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A progressive rash and fatigue
J AM ACAD DERMATOL
JAAD grand rounds 893
VOLUME 60, NUMBER 5
prognosis is better if many years have elapsed between the initial treatment and the recurrence. Because cutaneous metastases can mimic herpes zoster, it is common to consider herpes zoster the most likely diagnosis and to treat accordingly. This is particularly true in the case of breast cancer, because herpes zoster most frequently presents in the thorax after it reactivates from the dorsal root ganglia and travels down a sensory nerve. The most common vertebral dermatomes are T5 and T6, while the most common cranial nerve dermatome is the ophthalmic division of the trigeminal nerve. The appearance of crusted nodules and plaques effectively obscures the malignant nature. Zosteriform metastasis should be considered in the differential diagnosis in patients with linearly arranged pigmented or ulcerated nodules. For this series, the recommended choices are: 7, c; 8, c; 9, b; 10, d; 11, b; and 12, c. BIBLIOGRAPHY Cohen PR. Skin clues to primary and metastatic malignancy. Am Fam Physician 1995;51:1199-204. Heckmann M, Volkenandt M, Lengyel ER, Schirren CG, GizyckiNienhaus BV. Cytological diagnosis of zosteriform skin metastases in undiagnosed breast carcinoma. Br J Dermatol 1996;135:502-3. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a meta analysis of data. South Med J 2003;96:164-7. Lester S. The breast. In: Kumar V, Abbas A, Fausto N, editors. Pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders; 2005. pp. 1147-8. Manteaux A, Cohen P, Rapini R. Zosteriform and epidermotropic metastasis. J Dermatol Surg Oncol 1992;18:97-100. Niiyama S, Satoh K, Kaneko S, Aiba S, Takahashi M, Mukai H. Zosteriform skin involvement of nodal T-cell lymphoma: a review of the published work of cutaneous malignancies mimicking herpes zoster. J Dermatol 2007;34:68-73. Schoenlaub P, Sarraux A, Grosshans E, Heid E, Cribier B. Survival after the occurrence of cutaneous metastasis: a study of 200 cases. Ann Dermatol Venereol 2001;128:1310-5. Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and postherpetic neuralgia. Am Fam Physician 2000;61:2437-44. Weller S, Blum M, Doucette M, Burnette T, Cederberg D, de Miranda P, et al. Pharmacokinetics of the acyclovir pro-drug valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595-605. Williams LR, Levine LJ, Kauh YC. Cutaneous malignancies mimicking herpes zoster. Int J Dermatol 1991;30:432-4. Wilson D. Herpes zoster: prevention, diagnosis, and treatment. Nurse Pract 2007;32:19-24.
A progressive rash and fatigue M. Tandy Sutton and Laurie Massa, MD Lexington, Kentucky A 46-year-old white female presented with a 6-week history of a tender, pruritic rash that began
on both of her hands while she was on spring break. The rash quickly spread to her head, neck, bilateral upper extremities, and trunk. She was seen by her primary care provider and diagnosed with poison ivy. She was started on oral prednisone, intramuscular steroid injections, and hydroxyzine without any relief. She was then sent to our dermatology clinic. Her medical history was significant for chronic bronchitis, smoking, and a 10-pound weight loss over the past 3 months. Physical examination at the time of presentation demonstrated small, violaceous papules on the dorsal surfaces of both hands and auricles (Fig 6). Tender, erythematous, confluent macules and papules were present on the face, upper extremities, and trunk (Fig 7). Punch biopsies taken from the right upper extremity and dorsal surface of her left hand demonstrated a diffuse infiltrate of multinucleated histiocytes with ground glass cytoplasm in the superficial dermis (Figs 8 and 9). The patient returned 1 week later with no improvement in her cutaneous symptoms. The margins of the rash were continuing to spread and firm papules appeared on the dorsal surfaces of her fingers. She complained of tenderness and numbness over her hands. She later developed joint pain in her hands, generalized myalgia, and fatigue. She complained that it was difficult for her to hold a pencil. A physical examination revealed tenderness over the metacarpophalangeal joints of both hands. She had full range of motion and no tissue swelling, synovitis, deformity, or effusion. 13. What is the most likely diagnosis? a. Rheumatoid arthritis b. Multicentric reticulohistiocytosis c. Generalized eruptive histiocytoma d. Histiocytosis X e. Psoriatic arthritis 14. This disease has classically been found to be associated with all of the following except: a. Tuberculosis b. Hyperlipidemia c. Malignancy d. Infection e. Pregnancy 15. What is the most reliable immunohistochemistry marker for this disease? a. S-100 b. CD20 c. CD68 d. CD3 e. CD1a
