- Email: [email protected]
Complete remission of Merkel cell carcinoma of the scalp with local and regional metastases after topical treatment with dinitrochlorbenzol
Case reports 965
J AM ACAD DERMATOL VOLUME 50, NUMBER 6
5. 6.
7.
8. 9.
editors. Percutaneous absorption: drugs-cosmetics mechanismsmethodology. New York: Marcel Dekker; 1999. p. 177-192. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 2000;9:165-9. Marks JG Jr, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI, et al. North American Contact Dermatitis Group patch-test results, 1996-1998. Arch Dermatol 2000;136:272-3. Prystowsky SD, Nonomura JH, Smith RW, Allen AM. Allergic hypersensitivity to neomycin. Relationship between patch test reactions and ’use’ tests. Arch Dermatol 1979;115:713-5. Bjarnason B, Flosadottir E. Patch testing with neomycin sulfate. Contact Dermatitis 2000;43:295-302. Calnan CD, Sarkany I. Contact dermatitis from neomycin. Br J Dermatol 1958;70:435-45.
10. Epstein S. Contact dermatitis from neomycin due to dermal delayed (tuberculin-type) sensitivity. Dermatologica 1956;113: 191-201. 11. Epstein E. Contact dermatitis to neomycin with false negative patch tests: allergy established by intradermal and usage tests. Contact Dermatitis 1980;6:219-20. 12. Panzer JD, Epstein WL. Percutaneous absorption following topical application of neomycin. Arch Dermatol 1970;102:536-9. 13. Wester R, Maibach HI. Regional variation in percutaneous absorption. In: Bronaugh RL, Maibach HI, eds. Percutaneous absorption: drugs-cosmetics mechanisms-methodology. New York: Marcel Dekker; 1999. p. 107-16. 14. Matura M, Goossens A. Contact allergy to corticosteroids. Allergy 2000;55:698-704.
Complete remission of Merkel cell carcinoma of the scalp with local and regional metastases after topical treatment with dinitrochlorbenzol Gernot Herrmann, MD, Wolfgang Groth, MD, Thomas Krieg, MD, and Cornelia Mauch, MD Cologne, Germany Merkel cell carcinoma (MCC) is a highly aggressive tumor with a high percentage of recurrence, metastatic spread, and mortality. Treatment of metastasized MCC is not standardized and prognosis of metastasized MCC is often poor. Current protocols recommend surgery, adjuvant radiation therapy, and often lymph node dissection to prevent recurrences. A few sporadic reports of spontaneous regression of MCC suggest a so far not yet characterized role and potential of the immune system in controlling this tumor. We describe a 69-year-old man with extended inoperable MCC of the scalp including multiple local and regional metastases who responded with complete remission to 4 weekly treatments of topically applied immunemodulating dinitrochlorbenzol. Together with subsequent irradiation, remission has now lasted for more than 1 year. (J Am Acad Dermatol 2004;50:965-9.)
M
erkel cell carcinoma (MCC) is a rare and aggressive dermal neoplasm of neuroendocrine origin that is comparable with small cell lung carcinoma or melanoma with regards to recurrence, metastatic spread, and mortality. Of MCC, 85% occur in sun-exposed areas and 50% to 55% on the head and neck, which links this tumor to actinic damage.1 Most studies concerning guidelines for optimized initial therapy are limited by small From the Department of Dermatology, University of Cologne. Supported by the Medical Faculty, University of Cologne. Conflicts of interest: None identified. Reprint requests: Cornelia Mauch, MD, Klinik und Poliklinik fu¨r Dermatologie und Venerologie, Universita¨t Ko¨ln, JosephStelzmann-Str 9, 50924 Cologne, Germany. E-mail: cornelia. [email protected]. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.049
patient numbers. Traditional therapy is wide local excision with 2- to 3-cm margins. The usefulness of adjuvant radiotherapy or dissection of draining lymphatic regions is equivocal, even though recent studies indicate a potential benefit in the prevention of local recurrence.1,2 The value of chemotherapy for adjuvant therapy remains to be determined and is so far mainly used for the palliative treatment of metastatic MCC.3 A few reports of spontaneous remissions in patients with MCC4 and the anecdotal successful use of immune-modulating drugs such as tumor necrosis factor5 highlight the role of the immune system in potentially establishing tumor immunity against this very aggressive malignancy. In this report, we describe a patient with (stage II) MCC including local and regional metastases that were treated with topically applied immunomodulating DNCB. The patient subsequently showed
966 Case reports
J AM ACAD DERMATOL JUNE 2004
Fig 1. A, Primary tumor and local and regional metastases on scalp and forehead of patient before dinitrochlorbenzol (DNCB) therapy. B, Patient 2 weeks after fourth application of DNCB, before radiotherapy. C, Patient 6 months after DNCB therapy, after radiotherapy.
complete clinical remission and has now, after additional radiotherapy, had no evidence of disease for more than 1 year. This report may prompt further studies on the use of immunomodulating drugs for the treatment of MCC.
