Nonmelanoma Skin Cancer

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.

Pancreatic panniculitis represents a rare skin manifestation of underlying pancreatic pathology. The clinical presentation of the condition is remarkably consistent and privy to several unique clinical and histopathologic findings. We report a case of a 50-year-old white woman with pancreatic panniculitis and newly diagnosed pancreatic acinic cell adenocarcinoma. The clinical and histopathologic features, underlying causes, and treatments are reviewed.

Case Report
In June 2005, a 50-year-old white woman presented to the emergency department with a 6-month history of nausea, vomiting, abdominal pain, and weight loss, and a 3-week history of painful leg nodules that had been increasing in size and number in the days prior to admission. She currently was not taking any medications and was allergic to clindamycin and cefuroxime axetil. She smoked half a pack of cigarettes a day for the past 15 years and denied alcohol use. Her family history was notable for breast and colon cancer in her maternal grandmother and cervical cancer in her sister. Physical examination revealed multiple 2- to 4-cm, firm, tender, erythematous nodules on the anterior and anteromedial shins bilaterally (Figure 1). There also was mild tenderness on palpation of the abdomen in the epigastric region. The remainder of the physical examination was unremarkable. Pertinent laboratory findings included an elevated lipase level of 4000 U/L (reference range, 31–186 U/L) and a slightly elevated amylase level of 114 U/L (reference range, 27–131 U/L). A complete blood count and liver function panel were within reference range.

A 5-mm punch biopsy specimen obtained from one of the nodules revealed a predominantly septal panniculitis with some lacelike lobular infiltration of inflammatory cells (Figure 2). Lymphocytes and neutrophils were observed, and eosinophils were particularly prominent. In addition, there were small foci of lipocyte degeneration and calcification, with formation of ghost cells (Figure 3). Aggregates of granular basophilic material also were identified, particularly near the base of the specimen. Gram, Gomori methenamine-silver, and acid-fast bacilli stains were negative for organisms. A diagnosis of pancreatic panniculitis was made.

Further workup of the patient revealed a 5-cm ill-defined mass in the pancreatic head as well as a 2-cm liver mass. Biopsy specimens of the pancreatic and liver masses revealed pancreatic acinic cell adenocarcinoma with metastasis. The patient initially was started on octreotide acetate, gemcitabine hydrochloride, and nonsteroidal anti-inflammatory drugs. After 3 months of therapy, the tumor remained stable in size, but the leg nodules had begun to regress due to the octreotide acetate. Additional chemotherapeutic agents were added to her treatment, including streptozocin and doxorubicin hydrochloride liposome. In August 2005, the pancreatic carcinoma and liver metastasis had dramatically decreased in size and the panniculitis had resolved. The patient requested that the octreotide acetate and chemotherapy be discontinued. She presented again in December 2005 with the return of her panniculitis, this time involving her shins, arms, and hands. A few of the nodules on the shins were noted to express a brown-green oily fluid. Workup revealed an increase in size of her primary tumor and multiple liver masses. Octreotide acetate and chemotherapy were restarted. Two months later (February 2006), the patient's panniculitis had again regressed and her tumors slowly were decreasing in size.

Comment
Pancreatic panniculitis is a cutaneous finding marked by multiple subcutaneous, raised, firm, tender, edematous nodules varying from erythematous to violaceous to red-brown. These nodules most commonly present on the lower legs but also can involve the thighs, buttocks, trunk, and upper extremities.1-10 Individual nodules sometimes ulcerate and discharge a creamy, tan-brown, sterile, viscous substance made up of degenerated lipocytes. Lesions usually resolve with lipoatrophy and hypopigmented and/or hyperpigmented scars.1,2 Additional clinical findings can accompany the skin lesions and relate to lipocyte degeneration in other organs. Periarticular lipocyte degeneration results in a secondary acute arthritis that most frequently involves the ankles and may be migratory, intermittent, or persistent. Other joints subsequently or concurrently may be involved, including the knees, metacarpals, wrists, and elbows. Arthritis has been reported in 54% to 88% of cases.1,3 More rarely, submucosal lipocyte degeneration resulting in gastrointestinal tract bleeding can occur.1 Common laboratory abnormalities associated with pancreatic panniculitis include elevated sedimentation rates and lipase and trypsin levels (Table 1). Some cases are associated with eosinophilia and increased amylase.1-8 A differential diagnosis of panniculitides that may resemble pancreatic panniculitis could include erythema nodosum; sclerosing panniculitis (lipodermatosclerosis); α1-antitrypsin deficiency panniculitis; cutaneous polyarteritis nodosa; nodular vasculitis (erythema induratum); lupus panniculitis; and infective, traumatic, and factitial panniculitis (Table 2).2,5,11,12

