Calciphylaxis: An Unusual and Silent Usher for an Underlying Carcinoma

Calciphylaxis is an uncommon but serious and potentially life-threatening painful condition that is characterized by cutaneous vascular calcification and ischemia. It is typically seen in patients with end-stage renal disease but has been known to occur less commonly in patients with normal renal function. A rare but established etiology of non-uremic calciphylaxis is malignancy. We have thus far been successful in documenting an association between calciphylaxis and certain solid tumor types. The objective of this clinical case study is to better define a possible association between calciphylaxis and underlying malignancy.


Introduction
Calciphylaxis is an uncommon condition characterized by microvascular calcification and thrombosis, which subsequently leads to cutaneous tissue necrosis [1].Calciphylaxis has been long since established as a complication of end-stage renal disease (ESRD), especially in patients on dialysis.It has been thought that the predisposition in renal disease patients is because there is severe dysregulation of calcium-phosphate metabolism due to the ubiquitous nature of mineral bone abnormalities along with the use of procalcification treatments such as calcium salts in patients with kidney disease [2].However, over the years, calciphylaxis has presented in patients with normal kidney function, such as autoimmune conditions [3], POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome [4], and most recently coronavirus disease 2019 (COVID-19) [5] and rarely in some underlying malignancies [6,7].We present a case of calciphylaxis without any familiar risk factors, and we describe how his cutaneous presentation eventually led us to find an underlying hepatocellular carcinoma.

Case Presentation
A 65-year-old gentleman with a past medical history significant for liver cirrhosis secondary to chronic alcohol use, depression, and generalized anxiety disorder presented to the hospital with complaints of worsening bilateral lower limb discoloration which was associated with swelling, pain, and small ulcers.He reported that these symptoms began two months prior to presentation and denied any trauma, insect bite, change in food habits, or exposure to sick individuals preceding the development of symptoms.He reported about a 15-pound unintentional weight loss over a span of eight months.He denied any history of fevers, rash, or ulcers on other parts of the body, joint pain, abdominal pain, and easy bruising.Pertinent social history included daily consumption of three to four glasses of alcohol and a remote history of intravenous (IV) drug use.He also reported using over-the-counter cream for lower limb discoloration with no significant improvement.His other routine medications were quetiapine, mirtazapine, and citalopram, but he was noted to be non-compliant.At the time of presentation, he noted immense pain in both legs which was significantly limiting his ambulation.
On physical examination, his vitals were stable, but he appeared emaciated.He was found to have violaceous discoloration of both legs extending 4-6 inches above his ankles (Figure 1).There were also minor areas of scaling and ulceration with no associated discharge.The affected areas were exquisitely tender but had no appreciable warmth on palpation.The rest of his physical exam was grossly unremarkable.On initial laboratory evaluation, his complete blood count, basic metabolic panel, and urine analysis were normal.ESR was mildly elevated at 16 mm/hr with a normal C-reactive protein (CRP) of 4.61.Calcium was noted to be 8.5 mg/dL and phosphorus 3 mg/dL.His Liver function tests were deranged with total bilirubin elevated at 2.6 mg/dL, direct bilirubin at 0.8 mg/dL, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) elevated to 88 U/L and 69 U/L respectively, albumin 3.0 g/dL, and INR 1.2.Infectious diseases work up for Anaplasma, Babesia, Ehrlichia, Hepatitis panel, and HIV were negative.Autoimmune work up including antinuclear antibody, anti-cytoplasmic antibody, and complement levels were normal.Testing for nutritional deficiencies of zinc, niacin, and pyridoxine was non-contributory.Bilateral lower limb venous duplex did not reveal any deep vein thrombosis.Based on our testing and examination we were able to successfully rule out cellulitis, erythroderma, tick-borne conditions, deep vein thrombosis, and vasculitis.

FIGURE 1: Calciphylaxis of the lower extremity involving the feet and extending above the ankle
With an initial suspicion of vasculitis, a short course of oral prednisone along with topical betamethasone was tried with no improvement.For his persistent pain, he was given ibuprofen with adequate response.For further management, a punch biopsy of the affected skin was obtained (Figure 2).A Von Kossa staining was performed which showed subcutaneous fat necrosis, and hemorrhage with perivascular calcification, consistent with calciphylaxis (Figure 3).

FIGURE 3: Stippled calcification highlighted on special staining of Von Kossa
Due to the history of weight loss and liver cirrhosis, we obtained an abdominal CT that showed a 3.8 cm right hepatic lobe mass, and due to suspicion of hepatocellular carcinoma (HCC), an MRI with contrast was obtained.MRI revealed findings highly suggestive of hepatocellular carcinoma, with splenomegaly and lymphadenopathy in the porta and celiac regions (Figure 4).Unfortunately, after discussing the imaging findings with the patient, he denied further investigations and opted out of further treatment.