CASE REPORT A 69-year-old man presented to our outpatient clinic with multiple nodules on the scalp (Fig 1, A). The first lesion had appeared 3 months earlier on the central scalp and constantly increased in size. Two months later, several other lesions appeared on the scalp and forehead. Excision biopsy was performed on the right forehead and specimen showed the infiltration of dermis and subcutis with a tumor consisting of relatively monomorphous cells (Fig 2, A) with large vesicular nuclei and prominent nucleoli. The borders showed trabecular growth, satellites, and single file lining of tumor cells between connective tissue fibers and fat cells. Mitoses were frequent (10-13/HPF) and lymphatic invasion of tumor cells could be detected on the lateral edges of the tumor (Fig 2, B). Cytochemically, all tumor cells demonstrated a paranuclear dotlike expression of cytokeratin 20 (Fig 2, C). Approximately one third of the tumor cells were positive for chromogranin A. Staining for neuron-specific enolase was negative. On the basis of the clinical and histopathologic findings, MCC of the head and neck with local and regional metastases was diagnosed. Subsequent staging of the patient included computed tomography scans of the abdomen, chest, and neck; magnetic resonance tomography scans of the
head; and gave no evidence for further metastases. Only 1 nodular structure in the right submandibular area was considered suggestive by ultrasound criteria. This node was subsequently excised and diagnosed as a benign cystadenolymphoma (Warthin’s tumor) of a salivary gland. In addition, 2 basal cell carcinomas were excised from the middle of the forehead and left lateral eyelid. Other medical conditions of the patient included diabetes, increased blood pressure, arterial sclerosis, angina pectoris, the history of a myocardial infarction, an arteriocoronary venous bypass, and the implantation of an aortobifemoral prosthesis. Because of the reduced general condition of the patient and because a surgical approach was limited by the local extension of the tumor, we considered therapeutic alternatives. Reports of spontaneous regression of MCC4 suggest an as yet unclear role of the immune system in controlling this tumor. We, therefore, decided to treat the patient with topically applied dinitrochlorbenzol (DNCB). DNCB is an obligate contact sensitizer that has successfully been applied onto nonmelanocytic skin cancers or cutaneous lymphomas and is today most widely used for the treatment of cutaneous metastases of malignant melanoma alone or in combination with chemotherapy.6-13 The patient was informed about the experimental condition of this treatment and informed consent was obtained. Topical treatment was performed as described elsewhere8 and began with induction of hypersensitivity to DNCB. Therefore, DNCB (2% in petrola-
Case reports 967
J AM ACAD DERMATOL VOLUME 50, NUMBER 6
concentration of the topically applied DNCB. Local therapy was well tolerated and after 1 week the lesions started to decrease in size. DNCB was applied for 4 subsequent weeks until only erosions and crusts remained. Another biopsy specimen from a regressing lesion was taken after the third application of DNCB and showed few remaining cytokeratin 20 –positive tumor cell complexes in the mid to lower dermis, which were surrounded by a dense infiltration consisting of T lymphocytes (CD3⫹) and macrophages (CD28⫹, KP-1⫹) (Fig 3). Mitoses were still detectable (1-2/HPF), but less frequent as compared with the initial biopsy specimen. Fig 1, B, shows the patient after the fourth application of DNCB. After erosions and crusts on the head healed, an additional irradiation of the whole scalp was performed with 4 MeV electrons at daily dose of 1.8 Gy, and a cumulative dose of 54 Gy. Fig 1, C, shows the patient 6 months after finishing DNCB therapy. One year after treatment the patient still presents with no evidence of local recurrence or distant metastasis. Regular follow-up is being performed.
