|Year : 2019 | Volume
| Issue : 3 | Page : 79-84
Common cutaneous neoplasms in patients with immunodeficiency: A case series
Suhair Al Salihi1, Haider A Mejbel2, Victor G Prieto1, Phyu P Aung1
1 Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
2 Department of Pathology, East Tennessee State University, Johnson City, TN, USA
|Date of Submission||15-Apr-2019|
|Date of Acceptance||24-May-2019|
|Date of Web Publication||29-Jul-2019|
Dr. Phyu P Aung
Department of Pathology, Dermatopathology Section, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Office B3.4620 Houston, TX 77030
Source of Support: None, Conflict of Interest: None
Through humoral and cell-mediated mechanisms, the immune system plays a vital role in protecting every organ system. Disorders of the immune system may result in various cutaneous manifestations, including cutaneous malignancies. In patients with immunodeficiency, the risk of development of malignant cutaneous neoplasms is substantially increased. This increased risk may be due to oncogenic viruses that find a suitable microenvironment for tumorigenesis and cancer development. A subset of cutaneous malignancies that develop in patients with immunodeficiency may show aggressive clinical and biological behavior. Here, we report six cases of highly aggressive and deadly cutaneous neoplasms that arose in patients with a known history of immunodeficiency: two cases of Kaposi sarcoma in patients with immunosuppression due to human immunodeficiency virus infection; a case of Merkel cell carcinoma and a case of squamous cell carcinoma (SCC) in patients receiving immunosuppressive drugs after organ transplant; a case of multiple cutaneous tumors, including invasive melanoma, SCC, and sebaceous carcinoma, in a patient with hypogammaglobulinemia and a history of organ transplant; and a case of basal cell carcinoma and melanoma in situ in a patient with primary immunodeficiency.
Keywords: Cutaneous neoplasm, histophenotypic features, immunodeficiency
|How to cite this article:|
Al Salihi S, Mejbel HA, Prieto VG, Aung PP. Common cutaneous neoplasms in patients with immunodeficiency: A case series. J Immunother Precis Oncol 2019;2:79-84
|How to cite this URL:|
Al Salihi S, Mejbel HA, Prieto VG, Aung PP. Common cutaneous neoplasms in patients with immunodeficiency: A case series. J Immunother Precis Oncol [serial online] 2019 [cited 2019 Sep 19];2:79-84. Available from: http://www.jipoonline.org/text.asp?2019/2/3/79/263591
Suhair Al Salihi, Haider A Mejbel : These two authors contributed equally
| Introduction|| |
Cutaneous neoplasms are the most common type of malignancy in humans. The patient's immune status plays an important role in the pathogenesis and progression of malignant cutaneous tumors and their response to immunotherapy., Both melanocytic and nonmelanocytic cutaneous neoplasms have an increased incidence in patients with immunodeficiency. Although the relationship between immunodeficiency and increased risk of skin cancer development is well established, the exact causes of this relationship remain unclear. Certain oncogenic microorganisms and immunosuppressive medications may constitute the missing link between immunodeficiency and the development of several cutaneous neoplasms.
In this report, we describe six cases of cutaneous malignancies arising in patients with a known history of immunodeficiency: two cases in patients with immunosuppression due to human immunodeficiency virus (HIV) infection, two in patients who were receiving immunosuppressive drugs after organ transplant, and two in patients with primary immunodeficiency.
| Case Reports|| |
A 42-year-old male with a complex medical history including AIDS, cytomegalovirus infection, and hepatitis C virus infection presented with multiple enlarged right axillary lymph nodes. The patient was receiving highly active antiretroviral therapy (HAART) for the treatment of the HIV infection. A lymph node biopsy showed a preserved lymph node architecture with marked follicular hyperplasia, increased tingible-body macrophages, and numerous plasma cells in the paracortex. A diagnosis of mixed-type Castleman disease was rendered. Physical examination revealed a small (0.5 cm) erythematous papule on the left calf. Biopsy of this lesion showed a poorly circumscribed vascular lesion composed of fascicles of spindle cells with slit-like spaces, small vessels, extravasated red blood cells, and extracellular hyaline globules (Dorfman bodies) with occasional mitotic figures [Figure 1]a and [Figure 1]b. The tumor cells expressed ERG [Figure 1]c, CD31 [Figure 1]d, and human herpesvirus 8 (HHV8) [Figure 1]e. The histophenotypic features were consistent with Kaposi sarcoma (KS). The patient was reluctant to receive any new therapy; however, a few months later, the patient presented with a 1-week history of fatigue, fever, and increased abdominal girth, and physical examination showed pericardiopleural effusions causing shortness of breath. Both pericardio- and pleuro-centesis were diagnostic for large B-cell lymphoma. In addition to the HAART medication for KS, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was instituted to treat the lymphoma. A few months after the initiation of R-CHOP, the patient's condition deteriorated because of Staphylococcus aureus infection, for which he was treated with piperacillin and tazobactam. Because of the multiple comorbidities and continued deterioration in the patient's condition, the patient was referred to the palliative care service 15 days after the diagnosis of S. aureus and later discharged in poor condition to inpatient hospice, where he died of his multiple comorbidities.
