Humoral Hypercalcemia of Malignancy with Elevated Plasma PTHrP,TNFα and IL-6 in Cutaneous Squamous Cell Carcinoma

A case of humoral hypercalcemia of malignancy in cutaneous squamous cell carcinoma is reported. An 82-year-old male underwent surgery for cutaneous squamous cell carcinoma (SCC) of the left hand in 1992. He subsequently developed clouding of consciousness with remarkable hypercalcemia, a high parathyroid hormone related protein (PTHrP) level, and elevated plasma cytokine levels [tumor necrosis factor α (TNFα), interleukin-6 (IL-6)]. Diagnosis of humoral hypercalcemia of malignancy (HHM) was made on the basis of these findings. He died of renal insufficiency due to this hypercalcemia in spite of several replacement therapies and chemotherapies. The PTHrP might have derived from the SCC and have been responsible for the HHM in conjunction with IL-6 and TNFα.     

Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia associated with squamous cell carcinoma.

Paraneoplastic syndromes including leukocytosis, thrombocytosis and hypercalcemia are occasionally seen in patients suffering from progressive malignant disorders. Recent studies have revealed the production of several humoral factors by tumor cells and normal splenic cells of tumor-bearing patients to be the major cause of these reactions. Granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), parathyroid hormone-related peptide, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) have been implicated. We describe a 58-year-old Japanese man with squamous cell carcinoma (SCC) on the left sole, which developed in a deep linear scar after a train crash. He developed pulmonary and lymph node metastases, then leukocytosis (57,110/mm3 with 95% neutrophilia), thrombocytosis (86.3 x 10(4)/mm3), and hypercalcemia (7.0 mEq/1), and finally cachexia, followed by death. Serum G-CSF, IL-1 alpha, IL-1 beta, and TNF-beta were determined; revealing G-CSF and IL-1 beta levels were above the upper limits of their normal ranges at 39.2 pg/ml and 4.63 pg/ml, respectively. It is probable that these humoral factors were partially responsible for the paraneoplastic syndromes induced by the cutaneous SCC with metastasis in the present case.     

New options for the management of hyperparathyroidism after renal transplantation

The persistence and severity of hyperparathyroidism (HPT) post-renal transplantation is relatively frequent and primarily associated with the timing and its magnitude in the pre-transplant period and with the presence of parathyroid adenomas. HPT after renal transplantation is clinically manifested with hypercalcemia, hypophosphatemia, bone pain, fractures, and in more serious cases with cardiovascular calcifications that affect the survival. The primary clinical objective for patients with secondary HPT after renal transplantation is to obtain a level of parathyroid hormone (PTH) adequate to the renal transplanted function and to normalize levels of calcium, phosphorus and vitamin D. In many cases during this period, the development of hypercalcemia and/or hypophosphatemia makes it necessary to take different therapeutic measures. The use of vitamin D or its analogues has been extrapolated from the management of pre-transplant HPT obtaining variable outcomes, although its use is limited by its capacity to produce hypercalcemia. Calcimimetics are drugs that have proven be effective in reducing PTH levels in patients with HPT on dialysis and has been effective in reducing up to 50% PTH levels in moderate to severe HPT in post-renal transplantation.When HPT persists after renal transplantation and does not respond to medical treatment, invasive management by percutaneous ethanol injection therapy of parathyroid glands or parathyroidectomy should be considered. The emergence of new methods for the management of HPT expands the availability of therapeutic tools for transplant patients.     

Primary hyperparathyroidism and cutaneous T-cell lymphoma: fortuitous association?

This is the third report of an association between T-cell cutaneous lymphoma (mycosis fungoides) and primary hyperparathyroidism (adenoma). Some studies support the concept that hyperparathyroidism may have promotional activity for the development of certain malignant tumors. A high risk for successive or concurrent neoplasms has been reported in patients with parathyroid adenomas. Primary hyperparathyroidism in a neoplastic context may be underreported. Patients with tumor-associated hypercalcemia should be evaluated for the possibility of primary hyperparathyroidism.     