DISCUSSION
Fig 2. A, Histopathology shows infiltration of dermis and subcutis by relatively monomorphous tumor in detail (B). C, Positivity of tumor cells for cytokeratin 20. Long arrow, Trabecular growth of tumor surrounded by sparse inflammatoric infiltrate; short arrow, lymphatic invasion. (A-C, Hematoxylin-eosin stain; original magnifications: A, ⫻4; B, ⫻20; C, ⫻40.)
tum) was topically applied onto one lesion approximately 1.5 cm in diameter on the left side of the forehead under occlusive conditions. Occlusion was removed 48 hours later and we observed an irritant skin reaction around the metastasis that decreased within 48 hours. One week after the induction, DNCB (0.25% in petrolatum) was thickly applied on a weekly basis onto all visible nodules on the scalp and covered with usual strips under nonocclusive conditions for 48 hours. Under these conditions an acute contact dermatitis with reddening, infiltration, and itching developed. Ulceration and erosions were observed in the metastases but not in the surrounding eczema. As the intensity of this reaction was within the desired range, we did not alter the
MCC is a very aggressive skin tumor with a mortality around 25%. Fortunately, with an estimated 400 annual cases in the United States, it is a rare malignancy. Because of the limited number of cases, larger randomized trials are difficult to perform. This is one of the reasons why broadly generalizable recommendations regarding therapy do not exist. Similar to malignant melanoma, the curative treatment of extended disease is unsatisfactory and there is an ongoing discussion concerning optimal initial treatment regimens. Even to a higher extent as compared with malignant melanoma, there are several reports of spontaneous regression of MCC (1.67% in MCC vs 0.22%-0.27% in malignant melanoma),4 which has led to the demand of systematically studying immune responses in these cases. DNCB, alone or in combination with dacarbazine, has a long history of being used experimentally for the treatment of cutaneous metastases in malignant melanoma and other premalignant and malignant cutaneous tumors,6-13 which prompted us to test its efficacy in MCC with local and regional metastases in a situation in which other therapeutic options were limited. In the case of metastases of malignant melanoma, combined application of DNCB and dacarbazine seems to have synergistic effects and results in higher remission rates as compared with DNCB alone.8,14 However, because dacarbazine has no established role in the treatment of neuroendocrine tumors as MCC, we decided to solely use DNCB. Our patient showed clinical signs of tumor
968 Case reports
J AM ACAD DERMATOL JUNE 2004
Fig 3. A, Histopathology shows eczematous reaction of skin with dense nodular infiltrate in dermis consisting of some remaining cytokeratin 20 –positive tumor cells within dense, nodular inflammatory infiltrate (B), CD3⫹ cells surrounding tumor cells (C), and KP-1⫹ cells close to tumor cells in nodular dermal infiltrate (D). (A-D, Hematoxylin-eosin stain; original magnifications: A, ⫻4; B-D, ⫻40.)
regression 2 weeks after initial sensitization to DNCB and 1 week after the first application of DNCB to all visible nodules. Even though the close temporal context suggests a possible role of a DNCB-induced immune modulation in tumor regression, we cannot completely rule out a spontaneous, DNCB-independent regression of the MCC. Recently, 10 reports of spontaneously regressing MCC, including patients with local and regional metastases, were reviewed.4 However, all cases lack detailed histopathologic analysis of tumor regression so that comparisons concerning differences or similarities in the inflammatoric infiltrate can not be made. Two reports of successfully treated MCC using intralesionally applied tumor necrosis factor-␣ also lack detailed histologic analysis of regression.5 To our knowledge, there is currently only one histologic analysis of a spontaneously regressing MCC15 that would allow comparison of immune responses in spontaneous regression or contact sensitizer-induced changes. The authors identified CD3⫹ T cells as the major immune cells located in the dermis. In addition, they identified KP-1⫹ foamy macrophages that surrounded tumor cells. This is similar to our observations and it could, therefore, be possible that a local immune stimula-
tion by DNCB could help establish tumor immunity. However, the detailed mode of DNCB action still remains unclear. Data from animal experiments in which mice were injected with murine melanoma cells capable of forming subcutaneous and lung metastases point to the induction of a specific T cell– dependent antitumor response after treatment with DNCB in combination with dacarbazine.14 The main T-cell subpopulations that have the ability to lyse the injected melanoma cells were CD4⫹ and CD8⫹ lymphocytes, whereas natural killer cells do not seem to be involved.14 Interestingly, the authors could isolate increased numbers of T cells with cytolytic activity against melanoma cells also from the spleen of the animals, and could detect increased messenger RNA levels for interferon gamma, tumor necrosis factor-␣, and IL-6, which may mediate systemic tumor-host interactions. In our patient, the inflammatory infiltrate around the regressing tumors also contained many CD4⫹ and CD8⫹ cells (data not shown), which may represent activated tumor-infiltrating lymphocytes. As tumor cells were positive for both CD56 and CD57, we can not answer the question if in our patient the infiltrate also contained natural killer cells.
