18. Subsequent solid malignancies
+: <20%, ++:20‐50%; +++: >50%, CNI, calcineurin inhibitor
The usual suspects for late‐onset bacterial infections include staphylococcus species, pseudomonas species, and the encapsulated bacteria [16–18]. The risk of pneumococcal infection is greatest among patients with IgG deficiencies and with severe cGVHD [19], thereby re‐enforcing the need for prophylactic antibiotics (e.g., oral penicillin therapy) and pneumococcal vaccinations. Recently, Clostridium difficile (C. diff) colitis has been found to have a significantly increased incidence in HCT recipients [20], which occurred more frequently in early HCT periods. Interestingly, GI GVHD was found to be strongly associated with an increased risk for recurrent C. diff colitis (OR 4.23, P = 0.02).
HCT recipients residing in certain developing countries may be more susceptible to endemic conditions (e.g., tuberculosis, Chagas disease, and schistosomiasis) which may manifest as late effects post‐allogeneic‐HCT. These endemic infections can have a detrimental effect on QOL of HCT recipients who are already prone to organ dysfunction due to organ involvement; for example, ocular GVHD patients living in areas where Chlamydia trachomatis is endemic are at significantly higher risk of blindness compared with the trachoma‐free geographic locations.
Post‐HCT hypoglobulinemias can be related to cGVHD and are found most commonly in the cases of chronic lymphocytic leukemia. Routine use of antibiotics in asymptomatic hypoglobulinemic patients without evidence of recurrent infections is not indicated.
Cutaneous complications
Among the late effects, cutaneous cGVHD (skin and oral mucosal) is the most common organ/system involved by GVHD [21]. It expresses itself in a variety of manifestations from chronic eczematous form [22], to lichen planus‐like lesions [23]. The affected skin can become progressively indurated and fixed to the underlying fascia, resulting in prominent morphea and scleroderma, which can lead to joint contractures [24] and a significant compromise in QOL of HCT patients.
Though skin cGVHD is one of the leading causes of morbidity in HCT recipients, a thorough evaluation for other causes of cutaneous complications pertinent to allogeneic‐HCTs is warranted in symptomatic patients. Invasive mold infections can affect the skin of HCT recipients. Photosensitive rash may represent GVHD or may occur as an adverse effect of certain medications commonly utilized in HCT recipients for treatment or prevention of infections particularly with voriconazole [25]. In some patients, pre‐HCT chemotherapy with busulfan, cyclophosphamide, or hydroxyurea may lead to permanent darkening and/or thickening of the skin, which may masquerade as initial stages of cGVHD. Skin cancers are the most common solid malignancies occurring post‐HCT. Routine surveillance with dermatologic exams at annual intervals is recommended [1,26].
Oral/dental complications
The oral mucosal involvement with GVHD frequently leads to extreme xerostomia, often resulting in pain secondary to aphthous‐like ulcers [27]. Erythema within lichenoid plaques of the buccal mucosa is diagnostic of cGVHD; however, a biopsy is frequently required to exclude the presence of co‐infections or oral cancers. Oral cGVHD along with skin cGVHD can result in difficulty opening the mouth (similar to the manifestations of oral scleroderma), which can lead to many complications, including malnutrition and poor dental health. Complete loss of taste can also happen in oral cGVHD, which may further decrease QoL significantly. Prompt recognition of early oral cGVHD and referral to oral surgery for localized treatments (along with systemic therapy) may help in preventing the above‐mentioned complications.
Late dental complications may arise as a result of TBI, chemotherapy, oral cGVHD, DM, or corticosteroid therapy [28]. Common effects include dental caries, endodontic disease, and periodontal disease. General principles of dental care of cancer patients should be adopted [44]. Detailed management options are given in Chapter 17.
Hepatic complications
Late liver effects following allogeneic‐HCT include cGVHD, viral hepatitis, and drug‐induced hepatitis. Liver biopsies obtained from cGVHD patients have indicated chronic persistent hepatitis, lobular hepatitis, and reduction of small bile ducts with cholestasis, which resembles the pathologic manifestations of primary biliary cirrhosis. Untreated hepatic GVHD may lead to liver failure, which carries a very high mortality. Periodic evaluation with liver function tests (LFTs) may help in early diagnosis. Hepatitis B and C reactivations post‐HCT are rare, but a diagnostic workup must include the viral serology to exclude these conditions.
Some 7–64% of cancer patients utilize some form of complementary and alternative medicine (CAM) therapies, though a literature gap exists concerning this issue in the field of HCT. Many CAM therapies are known to be hepatotoxic and, in some cases, may lead to hepatic failure. Some of the more frequently reported hepatotoxic CAM therapies include the Chinese remedies [29], mistletoe [30], and kava [31]. Efforts should be made to obtain comprehensive CAM history and appropriate advice should be provided to those HCT patients who are using hepatotoxic CAM therapies to potentially avoid the possibly fatal late effect of hepatic failure.
Approximately one‐third of HCT survivors have evidence of iron overload [32] due to chronic transfusions during the pre‐ and peri‐HCT period that may lead to secondary hemochromatosis. It may be reasonable to evaluate serum ferritin levels at 6–12 months post‐HCT; and for patients in whom the evidence of iron overload is found, the general principles of secondary hemochromatosis should be applied for organ‐specific screening for complications (e.g., surveillance with ultrasound for liver cancers). Patients with evidence of significant iron overload can be considered for therapeutic phlebotomy if there is an adequate recovery of erythropoiesis or possibly for iron chelation therapy.
Gastrointestinal complications
Apart from the oral cavity complications (see Oral cavity complications” earlier), gastrointestinal (GI) involvement with cGVHD is not uncommon. Common manifestations include involvement of the esophagus, resulting in progressive dysphagia, painful ulcers, and gradual weight loss and esophageal webs. Since the incidence of secondary cancers is also increased in allogeneic‐HCT patients, endoscopies should be performed in patients with symptoms of dysphagia. Abdominal pain/cramping, nausea/ vomiting, weight loss, diarrhea, and early satiety are also common in GI GVHD [33].
Apart from GI GVHD, late GI effects include GI cancers, medication adverse effects, which include steroid‐induced gastritis/esophagitis, mycophenolate‐induced colitis, and lastly infections particularly due to CMV colitis. Prompt recognition and treatment of these conditions is warranted to avoid complications.
Genital complications
In females, the most frequent late effect manifesting as a genital complaint is vaginal–vulvar GVHD. It typically occurs around the 10th month post‐HCT and presents with vaginal pain, discomfort, and vaginal scarring [34]. As this late effect can be successfully treated with topical cyclosporine/steroids/estrogen therapies in the early stages, vaginal examinations at regular intervals (see Chapters 18 and 23) should be performed for early detection. Other late effects include cervical cancers, vaginal candidiasis, and herpes simplex