Unusual case of calciphylaxis associated with metastatic breast carcinoma

Calciphylaxis is a relatively rare disorder associated with calcification of small- and medium-sized blood vessels, progressive ischemic skin necrosis, and ulcerations. It is usually seen in patients with end-stage renal disease with secondary hyperparathyroidism and is occasionally seen in primary hyperparathyroidism, hypercalcemia of malignancy, and end-stage liver disease. We report an unusual case of calciphylaxis seen in association with metastatic breast carcinoma in the absence of end-stage renal or parathyroid disease. A 73-year-old woman presented with painful leg ulcers. Serum calcium levels and parathormone levels were within normal limits. Skin biopsies from the ulcers revealed small- to medium-sized subcutaneous arteries with calcification of the media. Some of the arteries were narrowed by fibrointimal hyperplasia and fibrin thrombi. Calcification of the subcutaneous fat, fat necrosis, and suppuration were also seen. Calciphylaxis associated with metastatic osteolytic breast carcinoma is rare. Although end stage renal disease with secondary hyperparathyroidism is the most common cause of calciphylaxis, this case demonstrates that less common conditions with normal serum calcium and parathormone levels may also cause it.     

Basal cell carcinoma with pulmonary and lymph node metastasis causing death

BACKGROUND: The incidence of metastatic basal cell carcinoma ranges from 0.003% to 0.55%. The 230 reported cases most often occurred in long-standing recurrent lesions and appeared in regional nodes or the lungs. OBSERVATIONS: The stromal dependence of the tumor provides an explanation for the nonmetastasizing nature of basal cell carcinoma. The dense fibrous stroma of the lymph node in the case of metastatic basal cell carcinoma reported in the present study is similar to other reported cases with metastases to lymph nodes, bone, bone marrow, glands, and subcutaneous tissue. CONCLUSIONS: This metastatic basal cell carcinoma demonstrated lymphatic and hematogenous dissemination to the lungs and lymph nodes. A dense accumulation of microvessels was present at the boundary of the tumor nests and dermal stroma and in the stroma surrounding the tumor in the lymph node.     

Rare syndromes

Dermatologists may also encounter patients presenting with skin lesions that reflect an underlying endocrine disorder not commonly seen in daily practice. Some of these endocrine disorders include glucagonoma, neurofibromatosis type 1, McCune-Albright syndrome, multiple endocrine neoplasia, the Carney complex, carcinoid tumors, and mastocytosis. The clinical syndrome classically associated with glucagonoma includes necrolytic migratory erythema, weight loss, diabetes mellitus, anemia, cheilitis, venous thrombosis, and neuropsychiatric symptoms. The hallmarks of neurofibromatosis type 1 are the multiple café-au-lait spots and associated cutaneous neurofibromas. Other presenting features include freckling, peripheral neurofibromas, Lisch nodules, bone abnormalities, tumors, neurologic abnormalities and hypertension. McCune-Albright syndrome is characterized by café-au-lait spots, polyostotic fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. Multiple endocrine neoplasia type 2A is characterized by medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. In some patients with multiple endocrine neoplasia type 2A, cutaneous lichen amyloidosis may also be present. Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer and pheochromocytoma but not hyperparathyroidism. The syndrome also includes mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas and a marfanoid habitus. Multiple endocrine neoplasia type 1 is an autosomal dominant predisposition to tumors of the parathyroid glands (four-gland hyperplasia), anterior pituitary, and pancreatic islet cells; hence, the mnemonic device of the "3 Ps"; multiple cutaneous lesions (angiofibromas and collagenomas) are frequent in patients with multiple endocrine neoplasia type 1. Carney complex may be viewed as a form of multiple endocrine neoplasia because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (some with Cushing's syndrome), pituitary adenoma, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts. Additional unusual manifestations include psammomatous melanotic schwannoma, breast ductal adenoma, and a rare bone tumor, osteochondromyxoma. Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors; the major manifestations are diarrhea, flushing, bronchospasm, and cardiac valvular lesions. Mast cell diseases include all disorders of mast cell proliferation. These diseases can be limited to the skin, referred to as "cutaneous mastocytosis," or involve extracutaneous tissues, called "systemic mastocytosis." Patients present with urticaria pigmentosa, mastocytoma, or diffuse cutaneous mastocytosis. Systemic involvement may be gastronintestinal, hematologic, neurologic, and skeletal.     