894 JAAD grand rounds
J AM ACAD DERMATOL MAY 2009
16. Which of the following radiographic features is least likely to be observed in this disease? a. Widened joint space b. Periosteal new bone formation c. Opera glass hand deformity d. Loss of cartilage e. Narrow joint space 17. Which of the following have been used to describe a manifestation of this disease? a. Gottron sign b. Rat bite necrosis c. Coral bead appearance d. Buttonhole sign e. Darier sign Discussion Multicentric reticulohistiocytosis (MRH) is a rare systemic disease causing cutaneous, articular, and mucosal manifestations. Approximately 200 cases have been reported. Classic cutaneous findings include nodules and papules on the face, ears, and extensor surfaces of the hands and elbows. Periungual papules create a ‘‘coral bead’’ appearance. The erosive articular changes associated with MRH are symmetrical and most commonly involve the distal interphalangeal (DIP) joints. Unlike other forms of inflammatory arthritis, the arthropathy of MRH can be identified by its characteristic joint space widening without periosteal bone growth. A recent review
by Trotta et al compares and contrasts the radiologic findings among various erosive arthropathies, such as rheumatoid arthritis and psoriatic arthritis, that are commonly confused with the arthritis of MRH. Joint destruction is suspected to be caused by the inflammatory response and cytokine release involved with MRH. Untreated MRH will eventually lead to destruction of the articular surface, disfigurement, and closure of the joint space. Histologic analysis of cutaneous lesions seen in MRH has demonstrated a monocyte/macrophage origin in the majority of studies. The classic findings, as described in this case, include the presence of multinucleated giant cells with ground glass cytoplasm. Immunohistochemical analysis shows positive staining for CD45 (leukocyte common antigen), CD68, and major histocompatibility complex class IIehuman leukocyte antigen DR-1. The monocyte/ macrophages associated with MRH are distinctly different from those seen in Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X. Unlike LCH, the origin is of the noneLangerhans cell lineage, and therefore stains negative for S-100 protein. The typical course of MRH often waxes and wanes, as our patient demonstrated with her disease progression. Over the course of a year following the initial rash, she continued to have more eruptions with erythematous papules across her face, chest,
J AM ACAD DERMATOL
JAAD grand rounds 895
VOLUME 60, NUMBER 5
arms, and trunk. She developed myalgia, fatigue, and pain over the plantar surface of her feet. Her cutaneous symptoms did not begin to improve until treatment was initiated. MRH is a rare disease and there are currently no randomized, controlled studies to provide a reliable gold standard for treatment. Some therapies used to treat MRH include steroids, cyclophosphamide, lowdose pulse methotrexate, and etanercept. Our patient showed improvement after she was started on 40 mg of prednisone daily and 20 mg of methotrexate weekly. There was a decrease in the number of nodules and a reduction in the erythema of her face. After 4 months of this regimen, the rash was almost cleared, she was gaining weight, and she denied any joint pain. A complete workup for malignancy was conducted because of the historical association of MRH and various malignancies in up to 25% of cases. Results following computed tomographic scans of the abdomen and pelvis, colonoscopy, mammogram, bone marrow biopsy, vaginal ultrasound, Pap smear, esophagogastroduodenoscopy, serum electrophoresis, and CA125 were all negative and ruled out the presence of any current malignancy. Our patient has continued treatment with methotrexate and low-dose prednisone. Her skin is clear and she does not have any joint complaints, but she continues to suffer from fatigue and decreased appetite.