The landmark article that first linked pancreatic disease with pancreatic panniculitis was published in 1883 by Chiari.13 Disease processes that resulted in pancreatic panniculitis included acute pancreatitis, chronic pancreatitis, pancreatic pseudocysts, pancreatic duct stenosis, abdominal trauma, and pancreatic carcinoma. A case of panniculitis associated with lupus pancreatitis also has been reported.14 Only 0.3% to 3.0% of patients with pancreatic disease develop associated panniculitis.2 Pancreatic carcinoma and pancreatitis are most intimately associated with pancreatic panniculitis.1 Specifically, acinic cell adenocarcinoma is responsible for more than 50% of all cases,4 though only 16% of acinic cell adenocarcinomas present with panniculitis.15 A small number of neuroendocrine carcinomas have been reported in the literature, as well as an isolated case of an intraductal carcinoid tumor in a pancreas divisum.2,9,10 Pancreatitis plays a role in the development of most of the remaining cases.1 Although pancreatic panniculitis only manifests in a small percentage of cases of pancreatic disease, its importance as a clinical sign should be recognized. As in our case, when panniculitis is observed, it is the presenting sign in 40% of cases of underlying pancreatic disease.16 The panniculitis usually precedes the diagnosis of pancreatic disease by an average of 13 weeks, with a reported range between 2 and 28 weeks.1 The characteristic histopathologic features of pancreatic panniculitis were first described by Szymanski and Bluefarb17 in 1961. Early lesions are nonspecific, marked by perivascular lymphocytic infiltrates that lack necrosis and may resemble erythema nodosum.4 In fact, Ball and colleagues18 have suggested that pancreatic panniculitis may begin as a septal panniculitis and only later develop lobular involvement. Biopsies performed on specimens from the nonulcerated, fully developed erythematous nodules reveal both lobular and septal panniculitis highlighted by focal areas of lipocyte degeneration populated by anucleate necrotic adipocytes surrounded by thickened acidophilic cell membranes, termed ghost cells. A unique feature, when present, is the deposition of granular or homogenous basophilic material resulting from the saponification of fat by calcium salts.12 A dense infiltration of lymphocytes, macrophages, neutrophils, and variable numbers of eosinophils exists at the periphery of the necrotic areas along with evidence of calcification. Resolution of the nodules is characterized by a granulomatous infiltrate that replaces the areas of necrotic tissue.1 The presence of numerous eosinophils was a striking feature in our case and has not been emphasized previously in the literature in this form of panniculitis. Although there is no universally accepted mechanism for the development of the skin lesions, a popular hypothesis states that a synergism exists between the elevated serum levels of lipase and trypsin. Trypsin alters the permeability of the tissue blood vessels, which allows lipase to hydrolyze lipids in the adipocyte cell membranes and interior, which leads to lipocyte degeneration of the tissue.16,19 Support for this hypothesis is garnered by the observations that more than 50% of patients with pancreatic portal fistulization develop panniculitis, and immunohistochemical analysis of the areas of lipocyte degeneration demonstrate pancreatic lipase.6,20 Potts and colleagues21 suggested a possible immunologic mechanism in a patient with pancreatic carcinoma and pancreatic panniculitis who was noted to have decreased complement levels and deposition of immunoglobulin G in the pleura. Successful treatment of pancreatic panniculitis usually requires diagnosis and treatment of the underlying pancreatic pathology. As the pancreatic enzyme levels decrease, the skin lesions usually tend to regress.3 There has been some success reported with the administration of octreotide acetate, a synthetic polypeptide that inhibits pancreatic enzyme production.1,2,4,6 In addition, general supportive measures, including rest, elevation of the legs, compression stockings, and nonsteroidal anti-inflammatory drugs, may be helpful.