Extensive basal cell carcinoma with probable bone metastasis

Metastasis of basal cell carcinoma (BCC) rarely occurs. Few cases have been reported in the literature; those cases reported generally resulted from chronic, extensive, recurrent lesions on the head or neck. Metastases may involve lymph nodes, the lungs, and bone, as well as abdominal viscera. Once distant metastasis takes place, survival usually is short and palliative treatment is sought. With regard to bone metastases, several case reports have demonstrated similar clinical features indicative of osseous involvement. We present a case report of a patient with an extensive BCC with histologic documentation and probable bone metastasis of BCC. Clinical and radiographic features of this case were consistent with previously reported patients. However, confirmatory postmortem biopsy of the bone specimen was refused by the patient's family.     

Dyskeratosis congenita associated with three malignancies

Dyskeratosis congenita is a rare inheritable disorder characterized by abnormalities of the skin, nails and oral mucosa. Aplastic anaemia resulting from bone marrow hypoplasia is a frequent cause of death. Squamous cell carcinoma developing from leukoplakia and visceral malignancies are other complications of the disease. We report here a case of dyskeratosis congenita in a man who developed three neoplasias of different systems over a period of many years. Squamous cell carcinoma and gastric adenocarcinoma manifested 17 years after the man was diagnosed with Hodgkin's disease.     

Calcitriol-induced hypercalcemia in a patient with granulomatous mycosis fungoides and end-stage renal disease

An 86-year-old man, diagnosed as having mycosis fungoides in May 2008 and treated with repeated radiation therapy, was admitted to our hospital for initiation of hemodialysis due to end-stage renal disease (ESRD) in April 2012. On admission, his corrected serum calcium level was 9.3 mg/dL, and his intact parathyroid hormone level was 121.9 pg/mL (normal range 13.9-78.5 pg/mL), indicating secondary hyperparathyroidism due to ESRD. After starting hemodialysis, urinary volume diminished rapidly. The serum calcium level increased (12.7 mg/dL), and the intact parathyroid hormone level was suppressed (< 5 pg/mL), while the 1,25-dihydroxyvitamin D₃ (calcitriol) level increased (114 pg/mL, normal range: 20.0-60.0 pg/mL) in June 2012. The possibilities of sarcoidosis and tuberculosis were ruled out. Skin biopsies from tumorous lesions revealed a diagnosis of granulomatous mycosis fungoides. The serum soluble interleukin-2 receptor levels and the degrees of skin lesions went in parallel with the increased serum calcium and calcitriol levels. Therefore, the patient was diagnosed as having calcitriol-induced hypercalcemia possibly associated with granulomatous mycosis fungoides. Granulomatous mycosis fungoides is rare, and its association with calcitriol-induced hypercalcemia has not been reported. Careful attention to calcium metabolism is needed in patients with granulomatous mycosis fungoides, especially in patients with ESRD.     

An Aggressive Spindle Cell Squamous Carcinoma Arising in a Patient with Long-standing Erythroderma

Spindle cell squamous carcinoma (SCSC) of the left hand arising in a patient with longstanding erythroderma is reported. Histopathologically, spindle shaped atypical cells were observed neighboring the cells of well differentiated squamous cell carcinoma. These two types of tumor cells, spindle cells and well differentiated cells, were present side by side and merged into each other. The erythroderma had been present for over 20 years, and both clinical and histopathological findings suggested cutaneous T cell lymphoma, but were not diagnostic for mycosis fungoides, Sézary syndrome, or adult T cell lymphoma. Flow cytometry of peripheral blood cells showed a low CD4/CD8 ratio which suggested impaired T cell function. Multiple metastases of SCSC occurred in a short period and the patient died ten months after his first visit to us. The aggressive course of this case was unusual, and may be due to immunological abnormalities associated with the long standing erythroderma with impaired T cell function.     