|Figure 1: Kaposi sarcoma in a 42-year-old male with AIDS, cytomegalovirus infection, and hepatitis C virus infection (case #1). (a and b) Representative tumor sections. There was a nodular proliferation of basaloid spindled cells admixed with hemorrhage in the dermis (a, ×40). The tumor was composed of fascicles of spindle cells with slit-like spaces, small vessels, and extravasated red blood cells (b, ×400). (c and e) An immunohistochemical study showed that the tumor cells diffusely and strongly expressed endothelial markers; ERG (c, ×400) and CD31 (d, ×400) as well as human herpesvirus 8 (e, ×400; nuclear staining pattern).|
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A 56-year-old HIV-positive male with a CD4 count > 1000 cell/mm3 presented with multiple asymptomatic erythematous papules and nodules on the right eyebrow and left high [Figure 2]a. The patient was receiving HAART for the HIV infection. Biopsies of lesions from both locations showed atypical spindle cell proliferations with blood-filled, slit-like spaces and sieve-like spaces between the spindle cells. A diagnosis of KS caused by HHV8 was rendered, and doxorubicin was instituted for the treatment of KS. Complete local excision of the skin lesions was performed, and the patient was disease stable for 10 years, after which, he presented with multiple, deep soft-tissue masses as well as a calcaneus fracture of the left ankle that were seen on magnetic resonance imaging. Biopsy of one of the soft masses showed KS involving the bone and fibroconnective tissue [Figure 2]b. Immunohistochemical (IHC) studies revealed that the tumor cells were reactive for CD31, ERG, and HHV8 [Figure 2]c, which further confirmed the diagnosis of KS. The patient underwent multiple surgical procedures and ultimately underwent a palliative below-knee amputation of the left leg, after which he was started on paclitaxel. However, because of poor tolerance and no positive clinical benefit, the treatment was discontinued. Eight months after the diagnosis of KS involving the ankle, the patient presented with new multifocal intramuscular KS lesions on the left thigh, which were treated with surgical excision followed by vinorelbine. However, the disease was complicated by numerous cutaneous, subcutaneous, and intramuscular KS lesions on the distal left thigh with intramedullary tumor extension into the proximal tibia and fibula, which were treated with the addition of gemcitabine to vinorelbine. At the time of this report, the patient is being followed up regularly.
|Figure 2: Kaposi sarcoma in a male with human immunodeficiency virus infection (case #2). (a) Representative clinical photographs of multiple erythematous nodules on the left thigh. (b) Representative section of Kaposi sarcoma involving the bone diagnosed 10 years after the initial diagnosis of Kaposi sarcoma (×200). (c) An immunohistochemical study showed that the tumor cells were diffusely and strongly positive for human herpesvirus 8 (×200).|
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A 62-year-old male who had a past medical history of three kidney transplants secondary to severe glomerulonephritis and who had been receiving immunosuppressive medication (cyclosporin, mycophenolate mofetil, and prednisone) for several years presented with several skin lesions involving the left arm, right hand, and frontal scalp. A biopsy of the frontal scalp lesion showed diffuse dermal involvement by sheets and nodules of atypical basophilic cells with neuroendocrine features and a thin Grenz zone separating the tumor from the epidermis [Figure 3]a and [Figure 3]b. Several apoptotic cells and atypical mitotic figures were noted. IHC studies were performed. The neoplastic cells were positive for cytokeratin 20 in a perinuclear dot-like staining pattern [Figure 3]c, synaptophysin [Figure 3]d, and Merkel cell polyomavirus [Figure 3]e. The histophenotypic features supported the diagnosis of Merkel cell carcinoma. Complete local excision was performed; however, metastasis of Merkel cell carcinoma to the right cervical lymph node and the liver was developed at 9 months of the initial diagnosis. Treatment with cyclophosphamide and vincristine was instituted; however, methicillin-resistant Staphylococcus aureus septicemia developed and led to cardiac arrest and death 18 months after the initial diagnosis of Merkel cell carcinoma.
