, which should be rendered only after the above-mentioned differential diagnoses have been considered. Sarcoidosis is known to commonly involve the skin, although it is not often thought to be associated with painful skin lesions. Here, we present a patient with painful pink papules, in which repeat biopsies showed numerous perineural sarcoid granulomas. Next, via investigation of 29 cases, we show that sarcoid perineural granulomas are more common than previously appreciated. Previous studies have shown between 13 and 25% of cutaneous sarcoidosis cases show perineural granulomas.8,16,17 In contrast to previous findings, our analyzes indicated that perineural granulomas were present in 62% of patients and in 55% of total biopsies. From our observations, small cutaneous nerves can be subtly identified within sarcoidal granulomas, which might be easily overlooked. This may account for the higher percentage of perineural granulomas
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found in our study. Furthermore, we identified two patients with painful skin lesions and one patient with regional pain in the vicinity of sarcoid lesions. In all three cases, perineural sarcoid granulomas were found. Unfortunately, comment on the presence or the absence of pain was not found in the remaining cases in our series. In the series of cases we investigated, the anatomical distribution of perineural involvement was most common on the nose, the proximal upper extremity and the head and neck biopsies (Fig. 3). Interestingly, the overall site distribution presented here seems to overlap with the entity known as sarcoidosis small-fiber neuropathy (SSFN). Sarcoidosis can manifest with inexplicable cutaneous sensory disturbances, referred to as SSFN. SSFN is considered a peripheral neuropathy in which injury is limited to small, thinly myelinated Adelta and unmyelinated C fibers.18 These fibers carry sensory information originating from the skin, such as thermal and nociceptive stimuli, to the spinal cord.18 Patients usually report burning pain, allodynia and hyperalgesia, in a patchy distribution that typically affects the face, the unilateral flank, the chest, the upper limbs and the thigh.19,20 Clinical signs include thermal and pinprick hypoesthesia, while others include hair loss, skin discoloration and hypohydrosis at the site of involvement.19 In one study, these signs and symptoms were present in 44% of sarcoidosis patients.21 The pain syndrome has occurred with the development of subcutaneous nodules, which on biopsy showed sarcoid granulomas, although without mention of perineural involvement.22 Routine nerve-conduction studies, which are unable to detect pathologic processes in cutaneous nerves, are invariably normal in this patient population. Newer, non-conventional tests have been developed, although each has been relatively unsuccessful, and there is currently no gold standard diagnostic test.20 Importantly, there are no studies of the skin in these patients and dermatology is not routinely consulted. Therefore, it is possible that cutaneous lesions are present in SSFN but are not detected because they are not evaluated. Indeed, the frequency of cutaneous lesion discovery in sarcoidosis is a product of how thoroughly they are sought after.23,24 Of particular note, SSFN appears to be an unusual, unconventional subtype of small-fiber neuropathy. The vast majority of patients with conventional small-fiber neuropathy are diabetic and present with lower extremity,
Perineural granulomas in cutaneous sarcoidosis
Fig. 3. Pattern of neuropathy in sarcoidosis small-fiber neuropathy (SSFN), sarcoidosis perineural granulomas and small fiber neuropathy (SFN). (A) The typical pattern of neuropathy in SFN (blue) is length dependent, in a stocking and glove distribution predominantly affecting the lower extremities. (B)The anatomical sites affected in SSFN (yellow) and (C) sarcoidosis perineural granulomas (red) have a similar pattern of distribution. Both SSFN and sarcoidosis perineural granulomas are quite distinct from the typical pattern of neuropathy in SFN (blue).
length-dependent, neuropathic symptoms.18 Nerve injury in diabetic patients is considered the result of metabolic injury of peripheral nerves. The diagnosis of small-fiber neuropathy is made when routine nerve-conduction studies fail to detect large fiber involvement in patients with length-dependent symptoms and abnormalities to small-fiber modalities. In any case, diabetic patients present with a classic stocking and glove pattern of conventional small-fiber neuropathy. In SSFN patients, however, the stocking and glove pattern of neuropathy is distinctly absent (Fig. 3).19 This is an important point because such a large majority of patients with conventional small-fiber neuropathy have length-dependent symptoms that it is considered a requirement for the diagnosis.18 Therefore, the distinctive, non length-dependent, clinical presentation of SSFN raises the possibility that it may be caused by pathology quite different than that of conventional small-fiber neuropathy. Furthermore, the pattern of skin involvement in SSFN is similar to the pattern of cutaneous sarcoid perineural granulomas identified in our study (Fig. 3). We suggest that the pathology of SSFN may be because of localized granulomas of small cutaneous nerves. Although sarcoidosis commonly affects the skin, the disease rarely affects the nervous system. Indeed, less than 5% of sarcoidosis patients have nervous system involvement, and among these rare cases, less than 20% are affected by a peripheral neuropathy.25 – 27 Thus, peripheral neuropathies in sarcoidosis are exceedingly rare. On the occasion that sarcoidosis does affect peripheral nerves, the pathologic process involves perineural granulomas, which cause destruction of peripheral
nerve axons and the myelin sheath.28,29 The clinical presentation includes distal sensory-motor polyneuropathy, acute inflammatory demyelinating polyneuropathy, mononeuritis multiplex, radiculopathy and mononeuropathy.25,26,30 In the majority of these clinical situations, the presenting complaint involves a motor component, and nerve-conduction studies are consistently abnormal.31,32 This is distinct from SSFN, in which there are no motor symptoms, and nerve-conduction studies are invariably normal. Additionally, “asymptomatic” sarcoidosis patients have been found to have abnormal
Fig. 4. Sarcoid neuropathy by nerve distribution. When sarcoid granulomas involve peripheral nerves (red), the pattern of neuropathy is both sensory and motor (SM). When granulomas are localized to small cutaneous nerve branches (green), the neuropathy is strictly sensory (S). When granulomas involve skeletal muscle nerve branches, the neuropathy is strictly motor (M).
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Munday et al. nerve-conduction studies.32 Often this is because of negative sensory deficits to which they are unaware. Therefore, when nerve-conduction studies are normal, as they are in SSFN, we can confidently assume peripheral nerves, aside from cutaneous nerves, are not involved in the pathologic process. Evidently, SSFN does not seem to have the typical pattern seen in peripheral neuropathy caused by sarcoidosis. However, the discrepancies cease to exist when we conceptualize the pathology of SSFN as localized to small, cutaneous nerves, which are simply the distal most cutaneous branches of the peripheral nerves from which they originate. If the pathology of SSFN is localized to these small cutaneous nerve branches, nerve-conduction studies would be
expected to be normal, and motor symptoms would also be absent (Fig. 4). The sensory abnormalities notable in SSFN are additionally explained by cutaneous granulomas, as in our index case. Thus, if sarcoid granulomas are located in a mixed peripheral nerve, the clinical manifestation is a sensory-motor disturbance; if the granulomas are confined to cutaneous nerves, the pathology is strictly sensory. In summary, perineural granulomas in cutaneous sarcoidosis are more common than previously appreciated and may be responsible for sensory disturbances. Furthermore, sarcoid perineural granulomas may provide the pathologic basis for the entity known as sarcoidosis small-fiber neuropathy.
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