Hypercalcemia in association with cutaneous squamous cell carcinoma. Occurrence as a late complication of hidradenitis suppurativa

Squamous cell carcinoma of the skin is a rare complication of hidradenitis suppurativa. We treated a case of hidradenitis-associated squamous cel carcinoma with metastases to the inguinal lymph nodes. Hypercalcemia also occurred, possibly in relation to the secretion of a hormonelike substance by the tumor. Chemotherapy with bleomycin sulfate, methotrexate sodium, and cisplatin led to tumor regression and control of the hypercalcemia.     

Laryngeal squamous cell carcinoma with infradiaphragmatic presentation of skin metastases

Distant metastases in squamous cell carcinoma of the larynx have an incidence of 6.5-7.2%, and most commonly involve the lungs, liver and bone. Metastases to the skin are exceedingly rare, with only 30 cases reported in the literature. Skin metastases may represent the first clinical evidence of impending locoregional recurrence, suggest distant metastatic spread, or rarely, be the first sign of 'silent' laryngeal tumour. They are usually considered a poor prognostic sign and most often affect the supradiaphragmatic area, i.e. the head, neck, thorax or upper extremities. Infradiaphragmatic presentation of metastatic laryngeal squamous cell carcinoma is exceptional, with only four cases reported in the literature. Here we present another.     

Mineral and bone disorder after kidney transplantation

After successful kidney transplantation, accumulated waste products and electrolytes are excreted and regulatory hormones return to normal levels. Despite the improvement in mineral metabolites and mineral regulating hormones after kidney transplantation,abnormal bone and mineral metabolism continues to present in most patients. During the first 3 mo, fibroblast growth factor-23(FGF-23) and parathyroid hormone levels decrease rapidly in association with an increase in 1,25-dihydroxyvitamin D production. Renal phosphate excretion resumes and serum calcium, if elevated before, returns toward normal levels. FGF-23 excess during the first 3-12 mo results in exaggerated renal phosphate loss and hypophosphatemia occurs in some patients. After 1 year, FGF-23 and serum phosphate return to normal levels but persistent hyperparathyroidism remains in some patients. The progression of vascular calcification also attenuates. High dose corticosteroid and persistent hyperparathyroidism are the most important factors influencing abnormal bone and mineral metabolism in long-term kidney transplant(KT) recipients. Bone loss occurs at a highest rate during the first 6-12 mo after transplantation. Measurement of bone mineral density is recommended in patients with estimated glomerular filtration rate 30 mL/min. The use of active vitamin D with or without bisphosphonate is effective in preventing early post-transplant bone loss. Steroid withdrawal regimen is also beneficial in preservation of bone mass in long-term. Calcimimetic is an alternative therapy to parathyroidectomy in KT recipients with persistent hyperparathyroidism. If parathyroidectomy is required, subtotal to near total parathyroidectomy is recommended. Performing parathyroidectomy during the waiting period prior to transplantation is also preferred in patients with severe hyperparathyroidism associated with hypercalcemia.     

Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin.

BACKGROUND AND DESIGN--We conducted a prospective roentgenographic survey of patients participating in a randomized, placebo-controlled, multicenter clinical trial that evaluated the effectiveness of chronic, very-low-dose (approximately 0.14 mg/kg per day for 3 years) isotretinoin in preventing the subsequent occurrences of new basal cell carcinoma in patients with previous basal cell carcinoma. To assess potential skeletal changes, a sample of 269 patients from among a total of 981 enrollees were randomly selected for comparative roentgenographic review. Baseline and 36-month roentgenograms of the cervical and thoracic spine of each patient were read side by side by a radiologist, masked to treatment group, who noted both the presence and extent of abnormalities at each vertebral level at baseline and the progression of existing or occurrence of new abnormalities at previously unaffected levels at 36 months. RESULTS--In comparison with the placebo group, significantly more patients in the isotretinoin group exhibited progression of existing hyperostotic abnormalities (40% vs 18%; P less than .001) and new hyperostotic involvement at previously unaffected vertebral levels (8% vs 1%; P = .015). CONCLUSION--Our findings indicate that chronic, very-low-dose isotretinoin can induce hyperostotic axial skeletal changes similar to those reported in patients taking higher doses.     