|Figure 3: Merkel cell carcinoma in a 62-year-old male with a past medical history of three kidney transplants secondary to severe glomerulonephritis who had been receiving immunosuppressive medication for several years (case #3). (a and b) Representative sections of Merkel cell carcinoma. There was a nodular proliferation of basaloid epithelioid cells in the dermis and subcutis (a, ×40). The tumor is composed of atypical cells with scant cytoplasmic rim, round and vesicular nuclei with finely granular and dusty chromatin, multiple nucleoli and apoptotic nuclei, and frequent mitotic figures (b; ×400). (c and e) An immunohistochemical study showed that the neoplastic cells were positive for cytokeratin 20 (peri/paranuclear dot-like staining pattern) (c, ×400), synaptophysin (d, ×400), and Merkel cell polyomavirus (e, ×400).|
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A 73-year-old male who had a history of double lung transplant secondary to severe chronic obstructive pulmonary disease and who was receiving immunosuppressive medication (tacrolimus 1.5 mg) presented with a scaly lesion on the right preauricular cheek 1 year after the bilateral lung transplant. The lesion was treated with Mohs micrographic surgery. Biopsy showed an ulcerated malignant epithelioid neoplasm with marked cytologic atypia and frequent mitotic figures [Figure 4]a and [Figure 4]b. The tumor cells were strongly and diffusely positive for p63 [Figure 4]c and high-molecular-weight cytokeratin 5/6 [Figure 4]d but negative for S100, supporting the diagnosis of a poorly differentiated ulcerated squamous cell carcinoma (SCC). Over the following years, the patient had multiple scaly lesions developed on the bilateral cheeks, scalp, and extremities. The lesions were diagnosed as SCC, moderately to poorly differentiated, invading the reticular dermis and subcutaneous adipose tissues. Some of the lesions were treated with CO2 laser ablation. Currently, the patient is being followed up on a regular basis.
|Figure 4: Squamous cell carcinoma in a 73-year-old male who was receiving immunosuppressive medication after having undergone double lung transplant secondary to severe chronic obstructive pulmonary disease 1 year earlier (case #4). (a and b) Representative sections of squamous cell carcinoma showing an ulcerated malignant epithelioid neoplasm with marked cytologic atypia and frequent mitotic figures in the dermis (a, ×20; b, × 400). (c and d) An immunohistochemical study showed that the tumor cells were strongly and diffusely positive for p63 (c, ×400) and high-molecular-weight cytokeratin 5/6 (d, ×400).|
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A 78-year-old male who had a long-term history of hypogammaglobulinemia, developed idiopathic pulmonary fibrosis for which he needed bilateral lung transplant few years later. He was on posttransplant immunosuppressive therapy (sirolimus and tacrolimus). One year later, he presented to our institution with two skin lesions: one lesion was located on the back of the head for which a local skin excision showed a hypocellular atypical spindle cell neoplasm with scattered mitotic figures [Figure 5]a and [Figure 5]b. The tumor cells expressed SOX10 [Figure 5]c and S100 [Figure 5]d but were negative for Melan-A and HMB45. Histophenotypic findings were consistent with an invasive melanoma, desmoplastic type, with a Breslow thickness of 4.85 mm, Clark level V, with perineural invasion and negative margins. The other skin lesion was located on the right anterior helix of the ear for which a shave biopsy showed a moderately differentiated SCC invading the reticular dermis that required complete local excision. Over the several months after the initial diagnosis of the aforementioned two skin lesions, the patient presented with multiple moderate-to-poorly differentiated SCCs in different skin locations, multiple recurrences, satellitosis, and in-transit metastases of melanoma on the scalp which were treated with multiple surgeries. Two years later after the initial diagnoses of the melanoma and SCC, the patient presented with a new skin lesion on the left lower eyelid, from which a shave biopsy showed malignant epithelioid cells with irregular nuclear borders, prominent nucleoli, and a pagetoid-type distribution throughout all levels of the epidermis [Figure 6]a. Some tumor cells exhibited clear cytoplasm and scalloped nuclei, consistent with sebaceous differentiation [Figure 6]b. IHC studies showed that the pagetoid tumor cells with clear cytoplasm were positive for cytokeratin 7, adipophilin [Figure 6]c, and EMA, supporting a diagnosis of sebaceous carcinoma that required a wide local excision. Subsequently, and after few months of the diagnosis of sebaceous carcinoma, the patient presented with a scalp lesion, which, on biopsy, rendered a diagnosis of poorly differentiated SCC.