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J AM ACAD DERMATOL VOLUME 50, NUMBER 6
Several studies argue for the benefit of adjuvant radiation therapy in the treatment of MCC.2,3,16,17 However, it will have to be discussed as to whether additional irradiation is necessary or if it even may counteract effects of immune stimulation once complete clinical remission is observed, like in our case. Further follow-up of the patient and studies of more patients will help to clarify this issue. Taken together, we report a complete remission of a stage II MCC upon treatment with the contact sensitizer DNCB. Although we can not exclude spontanous regression of the tumor, the easy handling and cost-efficiacy may legitimate further studies of immune-modulating drugs in MCC, especially in cases lacking other therapeutic options. REFERENCES 1. Brissett AE, Olsen KD, Kasperbauer JL, Lewis JE, Goellner JR, Spotts MS, et al. Merkel cell carcinoma of the head and neck: a retrospective case series. Head Neck 2002;24:982-8. 2. Eich HT, Eich D, Staar S, Mauch C, Stu¨tzer H, Groth W, et al. Role of postoperative radiotherapy in the management of Merkel cell carcinoma. Am J Clin Oncol 2002;25:50-6. 3. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002;20:588-98. 4. Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases. Dermatol Surg 2000;29:853-6. 5. Hata Y, Matsuka K, Ito O, Matsuda H, Furuichi H, Konstantinos A, et al. Two cases of Merkel cell carcinoma cured by intratumoral injection of natural human tumor necrosis factor. Plast Reconstr Surg 1997;99:547-53.
6. Klein E. Immunotherapeutic approaches to skin cancer. Hosp Pract 1976;11:107-16. 7. Klein E, Holtermann OA, Helm F, Milgrom H, Stoll HL, Rosner D, et al. Topical therapy for cutaneous tumors. Transplant Proc 1984; 16:507-11. 8. Trcka J, Ka¨mpgen E, Becker JC, Schwaaf A, Bro¨cker E-B. Immunochemotherapie des malignen Melanoms. Hautarzt 1998;49:1722. 9. Strobbe LJA, Ru¨mke P, Israels SP, Nieweg OE, Kroon BBR. Topical dinitrochlorobenzene combined with systemic dacarbazine in the treatment of recurrent melanoma. Melanoma Res 1997;7: 507. 10. Malek Mansour S. Remission of melanoma with DNCB treatment. Lancet 1973;2:503-4. 11. Budzanowska E, Pawlicki M. An attempt at topical DNCB immunomodulation in advanced malignant melanoma. Tumori 1988; 74:519-22. 12. Illig P, Paul E, Bodecker RH. Epifocal dinitrochlorobenzene therapy in malignant melanoma (experience during the last eight years). Anticancer Res 1984;4:293-8. 13. Sigg C, Schnyder UW. Successful immunotherapy by dinitrochlorobenzene in a case of recurrent acrolentiginous melanoma. Dermatologica 1990;181:250-1. 14. Wack C, Kirst A, Becker JC, Lutz WK, Bro¨cker E-B, Fischer WH. Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. Cancer Immunol Immunother 2002;51:431-9. 15. Maruo K, Kayashima K-I, Ono T. Regressing Merkel cell carcinoma–a case showing replacement of tumour cells by foamy cells. Br J Dermatol 2000;142:1184-9. 16. Cotlar AM, Gates JO, Gibbs FA Jr. Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 1986;52:159-64. 17. Fenig E, Brenner B, Katz A, Rakovsky E, Hana MB, Sulkes A. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-5.
An unusual combination: Lipedema with myiasis Tamara Koss, MD,a Nicole Lanatra, MD,b Mathew J. Stiller, MD,a and Marc E. Grossman, MDa Bronx and New York, New York Lipedema refers to the abnormal deposition of subcutaneous fat causing a striking enlargement of the lower extremities that is out of proportion to the upper body. Most clinicians are unaware of this disease and thus it is seldom diagnosed correctly. Cutaneous myiasis is the infestation of skin by fly larvae. We describe an unusual case of a woman with lipedema who developed cutaneous myiasis. (J Am Acad Dermatol 2004;50: 969-72.)
From the Departments of Dermatology, Columbia University College of Physicians and Surgeonsa and Medicine, Montefiore Medical Center.b Funding sources: None. Conflict of interest: None identified. Reprint requests: Marc E. Grossman, MD, FACP, 12 Greenridge Ave #403, White Plains, NY 10605. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.056
CASE PRESENTATION A 57-year-old woman with morbid obesity, Pickwickian syndrome, chronic obstructive pulmonary disease, congestive heart failure, and hypertension was hospitalized for increasing shortness of breath and worsening lower extremity edema. The patient had noted a malodorous, clear discharge from her distal legs for several weeks prior to admission.