For this series, the recommended choices are: 13, b; 14, d; 15, c; 16, b; and 17, c. We would like to thank Fernando deCastro, MD, for his critical review of the manuscript and histologic report and images. BIBLIOGRAPHY Baghestani S, Khosravi F, Dehghani Zahedani M, Mahboobi AA. Multicentric reticulohistiocytosis presenting with papulonodular skin eruption and polyarthritis. Eur J Dermatol 2005;15:196-200. Gorman JD, Danning C, Schumacher HR, Klippel JH, Davis JC Jr. Multicentric reticulohistiocytosis: case report with immunohistochemical analysis and literature review. Arthritis Rheum 2000;43:930-8. Liang GC, Granston AS. Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate. Case report, review of the literature, and proposal for treatment. Arthritis Rheum 1996;39:171-4. Luz FB, Gaspar TAP, Kalil-Gaspar N, Ramos-e-Silva M. Multicentric reticulohistiocytosis. J Eur Acad Dermatol Venereol 2001;15: 524-31. Salisbury JR, Hall PA, Williams HC, Mangi MH, Mufti GJ. Multicentric reticulohistiocytosis. Detailed immunophenotyping confirms macrophage origin. Am J Surg Pathol 1990;14:687-93. Santilli D, Lo Monaco A, Cavazzini PL, Trotta F. Multicentric reticulohistiocytosis: a rare cause of erosive arthropathy of the distal interphalangeal finger joints. Ann Rheum Dis 2002;61:485-7. Tajirian AL, Malik MK, Robinson-Bostom L, Lally EV. Multicentric reticulohistiocytosis. Clin Dermatol 2006;24:486-92. Trotta F, Castellino G, Monaco A. Multicentric reticulohistiocytosis. Clin Rheumatol 2004;18:759-72.
JAAD grand rounds 893
VOLUME 60, NUMBER 5
prognosis is better if many years have elapsed between the initial treatment and the recurrence. Because cutaneous metastases can mimic herpes zoster, it is common to consider herpes zoster the most likely diagnosis and to treat accordingly. This is particularly true in the case of breast cancer, because herpes zoster most frequently presents in the thorax after it reactivates from the dorsal root ganglia and travels down a sensory nerve. The most common vertebral dermatomes are T5 and T6, while the most common cranial nerve dermatome is the ophthalmic division of the trigeminal nerve. The appearance of crusted nodules and plaques effectively obscures the malignant nature. Zosteriform metastasis should be considered in the differential diagnosis in patients with linearly arranged pigmented or ulcerated nodules. For this series, the recommended choices are: 7, c; 8, c; 9, b; 10, d; 11, b; and 12, c. BIBLIOGRAPHY Cohen PR. Skin clues to primary and metastatic malignancy. Am Fam Physician 1995;51:1199-204. Heckmann M, Volkenandt M, Lengyel ER, Schirren CG, GizyckiNienhaus BV. Cytological diagnosis of zosteriform skin metastases in undiagnosed breast carcinoma. Br J Dermatol 1996;135:502-3. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a meta analysis of data. South Med J 2003;96:164-7. Lester S. The breast. In: Kumar V, Abbas A, Fausto N, editors. Pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders; 2005. pp. 1147-8. Manteaux A, Cohen P, Rapini R. Zosteriform and epidermotropic metastasis. J Dermatol Surg Oncol 1992;18:97-100. Niiyama S, Satoh K, Kaneko S, Aiba S, Takahashi M, Mukai H. Zosteriform skin involvement of nodal T-cell lymphoma: a review of the published work of cutaneous malignancies mimicking herpes zoster. J Dermatol 2007;34:68-73. Schoenlaub P, Sarraux A, Grosshans E, Heid E, Cribier B. Survival after the occurrence of cutaneous metastasis: a study of 200 cases. Ann Dermatol Venereol 2001;128:1310-5. Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and postherpetic neuralgia. Am Fam Physician 2000;61:2437-44. Weller S, Blum M, Doucette M, Burnette T, Cederberg D, de Miranda P, et al. Pharmacokinetics of the acyclovir pro-drug valacyclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595-605. Williams LR, Levine LJ, Kauh YC. Cutaneous malignancies mimicking herpes zoster. Int J Dermatol 1991;30:432-4. Wilson D. Herpes zoster: prevention, diagnosis, and treatment. Nurse Pract 2007;32:19-24.