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Basal cell carcinoma (BCC) is the most common of all malignant neoplasms; approximately 1 million new cases occur annually in the United States, with increasing incidence.¹ Although BCC is locally invasive, the occurrence of BCC metastasis is exceedingly rare, with an average rate of approximately 0.03%,² typically involving a large, long-standing, locally destructive, recalcitrant tumor of the head or neck.³ BCC metastasis is rare because of the early recognition of the disease, current treatment, and the noninvasive character of the tumor. In the event of metastatic spread, the most commonly involved sites (in descending order of frequency) include regional lymph nodes, the lungs, and bone, but also may involve the pleura and abdominal viscera.⁴ Criteria used to establish the diagnosis of metastatic BCC were put forth in 1951 by Lattes and Kessler⁵ and include: (1) the neoplasm must originate from skin, not mucous membranes; (2) direct invasion of the neoplasm to the presumed metastatic site must be ruled out; and (3) primary and metastatic lesions must show identical histologic features consistent with BCC.

Bone is involved in approximately 20% to 30% of metastatic BCCs.^3,6 In addition to the above guidelines, other objective findings in BCC metastatic to bone have been reported in the literature, such as increased skeletal uptake on bone scintigraphy, elevated serum levels of alkaline phosphatase, and radiographic imaging studies that demonstrate lytic bone lesions.⁷ We report a case of BCC with probable extensive metastases to the axial skeleton above the pelvis. Results of a physical examination, as well as x-ray and bone scintigraphy findings, were consistent with extensive skeletal involvement by metastatic tumor. Histologic confirmation of bone metastasis was not possible due to the patient's family's refusal of a postmortem biopsy of the bone specimen.

Case Report

A 56-year-old white male veteran presented to a Midwestern United States veterans affairs medical center with 2 prominent skin lesions of unknown duration. The patient stated that the lesions began as small boils on his upper back and right arm many years ago and subsequently enlarged. He had not been seen by a physician for many years. Results of a physical examination revealed the patient was a cachectic man in no apparent distress; he had no fever and his vital signs were within reference range. His skin examination revealed an extensive, ulcerated, weeping lesion with rolled borders on his upper back extending to the posterior neck, and another similar lesion on his right arm. The lesion on his back measured 26X15 cm, and the lesion on his arm measured 12X6 cm (Figure 1). No mucous membrane involvement was noted. Biopsies of skin specimens were obtained from both lesions for histologic diagnosis, which confirmed the presence of BCC (Figure 2). Because of the lesions' proximity to bone, bone radiographs were performed on the patient's chest, bilateral shoulders, and right arm, revealing punched-out lytic bone lesions in the ribs, left clavicle, scapulae, and right humerus (Figure 3A). Next, a bone scintigraphy scan was performed to survey the extent of disease, revealing a "superscan," with increased bony uptake in most of the axial skeleton above the pelvis along with other discrete areas of increased uptake in the upper extremities (Figure 3B). Additional laboratory data were not available. The patient was admitted to the medical center for improvement of his nutritional status and for the management of his skin lesions. On the seventh day of hospitalization, the patient unexpectedly died, and his family refused an autopsy.

Please refer to the PDF to view the figures

Comment

The first case of BCC metastatic to a submandibular lymph node was reported by Beadles⁸ in 1894. Few cases have been described in the literature since then, and rates of metastasis have been reported to be from 0.0028% to 0.4%, depending on the study protocol used.⁹ Although histologic confirmation of bone involvement is lacking, in the absence of other detectable malignancies, our objective clinical and radiographic findings point toward bone metastasis in our patient. A review of several case reports of BCC metastatic to bone demonstrates clinical and radiographic similarities with those of our patient (Table).

Please refer to the PDF to view the table

In contrast to nonmetastatic BCC, the age of onset of metastatic lesions is approximately 45 to 59 years, with an interval of approximately 9 to 11 years between primary tumor onset and spread.¹ However, cases of metastasis have been reported after latency periods of up to 23,²⁰ 26,²¹ and even 45³ years following diagnosis of primary lesions. Men are more often affected, and tumors generally are large, long-standing, and refractory to treatment.³ No significantly different histologic characteristics in metastatic tumors were identified by Wermuth and Fajardo²²; however, other authors have concluded that metatypical BCC, or BCC with foci of squamous differentiation, demonstrates more aggressive behavior and increased potential to metastasize.^9-11,16,19 Factors noted to be associated with an increased incidence of metastasis include long duration of a large primary lesion on the head or neck,²³ recalcitrance to treatment,¹ immunodeficiency combined with stromal independence of the tumor,²⁴ inadequate excision followed by immediate wound closure,²⁵ and lesion depth.²⁶ Farmer and Helwig¹⁶ noted a paucity of inflammatory cells in the vicinity of recurrent tumors, implicating the possibility of a defective cellular immune response as a contributing factor. Our patient's evolving history, however, was unclear due to his inability to provide an accurate account.