|Figure 5: Invasive melanoma in a 78-year-old male who was receiving immunosuppressive medication after having undergone bilateral lung transplants secondary to hypogammaglobulinemia and idiopathic pulmonary fibrosis 10 years earlier. (a and b) Representative sections of melanoma showing a hypocellular atypical spindle cell neoplasm with scattered mitotic figures and background myxoid stroma in the dermis (a, ×20; b, ×400). (c and d) An immunohistochemical study showed that the tumor cells were strongly and diffusely positive for S100 (c, ×400) and SOX10 (d, ×400).|
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|Figure 6: Sebaceous carcinoma in a male with hypogammaglobulinemia who was receiving immunosuppressive medication after having undergone bilateral lung transplants secondary to idiopathic pulmonary fibrosis (case #5). (a) There was a predominantly intraepidermal proliferation of atypical epithelioid cells with clear cell changes (×40). (b) High-power magnification showed atypical cells with clear cytoplasm and scalloped nuclei, consistent with sebaceous differentiation (×200). (c) Adipophilin immunostaining highlights the sebaceous differentiation of the atypical cells (×400).|
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At the time of this report, 3 months after the diagnosis of the most recent SCC, the patient is alive and being followed up every month regularly.
A 56-year-old female with a long-term history of common variable immunodeficiency (CVID)-associated hypogammaglobulinemia presented once with cutaneous lesions at many sites, including the right superior tragus, upper back and mid-back, and mid-abdomen. Biopsies of these lesions revealed malignant basaloid neoplasms with peripheral palisading and artifactual clefting embedded in the background of mucinous stroma [Figure 7]a and [Figure 7]b, consistent with basal cell carcinomas with nodular and infiltrative patterns. The lesions were treated with several Mohs micrographic surgeries. Five years later, the patient presented with a new skin lesion on the left upper back. Wide local skin excision with negative margins showed an atypical melanocytic proliferation involving the dermis and epidermis with an area of intraepidermal atypical melanocytes exhibiting a single-cell pattern of growth and pagetoid upward migration. This atypical proliferation was diagnosed as melanoma in situ. The remainder of the lesion was a compound proliferation of melanocytes comprising small intraepidermal melanocytes within elongated rete ridges and dermal nests and was morphologically consistent with compound dysplastic nevus. The patient was under a strict surveillance program; however, she was lost to follow-up and died of an unknown reason 13 months after her last follow-up, 55 months after the diagnosis of melanoma in situ.
|Figure 7: Basal cell carcinoma in a 56-year-old female with a history of common variable immunodeficiency and hypogammaglobulinemia since childhood (case #6). (a and b) The tumor was infiltrative and composed of islands and strands of basophilic cells with peripheral palisading, artifactual clefting, and background myxoid stroma (×100).|
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| Discussion|| |
In general, immunodeficiency disorders are classified as primary or secondary. Primary immunodeficiency disorders are divided into two main groups namely adaptive immune response disorders and innate immune disorders. Adaptive immune response disorders include severe combined immunodeficiency, combined immunodeficiencies, and primary antibody deficiency syndromes such as CVID and X-linked agammaglobulinemia. Innate immune disorders include disorders linked to defects of immune cells (e.g., phagocytes and natural killer cells) and primary toll-like receptor immunodeficiencies in which cellular proteins that should transmit messages from the toll-like receptors to the nucleus are abnormal, which results in a failure of cytokines to be produced in response to activating stimulus. Secondary immunodeficiency disorders are a group of diseases that suppress the immune system. Some are drug induced, such as transplant-related immune suppression, and others are secondary to viral infection, such as HIV.
Due to the emerging techniques of personalized medicine (i.e., the targeted medical treatment to the individual characteristics of each patient because every tumor may show unique clinical, histologic, and molecular features), survival times are increasing in individuals with immunodeficiency, thereby increasing the prevalence of these diseases in the population. Nonetheless, secondary immunodeficiency disorders are far more common than primary immunodeficiency disorders.