A progressive rash and fatigue M. Tandy Sutton and Laurie Massa, MD Lexington, Kentucky A 46-year-old white female presented with a 6-week history of a tender, pruritic rash that began
on both of her hands while she was on spring break. The rash quickly spread to her head, neck, bilateral upper extremities, and trunk. She was seen by her primary care provider and diagnosed with poison ivy. She was started on oral prednisone, intramuscular steroid injections, and hydroxyzine without any relief. She was then sent to our dermatology clinic. Her medical history was significant for chronic bronchitis, smoking, and a 10-pound weight loss over the past 3 months. Physical examination at the time of presentation demonstrated small, violaceous papules on the dorsal surfaces of both hands and auricles (Fig 6). Tender, erythematous, confluent macules and papules were present on the face, upper extremities, and trunk (Fig 7). Punch biopsies taken from the right upper extremity and dorsal surface of her left hand demonstrated a diffuse infiltrate of multinucleated histiocytes with ground glass cytoplasm in the superficial dermis (Figs 8 and 9). The patient returned 1 week later with no improvement in her cutaneous symptoms. The margins of the rash were continuing to spread and firm papules appeared on the dorsal surfaces of her fingers. She complained of tenderness and numbness over her hands. She later developed joint pain in her hands, generalized myalgia, and fatigue. She complained that it was difficult for her to hold a pencil. A physical examination revealed tenderness over the metacarpophalangeal joints of both hands. She had full range of motion and no tissue swelling, synovitis, deformity, or effusion. 13. What is the most likely diagnosis? a. Rheumatoid arthritis b. Multicentric reticulohistiocytosis c. Generalized eruptive histiocytoma d. Histiocytosis X e. Psoriatic arthritis 14. This disease has classically been found to be associated with all of the following except: a. Tuberculosis b. Hyperlipidemia c. Malignancy d. Infection e. Pregnancy 15. What is the most reliable immunohistochemistry marker for this disease? a. S-100 b. CD20 c. CD68 d. CD3 e. CD1a
894 JAAD grand rounds
J AM ACAD DERMATOL MAY 2009
16. Which of the following radiographic features is least likely to be observed in this disease? a. Widened joint space b. Periosteal new bone formation c. Opera glass hand deformity d. Loss of cartilage e. Narrow joint space 17. Which of the following have been used to describe a manifestation of this disease? a. Gottron sign b. Rat bite necrosis c. Coral bead appearance d. Buttonhole sign e. Darier sign Discussion Multicentric reticulohistiocytosis (MRH) is a rare systemic disease causing cutaneous, articular, and mucosal manifestations. Approximately 200 cases have been reported. Classic cutaneous findings include nodules and papules on the face, ears, and extensor surfaces of the hands and elbows. Periungual papules create a ‘‘coral bead’’ appearance. The erosive articular changes associated with MRH are symmetrical and most commonly involve the distal interphalangeal (DIP) joints. Unlike other forms of inflammatory arthritis, the arthropathy of MRH can be identified by its characteristic joint space widening without periosteal bone growth. A recent review