J AM ACAD DERMATOL VOLUME 50, NUMBER 6
5. 6.
7.
8. 9.
editors. Percutaneous absorption: drugs-cosmetics mechanismsmethodology. New York: Marcel Dekker; 1999. p. 177-192. Bos JD, Meinardi MM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 2000;9:165-9. Marks JG Jr, Belsito DV, DeLeo VA, Fowler JF Jr, Fransway AF, Maibach HI, et al. North American Contact Dermatitis Group patch-test results, 1996-1998. Arch Dermatol 2000;136:272-3. Prystowsky SD, Nonomura JH, Smith RW, Allen AM. Allergic hypersensitivity to neomycin. Relationship between patch test reactions and ’use’ tests. Arch Dermatol 1979;115:713-5. Bjarnason B, Flosadottir E. Patch testing with neomycin sulfate. Contact Dermatitis 2000;43:295-302. Calnan CD, Sarkany I. Contact dermatitis from neomycin. Br J Dermatol 1958;70:435-45.
10. Epstein S. Contact dermatitis from neomycin due to dermal delayed (tuberculin-type) sensitivity. Dermatologica 1956;113: 191-201. 11. Epstein E. Contact dermatitis to neomycin with false negative patch tests: allergy established by intradermal and usage tests. Contact Dermatitis 1980;6:219-20. 12. Panzer JD, Epstein WL. Percutaneous absorption following topical application of neomycin. Arch Dermatol 1970;102:536-9. 13. Wester R, Maibach HI. Regional variation in percutaneous absorption. In: Bronaugh RL, Maibach HI, eds. Percutaneous absorption: drugs-cosmetics mechanisms-methodology. New York: Marcel Dekker; 1999. p. 107-16. 14. Matura M, Goossens A. Contact allergy to corticosteroids. Allergy 2000;55:698-704.
Complete remission of Merkel cell carcinoma of the scalp with local and regional metastases after topical treatment with dinitrochlorbenzol Gernot Herrmann, MD, Wolfgang Groth, MD, Thomas Krieg, MD, and Cornelia Mauch, MD Cologne, Germany Merkel cell carcinoma (MCC) is a highly aggressive tumor with a high percentage of recurrence, metastatic spread, and mortality. Treatment of metastasized MCC is not standardized and prognosis of metastasized MCC is often poor. Current protocols recommend surgery, adjuvant radiation therapy, and often lymph node dissection to prevent recurrences. A few sporadic reports of spontaneous regression of MCC suggest a so far not yet characterized role and potential of the immune system in controlling this tumor. We describe a 69-year-old man with extended inoperable MCC of the scalp including multiple local and regional metastases who responded with complete remission to 4 weekly treatments of topically applied immunemodulating dinitrochlorbenzol. Together with subsequent irradiation, remission has now lasted for more than 1 year. (J Am Acad Dermatol 2004;50:965-9.)
M
erkel cell carcinoma (MCC) is a rare and aggressive dermal neoplasm of neuroendocrine origin that is comparable with small cell lung carcinoma or melanoma with regards to recurrence, metastatic spread, and mortality. Of MCC, 85% occur in sun-exposed areas and 50% to 55% on the head and neck, which links this tumor to actinic damage.1 Most studies concerning guidelines for optimized initial therapy are limited by small From the Department of Dermatology, University of Cologne. Supported by the Medical Faculty, University of Cologne. Conflicts of interest: None identified. Reprint requests: Cornelia Mauch, MD, Klinik und Poliklinik fu¨r Dermatologie und Venerologie, Universita¨t Ko¨ln, JosephStelzmann-Str 9, 50924 Cologne, Germany. E-mail: cornelia. [email protected]. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.049
patient numbers. Traditional therapy is wide local excision with 2- to 3-cm margins. The usefulness of adjuvant radiotherapy or dissection of draining lymphatic regions is equivocal, even though recent studies indicate a potential benefit in the prevention of local recurrence.1,2 The value of chemotherapy for adjuvant therapy remains to be determined and is so far mainly used for the palliative treatment of metastatic MCC.3 A few reports of spontaneous remissions in patients with MCC4 and the anecdotal successful use of immune-modulating drugs such as tumor necrosis factor5 highlight the role of the immune system in potentially establishing tumor immunity against this very aggressive malignancy. In this report, we describe a patient with (stage II) MCC including local and regional metastases that were treated with topically applied immunomodulating DNCB. The patient subsequently showed
966 Case reports
J AM ACAD DERMATOL JUNE 2004
Fig 1. A, Primary tumor and local and regional metastases on scalp and forehead of patient before dinitrochlorbenzol (DNCB) therapy. B, Patient 2 weeks after fourth application of DNCB, before radiotherapy. C, Patient 6 months after DNCB therapy, after radiotherapy.
complete clinical remission and has now, after additional radiotherapy, had no evidence of disease for more than 1 year. This report may prompt further studies on the use of immunomodulating drugs for the treatment of MCC.