Both primary and secondary immunodeficiency disorders are associated with an increased risk of development of malignant neoplasms. In immunocompetent individuals, the host immune response plays a vital role in fighting and eliminating tumorigenic pathogens through the complex process of immunological surveillance. Burnet  and Möller and Möller  described the concept of immunological surveillance against neoplasia in which cancer cells express certain antigens that the immune system can recognize and eliminate. In contrast, in patients with immunodeficiency, the host immune response is reduced, which creates a suitable microenvironment for cancer cells to escape the process of immune detection and elimination, leading to tumor development and progression.,
The cases in the series reported here occurred in patients with a spectrum of types of immunodeficiency disorders. Two of the patients in our series (case 1 and case 2) had chronic immunosuppression due to HIV infection. Both were diagnosed with KS over the course of infection with HIV. Studies in patients with immunodeficiency have documented an elevated incidence of virus-induced malignancies. People with immunosuppression due to HIV infection are at an increased risk for malignant tumors, most notably virus-related tumors, such as KS, which is due to HHV8, and anogenital carcinoma due to human papillomaviruses, in addition to other noncutaneous cancers.
We also report two patients (case 3 and case 4) who had a history of long-term therapy with immunosuppressive medication that was prescribed after organ transplant. Both were diagnosed with multiple cutaneous cancers after a few years of immunosuppressive therapy. Several other studies have shown a similar spectrum of cancers among solid organ transplant recipients who received immunosuppressive medications to prevent graft rejection., The increased risk of development of skin cancers in solid organ transplant recipients might be attributed to the posttransplant immunosuppressive medications reducing host immune surveillance against neoplasia and/or to the direct oncogenic effect of certain viruses.
Previous studies have shown that solid organ transplant recipients are at an increased risk of development of multiple cutaneous malignancies, with an incidence rate of primary malignant neoplasms of 6%–18%., Furthermore, certain neoplasms, such as SCC, may exhibit more aggressive clinical and histologic features, including more infiltrative tumor growth and earlier dermal invasion, in organ transplant recipients than in general population. Lanzet al. found that SCCs in organ transplant recipients were poorly or moderately differentiated and that 39% exhibited perineural invasion and 45% recurred locally, whereas in the general population of patients with SCC, the rate of perineural invasion was 2.5%–5.0% and the rate of local recurrence was 7%.,
Merkel cell carcinoma, a rare type of skin cancer, has also been reported to arise more frequently in transplant recipients and HIV-infected individuals than in the general population. In Merkel cell carcinoma, the Merkel cell polyomavirus plays an integral role in tumor pathogenesis. Fenget al. described clonal integration of a polyomavirus in 75% of cases of Merkel cell carcinoma. A new association of Merkel cell carcinoma and GATA2 deficiency, which is a form of primary immunodeficiency, has been described recently. GATA2 is an endothelial transcription factor that plays a major role in hematopoiesis and in the downstream effect of KRAS-mediated malignant neoplasms.,
The last two patients in our series (cases 5 and 6) had primary immunodeficiency in the form of CVID and/or hypogammaglobulinemia. In addition, the patient in case 5 had undergone double lung transplant for which he was prescribed immunosuppressive medication. Severe hypogammaglobulinemia in patients with CVID is due to impairment of B-cell maturation at its early stages of differentiation, a hallmark of which is recurrent infections. The risk of lymphoid neoplasia as well as other malignancies is increased in patients with CVID. We found one case report in literature describing multiple cutaneous carcinomas in a patient with CVID; however, the United States Immune Deficiency Network registry reported an increased incidence of skin cancers (15%) in patients with primary immune deficiency diseases.
In summary, in patients with primary or secondary immune deficiency, dysfunction of the immune system poses an independent risk for cancer development. Limiting the duration of treatment of immunosuppressive medications in such patients might be needed to decrease the risk of malignancy. Furthermore, the higher risk of cancers in patients with immunodeficiency necessitates careful surveillance and prompt treatment of cutaneous lesions.
All the patients had consented to the use of their tissues and medical data for research after de-identification, based on MD Anderson Research Consent Data Base. All aspects of our research were performed in accordance with recognized ethical guidelines.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
Financial support and sponsorship
The authors disclosed no funding related to this article.
Conflicts of interest
The authors disclosed no conflicts of interest related to this article.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]