by Trotta et al compares and contrasts the radiologic findings among various erosive arthropathies, such as rheumatoid arthritis and psoriatic arthritis, that are commonly confused with the arthritis of MRH. Joint destruction is suspected to be caused by the inflammatory response and cytokine release involved with MRH. Untreated MRH will eventually lead to destruction of the articular surface, disfigurement, and closure of the joint space. Histologic analysis of cutaneous lesions seen in MRH has demonstrated a monocyte/macrophage origin in the majority of studies. The classic findings, as described in this case, include the presence of multinucleated giant cells with ground glass cytoplasm. Immunohistochemical analysis shows positive staining for CD45 (leukocyte common antigen), CD68, and major histocompatibility complex class IIehuman leukocyte antigen DR-1. The monocyte/ macrophages associated with MRH are distinctly different from those seen in Langerhans cell histiocytosis (LCH), formerly known as histiocytosis X. Unlike LCH, the origin is of the noneLangerhans cell lineage, and therefore stains negative for S-100 protein. The typical course of MRH often waxes and wanes, as our patient demonstrated with her disease progression. Over the course of a year following the initial rash, she continued to have more eruptions with erythematous papules across her face, chest,
J AM ACAD DERMATOL
JAAD grand rounds 895
VOLUME 60, NUMBER 5
arms, and trunk. She developed myalgia, fatigue, and pain over the plantar surface of her feet. Her cutaneous symptoms did not begin to improve until treatment was initiated. MRH is a rare disease and there are currently no randomized, controlled studies to provide a reliable gold standard for treatment. Some therapies used to treat MRH include steroids, cyclophosphamide, lowdose pulse methotrexate, and etanercept. Our patient showed improvement after she was started on 40 mg of prednisone daily and 20 mg of methotrexate weekly. There was a decrease in the number of nodules and a reduction in the erythema of her face. After 4 months of this regimen, the rash was almost cleared, she was gaining weight, and she denied any joint pain. A complete workup for malignancy was conducted because of the historical association of MRH and various malignancies in up to 25% of cases. Results following computed tomographic scans of the abdomen and pelvis, colonoscopy, mammogram, bone marrow biopsy, vaginal ultrasound, Pap smear, esophagogastroduodenoscopy, serum electrophoresis, and CA125 were all negative and ruled out the presence of any current malignancy. Our patient has continued treatment with methotrexate and low-dose prednisone. Her skin is clear and she does not have any joint complaints, but she continues to suffer from fatigue and decreased appetite.
For this series, the recommended choices are: 13, b; 14, d; 15, c; 16, b; and 17, c. We would like to thank Fernando deCastro, MD, for his critical review of the manuscript and histologic report and images. BIBLIOGRAPHY Baghestani S, Khosravi F, Dehghani Zahedani M, Mahboobi AA. Multicentric reticulohistiocytosis presenting with papulonodular skin eruption and polyarthritis. Eur J Dermatol 2005;15:196-200. Gorman JD, Danning C, Schumacher HR, Klippel JH, Davis JC Jr. Multicentric reticulohistiocytosis: case report with immunohistochemical analysis and literature review. Arthritis Rheum 2000;43:930-8. Liang GC, Granston AS. Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate. Case report, review of the literature, and proposal for treatment. Arthritis Rheum 1996;39:171-4. Luz FB, Gaspar TAP, Kalil-Gaspar N, Ramos-e-Silva M. Multicentric reticulohistiocytosis. J Eur Acad Dermatol Venereol 2001;15: 524-31. Salisbury JR, Hall PA, Williams HC, Mangi MH, Mufti GJ. Multicentric reticulohistiocytosis. Detailed immunophenotyping confirms macrophage origin. Am J Surg Pathol 1990;14:687-93. Santilli D, Lo Monaco A, Cavazzini PL, Trotta F. Multicentric reticulohistiocytosis: a rare cause of erosive arthropathy of the distal interphalangeal finger joints. Ann Rheum Dis 2002;61:485-7. Tajirian AL, Malik MK, Robinson-Bostom L, Lally EV. Multicentric reticulohistiocytosis. Clin Dermatol 2006;24:486-92. Trotta F, Castellino G, Monaco A. Multicentric reticulohistiocytosis. Clin Rheumatol 2004;18:759-72.