When Benign Becomes Cancer: Malignant Degeneration of Chronic Inflammation

Abstract

Chronic inflammation, long implicated in the genesis of malignancy, is now understood to underlie an estimated 25% of all cancers. The most pertinent malignancies, to the plastic surgeon, associated with the degeneration of chronic inflammation include Marjolin's ulcer, breast implant-associated large cell lymphoma, radiation-induced sarcoma, and Kaposi's sarcoma. The cellular and genetic damage incurred by a prolonged inflammatory reaction is controlled by an increasingly understood cytokinetic system. Advances in understanding the chronic inflammatory cascade have yielded new therapeutics and therapeutic targets.

Inflammation has been implicated in the genesis of certain neoplasms since at least the nineteenth century, when Rudolf Virchow postulated in 1863 that “lymphoreticular infiltrate” was the origin of cancer in sites of chronic inflammation. ¹ It is now estimated that 25% of all cancers are caused by chronic inflammation, such gastric and hepatocellular carcinomas caused by Helicobacter pylori and hepatitis A and C infections, respectively. ² The chronic inflammatory response is mediated by proinflammatory signaling molecules and cytokines, largely secreted by helper T cells and macrophages. ³ T cell predominant inflammation is a positive prognosticator whereas macrophage predominant inflammation portends a poorer prognosis. ^{4 5} Chiefly implicated in this inflammatory process are the interleukins (ILs)—cytokines secreted by leukocytes that act directly on other leukocytes to trigger activation in response to physiologic stressors. ⁶ Reactive oxygen species generated by the immune response cause an accumulation of deoxyribonucleic acid (DNA) damage and predispose malignant degeneration. ³ This review article will focus on clinically relevant malignancies to the plastic surgeon that are associated with chronic inflammation and the physiologic basis for their degeneration and treatment.

Marjolin's Ulcer

In 1828, Jean Nicholas Marjolin first described an ulcerated lesion with dense villi originating in a burn scar. ⁷ Marjolin's ulcer is a highly aggressive squamous cell carcinoma (SCC) arising in a chronic wound. Commonly associated with burn injury, Marjolin's ulcer may also arise secondary to other chronic inflammatory processes, such as local trauma, venous insufficiency ulcers, pressure ulcers, and osteomyelitis. ^{8 9} These lesions can occur in nearly any anatomic location, but most frequently occur in the lower (53.3%) or upper (18.7%) extremity and occasionally on the scalp or neck. ^{9 10 11} Marjolin's ulcer associated with a burn injury, while the most common malignancy associated with burn scars at an incidence of 0.7 to 2%, is only part of the differential diagnosis for burn scar carcinoma. ^{7 12 13 14 15 16} A meta-analysis by Kowal-Vern and Criswell reviewed 412 cases of skin burns from 126 sources and found that 71% of cases represented SCC, 12% were basal cell carcinoma, 6% melanoma, 5% sarcoma, and 4% other neoplasms. ¹⁷

Diagnosis is based on a combination of patient history, clinical exam, and laboratory findings. The average age of diagnosis is during the fifth decade of life after an average latency period of 30 to 35 years. ¹⁰ Men are three times more likely than women to develop a lesion. ^{10 11} On clinical exam, the classic triad to look for is nodule formation, induration, and ulceration at the wound site. ¹⁸ Biopsy and histopathological confirmation are the gold standards for diagnosis. ¹¹ Once diagnosed, chest X-ray, brain computed tomography (CT), and abdominal ultrasound are the modalities of choice to check for distant metastases. ¹¹

Marjolin's ulcers are aggressive and have high rates of recurrence even when margins are clear. ^{8 11 19 20 21} Despite no definitive treatment protocol, treatment usually includes excision of the lesion with 2 cm margins or Moh's resection if more cosmetically sensitive. ^{11 13 22 23} Amputation proximal to the lesion is sometimes required for advanced-stage disease when wide local excision is not adequate or the tumor is determined to be unresectable. ^{13 22} Radiation therapy and chemotherapy are both reported either as adjuvant agents or in situations where surgical resection is not possible. ^{11 15 22 24}

Breast Implant-Associated Anaplastic Large Cell Lymphoma

First reported in 1997, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) was recognized by the World Health Organization as a novel lymphoma in 2016. ^{25 26} It is a very rare lymphoma with a total of 733 cases and 36 mortalities reported worldwide, as of January 2020. ²⁷ The inciting factor is believed to be increased inflammatory response resulting from microtexturing of breast implants and no cases have been identified in which a textured implant or tissue expander was not implicated. ^{28 29 30 31} While the most commonly implicated prosthetic was associated at a rate of less than 0.03%, ³² the risk of ALCL in women with textured implants is 67.6 times greater compared with primary ALCL in the general population. ²⁹ Doren et al analyzed 100 cases of BIA-ALCL in the U.S. from 1996 to 2015 and found the lifetime prevalence to be 1 in 30,000 for women with textured implants. ²⁹