Total excision of primary tumors following recommended treatment guidelines does not tend to halt metastatic spread,⁴ and prior to discovery of metastases, lesions generally tend to recur locally following excision and/or radiation therapy.^1,4,9 Approximately equal rates of hematogenous and lymphatic spread are observed, and the lung is the most likely distant organ to be involved, followed by bone, liver, and pleura.³ Cases of bone metastasis may present with symptoms of spinal cord compression⁶ or anemia,¹⁵ as well as bone pain¹⁷ and pathologic fractures,^7,15 and tend to involve the lumbar spine more frequently than the thoracic and cervical regions.¹⁰ Our patient did not complain of any such symptoms indicative of osseous lesions, even with extensive bony involvement.

von Domarus and Stevens³ noted a slightly better survival rate among patients with lymphatic metastases versus those patients whose tumors disseminated hematogenously. Patients with metastatic BCC have a 5-year survival rate of approximately 10%; patients with distant spread typically survive only 10 to 14 months.¹ Prognosis is especially poor with metastases to the lungs, bone, or liver,^12,16 and palliative treatment generally is used in these cases.

Aggressive treatment should be pursued if BCC metastasis has been detected. Unfortunately, once distant metastasis occurs, cure is not possible and survival generally is short.¹² Excision of the primary lesion with free margins is the initial objective, but it may not always be possible due to the size or extent of the tumor. Therapeutic options for bone metastases include chemotherapy with agents such as cyclophosphamide, etoposide, fluorouracil, methotrexate, cisplatin, bleomycin, and doxorubicin.¹¹ Radiation therapy is an effective palliative treatment, but its use has not demonstrated increased survival benefit.¹² Laminectomy has been used for vertebral involvement.^10,12 Because of the rare nature of metastatic BCC, appropriate treatment protocols have not been formulated, and combination therapy with the above modalities generally is employed. Nevertheless, therapeutic response to treatment usually is poor. Because of our patient's untimely death, no treatment options were sought. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective. 

Case Report

An otherwise healthy 54-year-old woman presented with a 6-month history of multiple asymptomatic papules on her nose. The patient's past medical history included hypertension and hyperlipidemia. Her medications included atenolol, hydrochlorothiazide, and gemfibrozil. She denied prior infection suggestive of Borrelia species or molluscum contagiosum. Results of a physical examination revealed 4 firm, skin-colored to pink, dome-shaped papules on the right nasal ala (Figure 1) and dorsum. A shave biopsy of a lesion on the right nasal ala was performed. Results of a routine histologic evaluation revealed a diffuse basophilic infiltrate in the dermis (Figure 2). The infiltrate consisted of polyclonal B and T cells (Figure 3). The B cells were CD20+ and T cells were CD4+ and CD8+. In addition, there was a mixed expression of κ and λ chains within the infiltrate. The patient was diagnosed with cutaneous lymphoid hyperplasia (CLH).

Please refer to the PDF to view the figures

For cosmetic reasons, numerous treatment modalities were attempted. The lesions initially were treated with a variety of topical steroids and immunomodulators, with minimal success. In addition, cryotherapy and intralesional steroids were used, with some short-lived response. However, the treated lesions never completely regressed and returned to their pretreatment size within 10 to 14 days after therapy. The lesions did respond well to shave removal, but the patient's personal fear of needles prevented her from continuing this treatment option. She subsequently was lost to follow-up.