CASE REPORT A 69-year-old man presented to our outpatient clinic with multiple nodules on the scalp (Fig 1, A). The first lesion had appeared 3 months earlier on the central scalp and constantly increased in size. Two months later, several other lesions appeared on the scalp and forehead. Excision biopsy was performed on the right forehead and specimen showed the infiltration of dermis and subcutis with a tumor consisting of relatively monomorphous cells (Fig 2, A) with large vesicular nuclei and prominent nucleoli. The borders showed trabecular growth, satellites, and single file lining of tumor cells between connective tissue fibers and fat cells. Mitoses were frequent (10-13/HPF) and lymphatic invasion of tumor cells could be detected on the lateral edges of the tumor (Fig 2, B). Cytochemically, all tumor cells demonstrated a paranuclear dotlike expression of cytokeratin 20 (Fig 2, C). Approximately one third of the tumor cells were positive for chromogranin A. Staining for neuron-specific enolase was negative. On the basis of the clinical and histopathologic findings, MCC of the head and neck with local and regional metastases was diagnosed. Subsequent staging of the patient included computed tomography scans of the abdomen, chest, and neck; magnetic resonance tomography scans of the
head; and gave no evidence for further metastases. Only 1 nodular structure in the right submandibular area was considered suggestive by ultrasound criteria. This node was subsequently excised and diagnosed as a benign cystadenolymphoma (Warthin’s tumor) of a salivary gland. In addition, 2 basal cell carcinomas were excised from the middle of the forehead and left lateral eyelid. Other medical conditions of the patient included diabetes, increased blood pressure, arterial sclerosis, angina pectoris, the history of a myocardial infarction, an arteriocoronary venous bypass, and the implantation of an aortobifemoral prosthesis. Because of the reduced general condition of the patient and because a surgical approach was limited by the local extension of the tumor, we considered therapeutic alternatives. Reports of spontaneous regression of MCC4 suggest an as yet unclear role of the immune system in controlling this tumor. We, therefore, decided to treat the patient with topically applied dinitrochlorbenzol (DNCB). DNCB is an obligate contact sensitizer that has successfully been applied onto nonmelanocytic skin cancers or cutaneous lymphomas and is today most widely used for the treatment of cutaneous metastases of malignant melanoma alone or in combination with chemotherapy.6-13 The patient was informed about the experimental condition of this treatment and informed consent was obtained. Topical treatment was performed as described elsewhere8 and began with induction of hypersensitivity to DNCB. Therefore, DNCB (2% in petrola-
Case reports 967
J AM ACAD DERMATOL VOLUME 50, NUMBER 6
concentration of the topically applied DNCB. Local therapy was well tolerated and after 1 week the lesions started to decrease in size. DNCB was applied for 4 subsequent weeks until only erosions and crusts remained. Another biopsy specimen from a regressing lesion was taken after the third application of DNCB and showed few remaining cytokeratin 20 –positive tumor cell complexes in the mid to lower dermis, which were surrounded by a dense infiltration consisting of T lymphocytes (CD3⫹) and macrophages (CD28⫹, KP-1⫹) (Fig 3). Mitoses were still detectable (1-2/HPF), but less frequent as compared with the initial biopsy specimen. Fig 1, B, shows the patient after the fourth application of DNCB. After erosions and crusts on the head healed, an additional irradiation of the whole scalp was performed with 4 MeV electrons at daily dose of 1.8 Gy, and a cumulative dose of 54 Gy. Fig 1, C, shows the patient 6 months after finishing DNCB therapy. One year after treatment the patient still presents with no evidence of local recurrence or distant metastasis. Regular follow-up is being performed.