The median interval from breast implant placement to diagnosis varied from 8 to 12 years with a range of 1 to 39 years. ^{28 29 30 31 33} The most common presenting symptoms are a late seroma or a palpable mass, with one or the other present in 96% of all identified cases. ^{28 31 33 34 35} Some less common clinical findings are regional lymphadenopathy, pain, cutaneous lesions, capsular contracture, erythema, and B symptoms. ^{28 31 33 35} Ultrasound or magnetic resonance imaging are recommended as the first line of evaluation, with fine-needle aspiration sampling of the fluid or mass biopsy performed for confirmation. ²⁶ Subsequent staging with positron emission tomography/CT scan is the preferred modality. ³⁶

The mainstay of BIA-ALCL treatment is complete capsulectomy and removal of implants. ³³ If nodal disease is present, nodes should also be removed. ³⁶ The majority of patients undergo chemotherapy; most commonly with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisolone). ²⁸ Immunotherapy with brentuximab vedotin is gaining popularity. ³⁶ Radiation is indicated for residual local disease, positive margins, or unresectable malignancy and is utilized in approximately 50% of the cases. ^{28 36} The prognosis is good with 89% overall survival at 5 years and a median survival of 12 years. ^{28 33} Five-year survival drops to 75% if lymph nodes are involved. ³¹

Radiation-Induced Sarcoma

Approximately 50% of cancer patients receive radiation therapy as part of their treatment protocol. ³⁷ These individuals are at risk of the carcinogenic effects of ionizing radiation, such as developing secondary malignancies. ³⁷ Radiation-induced sarcoma (RIS), first reported in the early 1920s, ³⁸ is a rare, late complication of radiotherapy that can arise at any previously irradiated site of mesenchymal origin. However, breast cancer patients have a higher risk of developing RIS than any other primary solid cancer site, at 0.48% at 15 years. ^{39 40 41} Moreover, incidence rates are increasing, likely due to the improved prognosis after breast cancer diagnosis. ^{41 42}

Workup is generally started based on a history of radiation therapy and physical exam findings of skin discoloration, elevation, and thickening. ⁴² The latency period for development of RIS of the breast is typically approximately 10 years, with a range of 3 to 20 years. ^{43 44} It is unclear whether dose of radiation is an independent risk factor. ^{39 45 46 47 48} A biopsy with preservation of cellular architecture is required for diagnosis. The biopsy must be consistent with a sarcoma and be of a different histology than the primary malignancy. ⁴⁹

Of those with RIS, 73% were diagnosed with already a high-grade malignancy. ⁵⁰ Surgical excision with wide negative margins is the standard of care. ^{41 42} The role of adjuvant and neoadjuvant chemotherapy remains uncertain. ^{41 42 50 51} Since the location is a previously irradiated field, most physicians are reluctant to use radiotherapy again due to concerns of toxicity. ⁵¹ Prognosis is poor with 5-year survival rates ranging from 27 to 48% and recurrence rates of 50 to 68%. ^{40 50 52 53 54 55} Despite the aggressiveness and poor prognosis of RIS, patients who undergo surgery have been shown to have improved survival. ^{50 51}

Kaposi's Sarcoma

Moritz Kaposi first described cases of multifocal pigmented lesions on the skin of elderly men in 1872. ⁵⁶ Kaposi's sarcoma (KS) is now commonly recognized as an acquired immunodeficiency syndrome (AIDS)-defining malignancy. Between 2008 and 2016 in the U.S., the age-adjusted KS rate for persons with human immunodeficiency virus (HIV) was 116/100,000. ⁵⁷ Rates have been found to be greater in men, younger age groups, and among individuals of Caucasian descent. ⁵⁷ However, KS can occur in other at-risk populations such as elderly men, sub-Saharan Africans, and transplant recipients. In the U.S., patients with AIDS have 500× relative risk and solid-organ transplant recipients have 200× greater relative risk than the general population. ⁵⁸ The disease is associated with human herpes virus 8 (HHV-8) and manifests in all populations with essentially identical histopathology. ⁵⁹

KS manifests as cutaneous lesions that are multiple, pigmented, raised or flat, painless, and do not blanch. ⁶⁰ Early lesions are often asymptomatic and present as flat red macules or patches composed of inflammatory infiltrate. ^{60 61} These develop into plaques and spindle cells increase in quantity. In advanced stage disease, spindle cell growth will form macroscopically visible nodules. ⁶¹ KS is often a clinical diagnosis based on appearance of the lesion, but this should be confirmed with histology from a biopsy. Hematoxylin and eosin is commonly used to look for features such as vascular proliferation in the dermis, spindle cell proliferation, extravasated red blood cells, and hemosiderin in macrophages. ⁶⁰