Discussion
Calciphylaxis is a serious medical condition with an insidious onset, with a male-to-female ratio of incidence being 12:1, and commonly affects the skin of the legs, followed by toes, fingers, abdomen, buttocks, and penis [8].It has been frequently associated with end-stage renal disease; however, there have been sporadic cases of non-uremic calciphylaxis.A systemic review in 2008, described 36 cases of nonuremic calciphylaxis, out of which eight cases were reported malignancies such as metastatic breast cancer, cholangiocarcinoma, osteosclerotic myeloma, malignant melanoma, and chronic myelomonocytic leukemia [9].
Our patient had no significant past medical history preceding this presentation apart from alcoholic cirrhosis and mood disorders for which he was non-compliant with medications.The drugs that have been identified to cause calciphylaxis are calcium supplements, calcium-based phosphate binders, vitamin D, warfarin, parenteral iron, corticosteroids, and trauma from subcutaneous administration of heparin and insulin [10][11][12].Thus, there was no identifiable risk factor at the time that could have predisposed him to develop calciphylaxis apart from the newly diagnosed hepatic malignancy.To our knowledge, there have been no such cases of calciphylaxis reported thus far.
Although MRI is currently the second-line imaging modality to diagnose hepatocellular carcinoma (HCC), it boasts an impressive sensitivity of 84.4% and a specificity of 93.8% for diagnosing HCC, based on 34 prior studies involving 4841 participants [13].Moreover, MRI is the gold standard imaging modality to identify HCC and is effective in differentiating neoplasm from benign lesions.Extracellular contrast agent MRI has been accepted as a diagnostic modality for liver transplantation without tissue biopsy in clinical practice for HCC less than 2 cm [14].
Calciphylaxis is typically a tissue diagnosis and histopathological findings include calcification, microthrombi, and fibro-intimal hyperplasia of dermal and subcutaneous arteries and arterioles with subsequent ischemia and septal panniculitis [2].Currently, it has been accepted that in vascular calcification, pathogenesis begins with the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes [15].This occurs via a complex interaction between the vascular smooth muscle cells with uremic toxins and reactive oxygen species, coupled with a decrease in matrix G1a protein (MGP), a potent inhibitor of calcification [16].It has been established that there is an increase in reactive oxygen species in almost all cancer types [17] and it has also been found that there is a reduced expression of matrix G1a protein messenger RNA in malignancy [18].In addition to vascular calcification and subintimal fibrosis, the role of hypercoagulability is integral in the pathogenesis of calciphylaxis, demonstrated by findings of thrombosis in histopathology [11].Inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 are known to decrease the anti-thrombotic receptor expression of thrombomodulin, protein C/S, and vascular heparin-like molecules, thus promoting thrombosis [19].
Neutrophil extracellular traps, which are externalized decondensed chromatin from the azurophilic granules have also been implicated in sterile inflammation leading to thrombosis in malignant and autoimmune conditions [20].
Unfortunately, there is no approved therapy for the management of calciphylaxis with treatment being primarily focused on preventing complications and symptom control.Pain should be adequately managed and disruptions in the skin should be promptly managed with appropriate wound care and if necessary, antibiotics.Several experimental options such as hyperbaric oxygen, bisphosphonates, vitamin K, and lowdose tissue plasminogen activators are being studied with variable results [21].Sodium thiosulphate has been found to be beneficial in managing both uremic and nonuremic calciphylaxis [22].

Conclusions
Besides the potentially lethal prognosis of the underlying malignancies that cause calciphylaxis, the added complications of calciphylaxis, such as superinfection leading to sepsis, are potentially fatal.In conclusion, calciphylaxis should be considered as a differential in patients having risk factors for malignancy along with typical symptom spectrum who present with a painful, non-healing cutaneous condition.Also, in the appropriate clinical setting, it is important to screen for cancers in patients diagnosed with calciphylaxis.
info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 2 :
FIGURE 2: Punch biopsy of the skin of the lower extremityFrom left to right in the image, are demonstrated fat necrosis, haemorrhage, and chronic inflammatory changes.

FIGURE 4 :
FIGURE 4: Contrast imaging MRI MRI images demonstrate a mass highly suspicious for hepatocellular carcinoma in the right hepatic lobe.Moving from left to right are the images of three post-contrast phases: arterial phase, portal phase, and vasculo-Kupffer phase.