Comment

The term cutaneous lymphoid hyperplasia was coined by Caro and Helwig¹ in 1969. The disease also has been called lymphadenosis benigna cutis, Spiegler-Fendt pseudolymphoma, lymphocytoma cutis, and cutaneous lymphoplasia.² Although the pathogenesis of CLH remains unknown and most cases are idiopathic, certain drugs and long-term antigenic stimulation are implicated in many cases.³ Anticonvulsant medications (ie, phenytoin, phenobarbital, carbamazepine, sodium valproate) appear to be the most common pharmaceutical agents to cause CLH. Losartan, gemcitabine, bromocriptine, fluoxetine, amitriptyline, and injected silicone also have been associated with this disease.^4-8 Rarely, infectious agents such as Borrelia species and molluscum contagiosum have been linked with CLH.^9-11 Additionally, CLH has occurred following exposure to various foreign antigens, including tattoos, trauma, body piercing jewelry, cobalt, leeches, and arthropod bites and stings.^9,12-14 Appearance of multiple lesions has been reported following injection of allergen for hyposensitization.^15,16 May et al³ described CLH localized to the site of influenza vaccination.

CLH is seen in both adults and pediatric patients and is 2 to 3 times more likely to occur in females.⁹ Morphologically, CLH appears as clusters of firm pink-colored to plum-colored papules, plaques, nodules, or tumors that occur on any skin surface but most commonly on the face. Although patients usually are asymptomatic, many seek treatment for cosmesis. CLH can be associated with regional lymphadenopathy, though most cases are not associated with other physical findings. The clinical differential diagnosis includes cutaneous lymphomas.^10,17

On histologic examination, lesions of CLH may display multiple lymphoid follicles and dense superficial to deep infiltration of mostly mature lymphocytes.^2,9 Lymphocytes often are admixed with histiocytes and occasional eosinophils and plasma cells.1 Germinal centers with tingible body macrophages often are apparent.^9,10,18 Because these features also may be seen in lymphomas, determination of polyclonality by immunophenotyping with either polymerase chain reaction or other techniques is helpful in the evaluation of CLH. Lesions of CLH may consist of an infiltrate that mostly consists of mixed CD4⁺ and CD8⁺ T lymphocytes in the periphery, with B lymphocytes predominating within germinal centers. Mixed expression of κ and λ chains also has been suggested as a marker for CLH because most lymphomas demonstrate restricted expression of κ or λ chains.^3,10 Despite the general rule of polyclonality with CLH and monoclonality with lymphomas, there have been reports of CLH in the presence of a monoclonal lymphocyte population and clinically malignant cutaneous B-cell lymphomas without evidence of monoclonality.^9,19

Although the characteristic lymphocytic proliferation appears to be reactive and polyclonal, the literature suggests that some cases of CLH have the potential to become malignant.^9,20 A study by Nihal et al⁹ identified several cases of CLH that harbored monoclonal B-cell populations that eventually progressed to overt lymphomas. During follow-up of these patients, polymerase chain reaction analysis of their lymphomas revealed malignant lymphocytes from the same cell lineage noted in the original CLH lesion. Although the molecular pathogenesis of B-cell proliferations in CLH is poorly understood, recent literature has shown that a B-cell chemoattractant, BCA-1 (B-cell attracting chemokine 1), and its receptor, CXCR5 (chemokine receptor 5), are expressed by lymphocytes in moderate quantities in lesions of CLH.²⁰ The same lesions also have shown expression of BCA-1 on dendritic cells within lymphoid follicles. Low-grade and high-grade B-cell lymphomas also express both BCA-1 and its receptor, but expression is restricted to neoplastic B cells.²⁰ Neither BCA-1 nor CXCR5 are expressed in healthy skin.

Lesions of CLH often regress spontaneously, though some cases become chronic and others recur locally.¹⁹ Rarely, some lesions progress to cutaneous lymphoma. However, it is uncertain if this represents true progression of a benign lesion along a continuum leading to lymphoma or a failure to diagnose a lesion that was malignant from the start.^2,9,21

For CLH that results from known stimuli, the first step in treatment is removal of the causative agent. Antibiotic therapy has been effective in cases related to infective causes.^10,18 Reported therapies for persistent or idiopathic cases include topical or intralesional corticosteroids, cryosurgery, local radiation, excision, interferon alfa, and laser ablation.^19,22,23 Good response to thalidomide has been documented in one small study.²⁴ 

Conclusion

CLH is a benign lymphoid proliferation resulting from various antigenic stimuli and may have the potential for progression to overt lymphoma. Lesions may closely resemble lymphoma both clinically and histologically, highlighting the importance of immunophenotyping in establishing a diagnosis. Treatment of this benign disease entity needs to be individualized for each patient. Although there are numerous treatment options for CLH, none are consistently effective.