Initial treatment for KS is increasing the patient's immune competence via antiretroviral therapy or altering the immunosuppressive regimen, for HIV-associated and transplant-associated cases, respectively. ⁶⁰ Advanced-stage KS indicates chemotherapy with pegylated liposomal doxorubicin. ⁶⁰ This regimen is more efficacious and less toxic than the ABV (bleomycin, vincristine, doxorubicin) regimen used in the past. ^{62 63} Paclitaxel is an acceptable alternative in resource-limited settings, with similar disease response rate and outcomes but increased toxicity. ⁶⁴ Immunotherapy agents have shown promise in clinical trials but currently available immunomodulatory agents, such as vascular endothelial growth factor (VEGF)-neutralizing antibodies (bevacizumab) and receptor tyrosine kinase inhibitors (imatinib), have limited efficacy as single agent therapies. ⁶⁵

Common Pathways of Chronic Inflammation and Potential Therapeutics

Chronic irritation and repeated reepithelization associated with chronic insult cause cellular atypia, increase mitotic activity, and stimulate cell proliferation. ⁷ Chronic inflammation includes the activation of multiple pathways to eliminate the source of the inflammation and, as a side effect, causes damage to cellular DNA. This chronic stimulation can cause malignant changes in cells. Mutations in various genes, such as p53 and Fas, that are responsible for cell division and apoptosis have been implicated in the malignant degeneration of chronic inflammatory lesions. ^{66 67} A variety of cell lines are implicated in this process and their functions and malfunctions contribute to carcinogenesis.

Monocytes and tissue resident macrophages are drawn to the neoplasm by inflammatory cytokines—CCL2, CCL5, C5a, colony-stimulating factor 1 (CSF-1), VEGF, and IL-34 and CSF-1 and IL-34, respectively. ⁴ These tumor-associated macrophages (TAMs), while they have the potential to kill tumor cells and destroy the local vascular endothelium, contribute to tumor cell division, genetic instability, angiogenesis, extracellular matrix degradation, and metastasis. ^{4 68} TAMs inhibit the immune response against unregulated growth by secreting prostaglandins and tryptophan derivatives and expressing checkpoint-blockade triggers such as programmed death-ligand 1 (PDL1). ⁴ Even the immunogenic effects of decreased vascularity and weakened epithelium may contribute to carcinogenesis. ⁶⁹ Avascularity of scar tissue associated with Marjolin's ulcers has, for example, been shown to cause lymphocyte immobility and impaired immunosurveillance. ⁷⁰ CSF-1 receptors are expressed exclusively in the monocytic lineage and represent a target for therapeutics, such as humanized monoclonal antibody RG7155 (emactuzumab). ⁷¹

Other tumor-associated cells that serve to clear inflammatory instigators exhibit stunted function in the tumor microenvironment. Tumor-associated dendritic cells are of an immature phenotype and are likely poor at eliciting an effective response against tumor antigens. ⁷² Tumor-infiltrating lymphocytes are predominantly memory T cells. They attract predominantly Th2 cells via secretion of IL-4 and IL-5 and elicit a minimal response from Th1 cells via downregulated interferon-g secretion. The Th2 dominant response is ineffective in the tumor microenvironment. ⁷³ As therapeutic targets, T cell deactivation to abort the chronic inflammatory cascade can be triggered via cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptors. ⁷⁴ Alternatively, T cell exhaustion and tolerance can be stimulated via PDL1. ^{75 76} Neoplasms access these pathways to induce T cell anergy and inhibitors to both CTLA-4 and PDL1 are under investigation as immunomodulatory agents. ^{74 75 76}

ILs play a key role in modulating the immune response. ⁶ IL-13, associated with allergic inflammation and repulsion of foreign bodies, is secreted by BIA-ALCL cell lines. ^{77 78} IL-13 triggers the differentiation of fibroblasts to myofibroblasts and collagen deposition. ⁷⁹ Dupilumab is an IL-13 receptor inhibitor developed for asthma treatment. ⁸⁰ IL-2 and IL-6 exhibit increased expression in BIA-ALCL and promote lymphocyte cell division, suggesting a role in lymphoma development. ⁸¹ IL-6 levels are found to be correlated to HHV-8 viral load as well. ⁸² IL-1β and IL-18 are produced by the interactions of HHV-8 fragments and pattern-recognition receptors and trigger the proinflammatory response. ^{65 83}

DNA suffers structural damage during inflammation from the reactive oxygen species created by myeloperoxidase reaction, resulting in 5-chlorocytosine mutations. ⁸⁴ These lesions are inherently unstable and are more prone to base pair substitutions. ⁸⁴ These point mutations are implicated as a major DNA mutant that links chronic inflammation and cancer. ⁸⁴ It is hypothesized that “sublethal” DNA damage accumulates over time. ⁴¹ Defects in DNA repair mechanisms, such as with the BRCA-1 mutation and other hereditary cancer syndromes, ^{48 85} are known to increase susceptibility to carcinogenesis, such as RIS. ⁴¹

Conclusion

Chronic inflammation is well established as a causative factor in the development of cancer. For the plastic surgeon, Marjolin's ulcer, KS, RIS, and BIA-ALCL are the most relevant degenerative malignancies. As the common pathways of inflammation are further elucidated and the mechanisms better understood, therapeutic targets will avail themselves to intervention—with the potential to abort the chronic inflammatory process and treat the neoplasms if established.