DISCUSSION
Fig 2. A, Histopathology shows infiltration of dermis and subcutis by relatively monomorphous tumor in detail (B). C, Positivity of tumor cells for cytokeratin 20. Long arrow, Trabecular growth of tumor surrounded by sparse inflammatoric infiltrate; short arrow, lymphatic invasion. (A-C, Hematoxylin-eosin stain; original magnifications: A, ⫻4; B, ⫻20; C, ⫻40.)
tum) was topically applied onto one lesion approximately 1.5 cm in diameter on the left side of the forehead under occlusive conditions. Occlusion was removed 48 hours later and we observed an irritant skin reaction around the metastasis that decreased within 48 hours. One week after the induction, DNCB (0.25% in petrolatum) was thickly applied on a weekly basis onto all visible nodules on the scalp and covered with usual strips under nonocclusive conditions for 48 hours. Under these conditions an acute contact dermatitis with reddening, infiltration, and itching developed. Ulceration and erosions were observed in the metastases but not in the surrounding eczema. As the intensity of this reaction was within the desired range, we did not alter the
MCC is a very aggressive skin tumor with a mortality around 25%. Fortunately, with an estimated 400 annual cases in the United States, it is a rare malignancy. Because of the limited number of cases, larger randomized trials are difficult to perform. This is one of the reasons why broadly generalizable recommendations regarding therapy do not exist. Similar to malignant melanoma, the curative treatment of extended disease is unsatisfactory and there is an ongoing discussion concerning optimal initial treatment regimens. Even to a higher extent as compared with malignant melanoma, there are several reports of spontaneous regression of MCC (1.67% in MCC vs 0.22%-0.27% in malignant melanoma),4 which has led to the demand of systematically studying immune responses in these cases. DNCB, alone or in combination with dacarbazine, has a long history of being used experimentally for the treatment of cutaneous metastases in malignant melanoma and other premalignant and malignant cutaneous tumors,6-13 which prompted us to test its efficacy in MCC with local and regional metastases in a situation in which other therapeutic options were limited. In the case of metastases of malignant melanoma, combined application of DNCB and dacarbazine seems to have synergistic effects and results in higher remission rates as compared with DNCB alone.8,14 However, because dacarbazine has no established role in the treatment of neuroendocrine tumors as MCC, we decided to solely use DNCB. Our patient showed clinical signs of tumor
968 Case reports
J AM ACAD DERMATOL JUNE 2004
Fig 3. A, Histopathology shows eczematous reaction of skin with dense nodular infiltrate in dermis consisting of some remaining cytokeratin 20 –positive tumor cells within dense, nodular inflammatory infiltrate (B), CD3⫹ cells surrounding tumor cells (C), and KP-1⫹ cells close to tumor cells in nodular dermal infiltrate (D). (A-D, Hematoxylin-eosin stain; original magnifications: A, ⫻4; B-D, ⫻40.)
regression 2 weeks after initial sensitization to DNCB and 1 week after the first application of DNCB to all visible nodules. Even though the close temporal context suggests a possible role of a DNCB-induced immune modulation in tumor regression, we cannot completely rule out a spontaneous, DNCB-independent regression of the MCC. Recently, 10 reports of spontaneously regressing MCC, including patients with local and regional metastases, were reviewed.4 However, all cases lack detailed histopathologic analysis of tumor regression so that comparisons concerning differences or similarities in the inflammatoric infiltrate can not be made. Two reports of successfully treated MCC using intralesionally applied tumor necrosis factor-␣ also lack detailed histologic analysis of regression.5 To our knowledge, there is currently only one histologic analysis of a spontaneously regressing MCC15 that would allow comparison of immune responses in spontaneous regression or contact sensitizer-induced changes. The authors identified CD3⫹ T cells as the major immune cells located in the dermis. In addition, they identified KP-1⫹ foamy macrophages that surrounded tumor cells. This is similar to our observations and it could, therefore, be possible that a local immune stimula-
tion by DNCB could help establish tumor immunity. However, the detailed mode of DNCB action still remains unclear. Data from animal experiments in which mice were injected with murine melanoma cells capable of forming subcutaneous and lung metastases point to the induction of a specific T cell– dependent antitumor response after treatment with DNCB in combination with dacarbazine.14 The main T-cell subpopulations that have the ability to lyse the injected melanoma cells were CD4⫹ and CD8⫹ lymphocytes, whereas natural killer cells do not seem to be involved.14 Interestingly, the authors could isolate increased numbers of T cells with cytolytic activity against melanoma cells also from the spleen of the animals, and could detect increased messenger RNA levels for interferon gamma, tumor necrosis factor-␣, and IL-6, which may mediate systemic tumor-host interactions. In our patient, the inflammatory infiltrate around the regressing tumors also contained many CD4⫹ and CD8⫹ cells (data not shown), which may represent activated tumor-infiltrating lymphocytes. As tumor cells were positive for both CD56 and CD57, we can not answer the question if in our patient the infiltrate also contained natural killer cells.