Subcutaneous fat necrosis of the newborn and associated hypercalcemia: A systematic review of the literature

Subcutaneous fat necrosis of the newborn is an uncommon disorder, and although usually benign, associated hypercalcemia can lead to complications such as failure to thrive and renal failure. Many sources suggest screening for hypercalcemia for 6 months following resolution of skin lesions, but little data are available to support this recommendation. This study examines existing published literature to better guide practitioners regarding screening evaluations of asymptomatic patients with subcutaneous fat necrosis. A systematic review of the literature was conducted using a PubMed English literature search. Data from case reports and case series were collected regarding the presence of hypercalcemia and associated complications, birth history, and age of onset/resolution of skin lesions and laboratory abnormalities. Approximately half (51%) of infants reported had hypercalcemia. Most (77%) developed detectable hypercalcemia within 30 days of skin lesion onset, and 95% developed detectable hypercalcemia within 60 days of skin lesion onset. Hypercalcemia was detected in only 4% of patients > 70 days following onset of skin lesions. Seventy‐six percent had resolution of hypercalcemia within 4 weeks of detection. Hypercalcemia was more prevalent in full‐term vs pre‐term infants (P‐value = 0.054), and higher birthweight was significantly associated with an increased risk of developing hypercalcemia (P‐value = 0.022). Although gestational age trended toward significance, the only statistically significant clinical feature predicting the development of hypercalcemia was higher birthweight. Current recommendations for laboratory monitoring are not evidence‐based, and this study provides interim data to guide practitioners until prospective, randomized controlled trials are conducted.     

Neonatal mastocytosis with pachydermic bullous skin without c-Kit 816 mutation

BACKGROUND: Bullous mastocytosis is an unusual variant of mast cell disease with widespread bullae as the main cutaneous feature induced by mast cell proteases that cause dermoepidermal separation. CASE REPORT: A rare case of diffuse cutaneous bullous mastocytosis with pachydermia and unusually extensive skin folding is described in a 3-week-old girl. The diagnosis was confirmed by immunohistochemistry with Giemsa stain, the naphthol ASD chloroacetate esterase reaction and elevated blood levels for tryptase, histamine in serum and histamine and 1.4-methylimidazol acetic acid in the 24-hour urine. Blood cell count was normal, as were thrombocytosis and leukocytosis. FACS analysis of the bone marrow aspiration material showed 1% mast cells. No c-Kit 816 [Asp-->Val] somatic mutation was found. Systemic involvement of other organs was excluded. DISCUSSION: The prognosis of c-Kit-negative diffuse bullous mastocytosis is not known. Regular blood controls are mandatory, and screening for germ cell ovarian cancer and bone marrow controls should be performed as well.     

Giant Basal Cell Carcinoma Associated with Systemic Amyloidosis

A large basal cell carcinoma, 39 times 26 cm in size, is presented as second in size only to the largest basal cell carcinoma documented (40 times 30 cm), reported by Beck and co-workers (1). A 61-year-old Japanese male visited our clinic with a huge ulcerating tumor on the back. He had hidden the tumor for the previous 30 years. The tumor was histologically confirmed as basal cell carcinoma. The condition was associated with anemia, hypoproteinemia, and dyspnea, and with systemic amyloidosis in the skin, in the lymph nodes, and in the intestinal canal. On admission, the tumor had metastasized to the regional lymph nodes, and, about two years after the first operation, there were metastases to bone and lung, leading to death due to respiratory failure.