Case reports 969
J AM ACAD DERMATOL VOLUME 50, NUMBER 6
Several studies argue for the benefit of adjuvant radiation therapy in the treatment of MCC.2,3,16,17 However, it will have to be discussed as to whether additional irradiation is necessary or if it even may counteract effects of immune stimulation once complete clinical remission is observed, like in our case. Further follow-up of the patient and studies of more patients will help to clarify this issue. Taken together, we report a complete remission of a stage II MCC upon treatment with the contact sensitizer DNCB. Although we can not exclude spontanous regression of the tumor, the easy handling and cost-efficiacy may legitimate further studies of immune-modulating drugs in MCC, especially in cases lacking other therapeutic options. REFERENCES 1. Brissett AE, Olsen KD, Kasperbauer JL, Lewis JE, Goellner JR, Spotts MS, et al. Merkel cell carcinoma of the head and neck: a retrospective case series. Head Neck 2002;24:982-8. 2. Eich HT, Eich D, Staar S, Mauch C, Stu¨tzer H, Groth W, et al. Role of postoperative radiotherapy in the management of Merkel cell carcinoma. Am J Clin Oncol 2002;25:50-6. 3. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002;20:588-98. 4. Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases. Dermatol Surg 2000;29:853-6. 5. Hata Y, Matsuka K, Ito O, Matsuda H, Furuichi H, Konstantinos A, et al. Two cases of Merkel cell carcinoma cured by intratumoral injection of natural human tumor necrosis factor. Plast Reconstr Surg 1997;99:547-53.
6. Klein E. Immunotherapeutic approaches to skin cancer. Hosp Pract 1976;11:107-16. 7. Klein E, Holtermann OA, Helm F, Milgrom H, Stoll HL, Rosner D, et al. Topical therapy for cutaneous tumors. Transplant Proc 1984; 16:507-11. 8. Trcka J, Ka¨mpgen E, Becker JC, Schwaaf A, Bro¨cker E-B. Immunochemotherapie des malignen Melanoms. Hautarzt 1998;49:1722. 9. Strobbe LJA, Ru¨mke P, Israels SP, Nieweg OE, Kroon BBR. Topical dinitrochlorobenzene combined with systemic dacarbazine in the treatment of recurrent melanoma. Melanoma Res 1997;7: 507. 10. Malek Mansour S. Remission of melanoma with DNCB treatment. Lancet 1973;2:503-4. 11. Budzanowska E, Pawlicki M. An attempt at topical DNCB immunomodulation in advanced malignant melanoma. Tumori 1988; 74:519-22. 12. Illig P, Paul E, Bodecker RH. Epifocal dinitrochlorobenzene therapy in malignant melanoma (experience during the last eight years). Anticancer Res 1984;4:293-8. 13. Sigg C, Schnyder UW. Successful immunotherapy by dinitrochlorobenzene in a case of recurrent acrolentiginous melanoma. Dermatologica 1990;181:250-1. 14. Wack C, Kirst A, Becker JC, Lutz WK, Bro¨cker E-B, Fischer WH. Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. Cancer Immunol Immunother 2002;51:431-9. 15. Maruo K, Kayashima K-I, Ono T. Regressing Merkel cell carcinoma–a case showing replacement of tumour cells by foamy cells. Br J Dermatol 2000;142:1184-9. 16. Cotlar AM, Gates JO, Gibbs FA Jr. Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 1986;52:159-64. 17. Fenig E, Brenner B, Katz A, Rakovsky E, Hana MB, Sulkes A. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997;80:881-5.
An unusual combination: Lipedema with myiasis Tamara Koss, MD,a Nicole Lanatra, MD,b Mathew J. Stiller, MD,a and Marc E. Grossman, MDa Bronx and New York, New York Lipedema refers to the abnormal deposition of subcutaneous fat causing a striking enlargement of the lower extremities that is out of proportion to the upper body. Most clinicians are unaware of this disease and thus it is seldom diagnosed correctly. Cutaneous myiasis is the infestation of skin by fly larvae. We describe an unusual case of a woman with lipedema who developed cutaneous myiasis. (J Am Acad Dermatol 2004;50: 969-72.)
From the Departments of Dermatology, Columbia University College of Physicians and Surgeonsa and Medicine, Montefiore Medical Center.b Funding sources: None. Conflict of interest: None identified. Reprint requests: Marc E. Grossman, MD, FACP, 12 Greenridge Ave #403, White Plains, NY 10605. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.11.056
CASE PRESENTATION A 57-year-old woman with morbid obesity, Pickwickian syndrome, chronic obstructive pulmonary disease, congestive heart failure, and hypertension was hospitalized for increasing shortness of breath and worsening lower extremity edema. The patient had noted a malodorous, clear discharge from her distal legs for several weeks prior to admission.